获得性再生障碍性贫血患者Th1偏移及抗IL-12受体β1亚基单克隆抗体（2.4E6）对其影响
|
摘要
再生障碍性贫血(简称再障)是一种异质性疾病,多种病因引起骨髓造血功能衰竭,临床表现为全血细胞减少。再障发病机制复杂,涉及造血干细胞损伤、免疫异常、造血微环境改变等因素。目前认为,在大多数病例中,再障是一种获得性的、免疫介导的疾病,伴有T淋巴细胞异常活化造成的造血干细胞破坏。效应性T细胞活化及作为攻击靶点的骨髓造血干/祖细胞损伤的分子机制至今尚未阐明。临床可观察到大多数患者对免疫抑制治疗有所反应,此为免疫系统在再障发病的病理过程中扮演关键角色的有力证明。
T淋巴细胞是机体免疫系统中的主要效应细胞,通过对抗原的识别、处理、递呈等作用构成多种细胞同细胞因子间的网络联系,维持机体免疫功能的平衡状态。细胞因子调节的中心是CD4~+T淋巴细胞,即辅助性T淋巴细胞(Th)。Th1/Th2亚群及其相互之间的平衡在免疫应答的调节中起着关键的作用。
Th1/Th2分化和转化受多种因素影响,其中局部微环境中细胞因子的调节尤为重要。IL-12是IFN-γ产生的强诱导剂,可促进静息CD4~+T细胞向Th1细胞的分化,IL-23则促进中晚期Th1细胞的进一步分化并作用于记忆T细胞。两者均通过结合于IL-12受体β1亚基(IL-12Rβ1)而诱导Th1细胞的分化以及IFN-γ的产生。已知再障患者血清内源性IL-12显著增高,且体外细胞培养实验中可观察到Tc1的活化及Th1细胞因子的优势。推测抗IL-12受体β1亚基单克隆抗体(anti-IL-12Rβ1mAb)可能通过阻断IL-12信号通路而对再障患者的Th1偏移进行调节。
第一部分TIM-3在再生障碍性贫血患者中的表达
目的:测定再生障碍性贫血患者血清中细胞因子IFN-γ、IL-18、IL-23、IL-17的浓度,三色流式细胞术检测再障患者及正常对照外周血单个核细胞各亚群Th1特征性表面分子TIM-3表达水平,并通过荧光实时定量RT-PCR检测再障患者外周血单个核细胞及骨髓单个核细胞TIM-3及其他相关因子的表达,探讨TIM-3的表达与再障相关性,为进一步阐明再障的发病机制及TIM-3与再障的关系奠定基础。
材料和方法:
1.病例选择:再障患者29例,其中重型再障(SAA)16例,非重型再障(NSAA)13例。正常对照31例。
(1)抽取空腹外周静脉血10ml,肝素抗凝;
(2)抽取清晨空腹外周静脉血5ml,自凝后分离血清;
(3)抽取患者髂后上棘骨髓8～10ml或胸骨骨髓约5ml,抽取正常对照骨髓5ml,肝素抗凝。
2.密度-梯度法分离外周血单个核细胞及骨髓单个核细胞。
3.ELISA检测血清中细胞因子IFN-γ、IL-18、IL-23及IL-17的浓度。
4.流式细胞术分析再障患者及正常对照外周血单个核细胞各亚群TIM-3表达水平及CD4~+CD25~+Foxp3~+调节性T细胞的比例。
5.荧光实时定量RT-PCR检测再障患者外周血单个核细胞及骨髓单个核细胞IFN-γ、TIM-3的mRNA表达,并进行二者表达的相关性分析。检测外周血单个核细胞galectin-9及Foxp3的mRNA表达。
6.统计学处理。
结果:
1.再障患者血清中细胞因子IFN-γ、IL-18、IL-23、IL-17浓度均显著高于正常对照。依次为:IFN-γ:108.96±35.80 vs.42.41±39.36,pg/ml,p＜0.001;IL-18:485.40±227.08 vs.71.59±73.91,pg/ml,p＜0.001;IL-23:606.88±110.16 vs.213.52±143.10,pg/ml,p＜0.001;IL-17:238.05±173.28 vs.32.38±29.19,pg/ml,p＜0.001。SAA组高于NSAA组(差异界值分别为:p=0.023,p=0.028,p=0.002,p=0.032)。
2.正常对照及再障患者不同细胞亚群均可检测到TIM-3表达,正常对照以CD14~+单核细胞、NKT细胞表达较高;而再障患者则以CD4~+T细胞表达较高,其次为CD14~+单核细胞及CD8~+T细胞。再障患者外周血TIM-3~+细胞百分比显著高于正常对照(51.45±10.95 vs.28.11±12.31,%,p＜0.001);TIM-3蛋白的相对表达强度也高于正常对照(68.68±14.76 vs.41.66±15.19,p＜0.001)。
3.再障患者外周血CD4~+CD25~+Foxp3~+调节性T细胞的百分比显著低于正常对照(0.69±0.52 vs.2.24±1.56,%,p=0.002),Foxp3的相对表达强度也低于正常对照(51.71±32.12 vs.100.14±60.24,p=0.006)。
4.与正常对照相比,再障患者外周血单个核细胞中TIM-3及IFN-γ的mRNA表达值分别增高3.17倍及4.71倍(p＜0.001,p＜0.001)。骨髓单个核细胞中TIM-3及IFN-γ的表达值分别增高4.78倍及7.13倍(p=0.001,p＜0.001)。SAA组高于NSAA组。转录水平IFN-γ的增高与TIM-3的增高在外周血单个核细胞(r=0.806;p＜0.001)及骨髓单个核细胞(r=0.811;p=0.001)均呈正相关。
5.与正常对照相比,再障患者外周血单个核细胞中galectin-9 mRNA的表达值增高4倍(p=0.03)。
6.再障患者外周血单个核细胞中Foxp3的表达值显著低于正常对照(p=0.001)。
结论:
1.再障患者血清中细胞因子IFN-γ、IL-18、IL-23、IL-17浓度均显著高于正常。
2.再障患者TIM-3在蛋白水平及转录水平均显著高于正常,并与IFN-γ的表达呈正相关,进一步证实再障为Th1优势免疫应答。
3.再障患者galectin-9在转录水平显著高于正常,提示TIM-3-galectin-9途径的异常可能参与再障发病。
4.再障患者的外周血CD4~+CD25~+Foxp3~+调节性T细胞比例显著降低,且其特征性转录因子Foxp3在蛋白水平及转录水平均显著低于正常,提示再障患者免疫调节能力降低,外周免疫耐受异常。
第二部分抗IL-12受体β1亚基单克隆抗体对再生障碍性贫血患者Th1偏移的调节
目的:以再障患者来源的骨髓单个核细胞在抗CD3 mAb刺激下培养,观察不同浓度抗IL-12Rβ1 mAb的效应,采用ELISA检测细胞培养上清中IFN-γ的水平;采用荧光实时定量RT-PCR分析培养细胞IFN-γ、T-bet及GATA-3的mRNA表达;并用Western Blot检测培养细胞T-bet、GATA-3、STAT4及磷酸化的STAT4(phospho-STAT4,pSTAT4)的蛋白表达,初步判断抗IL-12Rβ1 mAb在体外纠正再障患者骨髓单个核细胞的Th1偏移状态的可能作用。
材料和方法:
1.病例选择:再障患者13例,其中SAA7例,NSAA6例。正常对照10例。无菌抽取患者髂后上棘骨髓8～10ml或胸骨骨髓约5ml,抽取正常对照骨髓5ml,肝素抗凝。
2.骨髓单个核细胞的培养
(1)初次细胞培养:分离来自10例再障患者及5例正常对照的骨髓单个核细胞,不同刺激条件下(未加任何初始刺激组/anti-CD3 mAb 5μg/ml组)培养72h。收集培养上清。
(2)不同因素对骨髓单个核细胞的影响:分离来自13例再障患者的骨髓单个核细胞,每例标本均随机分为anti-CD3 mAb(5μg/ml)组、anti-CD3mAb(5μg/ml)+anti-IL-12Rβ1 mAb(0.05μg/ml)组、anti-CD3 mAb(5μg/ml)+anti-IL-12Rβ1 mAb(0.5μg/ml)组及anti-CD3 mAb(5μg/ml)+anti-IL-12Rβ1 mAb(5μg/ml)组。另分离来自10例正常对照的BMMCs,仅给予anti-CD3 mAb(5μg/ml)作为刺激因素。收集细胞及培养上清。
3.ELISA检测细胞培养上清中IFN-γ浓度。
4.荧光实时定量RT-PCR检测体外培养的再障患者骨髓单个核细胞IFN-γ、T-bet及GATA-3的mRNA表达。
5.Western Blot检测体外培养的再障患者骨髓单个核细胞T-bet、GATA-3、STAT4及pSTAT4的蛋白表达。
6.统计学处理。
结果:
1.在没有任何刺激的条件下,多数正常对照骨髓单个核细胞产生IFN-γ量极低(18.64±11.95,pg/ml),而在anti-CD3 mAb刺激后产生IFN-γ显著增加(173.08±67.85,pg/ml,p＜0.001)。再障患者骨髓单个核细胞体外培养不需任何刺激即可产生IFN-γ(127.42±60.16,pg/ml),加入anti-CD3 mAb刺激后IFN-γ分泌显著增加(300.34±99.33,pg/ml,p=0.001)。
2.再障患者骨髓单个核细胞培养体系中加入不同浓度anti-IL-12Rβ1 mAb后,细胞培养上清中IFN-γ显著降低(差异界值均为P＜0.001),但仍高于正常对照(差异界值分别为p＜0.001,p=0.014,p=0.034)。
3.再障患者骨髓单个核细胞培养体系中加入不同浓度anti-IL-12Rβ1 mAb后,IFN-γ及T-bet在转录水平均有所下调(差异界值分别为IFN-γ:p=0.046,p=0.002,P＜0.001;T-bet:p=0.005,p＜0.001,P＜0.001)。GATA-3在转录水平无显著变化,但T-bet/GATA-3比值降低(差异界值均为p＜0.001)。
4.再障患者骨髓单个核细胞培养体系中加入anti-IL-12Rβ1 mAb后,T-bet蛋白表达显著降低(差异界值均为p＜0.001),GATA-3蛋白表达改变不显著,而T-bet/GATA-3比值降低(差异界值均为p＜0.001)。pSTAT4蛋白表达降低(差异界值分别为p=0.048,p＜0.001,p＜0.001),而STAT4蛋白表达变化不显著,pSTAT4/STAT4比值降低(差异界值分别为p=0.046,p＜0.001,p＜0.001)。
结论:
1.再障患者骨髓单个核细胞处于异常激活状态,不需初始刺激即可分泌IFN-γ。
2.Anti-IL-12Rβ1 mAb在转录水平及蛋白水平均可降低体外培养的再障患者骨髓单个核细胞IFN-γ的产生,此作用呈浓度依赖性。
3.Anti-IL-12Rβ1 mAb在转录水平及蛋白水平均可降低体外培养的再障患者骨髓单个核细胞Th1转录因子T-bet表达,但对GATA-3的表达影响不显著,并可显著降低T-bet/GATA-3比值,部分纠正Th1偏移,此作用呈浓度依赖性。
4.Anti-IL-12Rβ1 mAb对体外培养的再障患者骨髓单个核细胞转录因子STAT4的表达影响不显著,但可显著抑制STAT4磷酸化,降低pSTAT4/STAT4比值。此作用具有浓度依赖性。
The pathophysiology of acquired aplastic anemia(AA)can be characterized by a marked reduction in both the quality and quantity of hematopoietic stem cells resulting in pancytopenia.Pathophysiologically,acquired AA seems to be immune-mediated,causing an organ-specific destruction of bone marrow hematopoietic stem cells and progenitor cells through abnormal T cell activation in most patients.The most convicing evidence for the dominant role of the immune system in pathophysiology of AA was lately supported by the efficacy of immunesuppressive treatment in the majority of patients.Nevertheless,understanding of the initiating and perpetuating mechanisms in AA is still incomplete.The imbalance of Th1/Th2 plays an important role in the onset and developmentof AA.
Previous studies have also demonstrated endogenous stimulation in AA T cells and supported the Th1/Tc1 autoimmune basis of this complex disease.Aberrant type 1 immune responses have been linked to the pathogenesis of aplastic anemia,and cytokine drives a highly pathogenic T cell population involved in its initiation. Numerous studies have established IL-12 as an important factor for the differentiation ofnaive T cells into IFN-γ-producing Th1 cells,IL-23,a cytokine that shares the p40 subunit with IL-12,has since prompted reevaluation of the role of IL-12/Th1 response in autoimmunity.These cytokines play a pivotal role in the establishment and maintenance of autoimmune diseases and would be new therapeutic targets.
PARTⅠEXPRESSION OF TIM-3 AND ITS LIGAND IN APLASTIC ANEMIA PATIENTS
Objective:To investigate the Th1 shift in the cytokines and Th1 specific surface molecule in AA patients and to explore the immune mechanism of TIM-3 in aplastic anemia development.
Material and methods:
1.Bone marrow and peripheral blood samples were collected from 29 AA patients and 31 patients with non-hematopoietic diseases.
2.Bone marrow mononuclear cells and peripheral blood mononuclear cells were prepared by ficoll gradient centrifugation technique.
3.Concentration of IFN-γ,IL-18,IL-23 and IL-17 in sera from AA patients and controls were determined by ELISA.
4.The peripheral blood was incubated with different combination of cell surface antibodies.The analysis of the TIM-3 expression in CD3~+CD4~+(CD4~+ T cells), CD3~+CD8~+(CD8~+ T cells),CD14~+(monocytes),CD19~+(B cells), CD3~-CD16~+CD56~+(NK cells),and CD3~+CD16~+CD56~+(T cells with NK markers) cells were accomplished with flow cytometry.Intracellular staining was performed for analysis of CD4~+CD25~+Foxp3~+ regulatory T cells.The datas were analyzed using the CellQuest software.
5.Real-time quantitative RT-PCR was used for relative quantitation of mRNA in bone marrow mononuclear cells and peripheral blood mononuclear cells. Expression of TIM-3,IFN-γ,galectin-9 and Foxp3 transcripts were normalized respectively toβ-actin mRNA.
6.The results were expressed in mean±standard deviation(mean±s).Student's t-test and Spearman's rank test were performed.P value＜0.05 is considerated as significant.
Result:
1.The serum concentration of IFN-γ,IL-18,IL-23 and IL-17 all increased in AA patients compared with controls(IFN-γ:108.96±35.80 vs.42.41±39.36,pg/ml, p=0.002;IL-18:485.40±227.08 vs.71.59±73.91,pg/ml,p＜0.001;IL-23: 606.88±110.16 vs.213.52±143.10,pg/ml,p＜0.001;IL-17:238.05±173.28 vs. 32.38±29.19,pg/ml,p＜0.001,respectively).They are both higher in SAA than in NSAA(p=0.001,p=0.028,p=0.002,p=0.032,respectively).
2.The major cellular source of TIM-3 in peripheral blood in the controls was CD14~+ monocytes and NKT cells.There was remarkable elevation in TIM-3 protein as well as the frequency of TIM-3~+ cells in peripheral blood mononuclear cells from AA patients compared with controls(68.68±14.76 vs 41.66±15.19,p＜0.001; 51.45±10.95 vs 28.11±12.31,%,p＜0.001,respectively).In AA patients,the majority expressing TIM-3 protein was CD4~+ T cells,CD14~+ monocytes and CD8~+ T cells.
3.The frequency of CD4~+CD25~+Foxp3~+T cells in AA patients was much decreased compared with that from the controls(0.69±0.52 vs 2.24±0.16,%,p=0.002).The intracellular Foxp3 protein was also significantly reduced in AA patients (51.71±32.12 vs 100.14±60.24,p=0.006).
4.Compared with controls,the expression of TIM-3 and IFN-γmRNA was increased in peripheral blood mononuclear cells from AA patients by 3.17-fold and 4.71-fold respectively(both p＜0.001),and by 4.78-fold and 7.13-fold respectively in bone marrow mononuclear cells of AA patients(p=0.001,p＜0.001, respectively).Significant correlation was determined between the mRNA expression of TIM-3 and IFN-γin both peripheral blood mononuclear cells (r=0.806;p＜0.001)and bone marrow mononuclear cells(r=0.811;p=0.001)from AA patients.
5.The expression of galectin-9 transcript increased by 4.0-fold in peripheral blood mononuclear cells from AA patients than controls(p=0.03).
6.The expression of Foxp3 transcript significantly decreased in peripheral blood mononuclear cells from AA patients than controls(p=0.001).
Conclusion:
1.Overproduction of IFN-γ,IL-18,IL-23 and IL-17 was observed in sera from AA patients.
2.Realtime RT-PCR results revealed significantly higher mRNA expression of TIM-3 in peripheral blood mononuclear cells and bone marrow mononuclear cells from AA patients compared with controls,which well correlated with IFN-γmRNA.
3.Decreased number of regulatory T cell and low expression of Foxp3 were observed in AA patients.
4.High expression of galectin-9,the ligand of TIM-3,may be implicated in autoimmune marrow failure.
PARTⅡANTI-IL-12Rβ1 mAb REGULATES T-bet AND pSTAT4 EXPRESSION IN BMMCs FROM APLASTIC ANEMIA PATIENTS IN VITRO
Objective:To investigate the effect of anti-IL-12Rβ1 mAb on Th1 shift in bone marrow mononuclear cells from AA patients in vitro.
Material and methods:
1.Bone morrow samples were collected from 13 AA patients and 10 patients with non-hematopoietic diseases.
2.Bone marrow mononuclear cells were prepared by Ficoll gradient centrifugation technique.
(1)Freshly isolated bone marrow mononuclear cells from 10 AA patients and 5 controls were incubated for 72 hours in culture media with anti-CD3 mAb (5μg/ml)or without any stimulation.Supernatant was collected.
(2)Freshly isolated bone marrow mononuclear cells from 13 AA patients were cultured by stimulation with anti-CD3 mAb(5μg/ml)in the presence or absence of anti-IL-12Rβ1 mAb for 72 hours.Freshly isolated bone marrow mononuclear cells from 10 controls were cultured by stimulation with anti-CD3 mAb(5μg/ml) for 72 hours.Cell pellets and supernatant were collected.
3.The level of IFN-γin culture supernatant was determined by ELISA.
4.Real-time quantitative RT-PCR was used for relative quantitation of mRNA in bone marrow mononuclear cells.Expression of GATA-3,IFN-γand T-bet transcripts were normalized respectively toβ-actin mRNA.
5.Western blotting was used for determination of protein in bone marrow mononuclear cells.Expression of GATA-3,pSTAT4,STAT4 and T-bet was normalized respectively toβ-actin protein.
6.The results were expressed in mean±standard deviation(mean±s).One-way analysis of variance(ANOVA)or Kruskal-Wallis test were performed.P value＜0.05 is considerated as significant.
Result:
1.Bone marrow mononuclear cells from controls without any stimulation produced lower level of IFN-γin supernatants(18.64±11.95,pg/ml).IFN-γproduction was elevated by 9.29-fold by stimulation with anti-CD3 mAb(p＜0.001).Bone marrow mononuclear cells from AA patients without any stimulation produced increased levels of IFN-γcompared with controls(127.42±60.16,pg/ml,p＜0.001).IFN-γproduction was elevated by 2.36-fold by stimulation with anti-CD3 mAb (p=0.001).
2.Anti-IL-12Rβ1 mAb significantly decreased production of IFN-γin culture supernatant in a dose-dependent manner(all p＜0.001).
3.Anti-IL-12Rβ1 mAb significantly decreased expression of IFN-γand T-bet at transcript level in anti-CD3 mAb-stimulated bone marrow mononuclear cells from AA patients in a dose-dependent manner(p=0.046,p=0.002,p＜0.001 for IFN-γ; p=0.002,p＜0.001,p＜0.001 for T-bet,respectively).
4.Anti-IL-12Rβ1 mAb significantly decreased expression of T-bet and pSTAT4 at protein level in anti-CD3 mAb-stimulated bone marrow mononuclear cells from AA patients in a dose-dependent manner(all p＜0.001 for T-bet;p=0.048,p＜0.001, p＜0.001 for pSTAT4,respectively).
Conclusion:
1.There is aberrant activation of Th1 cell in AA resulting in overproduction of IFN-γwithout any prior stimulation.
2.Anti-IL-12Rβ1 mAb may significantly decrease expression of IFN-γat both transcript and protein levels in a dose-dependent manner in anti-CD3 mAb-stimulated bone marrow mononuclear cells from AA patients in vitro.
3.Anti-IL-12Rβ1 mAb may significantly decrease expression of T-bet at both transcript and protein levels in a dose-dependent manner in anti-CD3 mAb-stimulated bone marrow mononuclear cells from AA patients in vitro.
4.Anti-IL-12Rβ1 mAb may significantly decrease pSTAT4 at protein level in a dose-dependent manner in anti-CD3 mAb-stimulated bone marrow mononuclear cells from AA patients in vitro.
T淋巴细胞是机体免疫系统中的主要效应细胞,通过对抗原的识别、处理、递呈等作用构成多种细胞同细胞因子间的网络联系,维持机体免疫功能的平衡状态。细胞因子调节的中心是CD4~+T淋巴细胞,即辅助性T淋巴细胞(Th)。Th1/Th2亚群及其相互之间的平衡在免疫应答的调节中起着关键的作用。
Th1/Th2分化和转化受多种因素影响,其中局部微环境中细胞因子的调节尤为重要。IL-12是IFN-γ产生的强诱导剂,可促进静息CD4~+T细胞向Th1细胞的分化,IL-23则促进中晚期Th1细胞的进一步分化并作用于记忆T细胞。两者均通过结合于IL-12受体β1亚基(IL-12Rβ1)而诱导Th1细胞的分化以及IFN-γ的产生。已知再障患者血清内源性IL-12显著增高,且体外细胞培养实验中可观察到Tc1的活化及Th1细胞因子的优势。推测抗IL-12受体β1亚基单克隆抗体(anti-IL-12Rβ1mAb)可能通过阻断IL-12信号通路而对再障患者的Th1偏移进行调节。
第一部分TIM-3在再生障碍性贫血患者中的表达
目的:测定再生障碍性贫血患者血清中细胞因子IFN-γ、IL-18、IL-23、IL-17的浓度,三色流式细胞术检测再障患者及正常对照外周血单个核细胞各亚群Th1特征性表面分子TIM-3表达水平,并通过荧光实时定量RT-PCR检测再障患者外周血单个核细胞及骨髓单个核细胞TIM-3及其他相关因子的表达,探讨TIM-3的表达与再障相关性,为进一步阐明再障的发病机制及TIM-3与再障的关系奠定基础。
材料和方法:
1.病例选择:再障患者29例,其中重型再障(SAA)16例,非重型再障(NSAA)13例。正常对照31例。
(1)抽取空腹外周静脉血10ml,肝素抗凝;
(2)抽取清晨空腹外周静脉血5ml,自凝后分离血清;
(3)抽取患者髂后上棘骨髓8～10ml或胸骨骨髓约5ml,抽取正常对照骨髓5ml,肝素抗凝。
2.密度-梯度法分离外周血单个核细胞及骨髓单个核细胞。
3.ELISA检测血清中细胞因子IFN-γ、IL-18、IL-23及IL-17的浓度。
4.流式细胞术分析再障患者及正常对照外周血单个核细胞各亚群TIM-3表达水平及CD4~+CD25~+Foxp3~+调节性T细胞的比例。
5.荧光实时定量RT-PCR检测再障患者外周血单个核细胞及骨髓单个核细胞IFN-γ、TIM-3的mRNA表达,并进行二者表达的相关性分析。检测外周血单个核细胞galectin-9及Foxp3的mRNA表达。
6.统计学处理。
结果:
1.再障患者血清中细胞因子IFN-γ、IL-18、IL-23、IL-17浓度均显著高于正常对照。依次为:IFN-γ:108.96±35.80 vs.42.41±39.36,pg/ml,p＜0.001;IL-18:485.40±227.08 vs.71.59±73.91,pg/ml,p＜0.001;IL-23:606.88±110.16 vs.213.52±143.10,pg/ml,p＜0.001;IL-17:238.05±173.28 vs.32.38±29.19,pg/ml,p＜0.001。SAA组高于NSAA组(差异界值分别为:p=0.023,p=0.028,p=0.002,p=0.032)。
2.正常对照及再障患者不同细胞亚群均可检测到TIM-3表达,正常对照以CD14~+单核细胞、NKT细胞表达较高;而再障患者则以CD4~+T细胞表达较高,其次为CD14~+单核细胞及CD8~+T细胞。再障患者外周血TIM-3~+细胞百分比显著高于正常对照(51.45±10.95 vs.28.11±12.31,%,p＜0.001);TIM-3蛋白的相对表达强度也高于正常对照(68.68±14.76 vs.41.66±15.19,p＜0.001)。
3.再障患者外周血CD4~+CD25~+Foxp3~+调节性T细胞的百分比显著低于正常对照(0.69±0.52 vs.2.24±1.56,%,p=0.002),Foxp3的相对表达强度也低于正常对照(51.71±32.12 vs.100.14±60.24,p=0.006)。
4.与正常对照相比,再障患者外周血单个核细胞中TIM-3及IFN-γ的mRNA表达值分别增高3.17倍及4.71倍(p＜0.001,p＜0.001)。骨髓单个核细胞中TIM-3及IFN-γ的表达值分别增高4.78倍及7.13倍(p=0.001,p＜0.001)。SAA组高于NSAA组。转录水平IFN-γ的增高与TIM-3的增高在外周血单个核细胞(r=0.806;p＜0.001)及骨髓单个核细胞(r=0.811;p=0.001)均呈正相关。
5.与正常对照相比,再障患者外周血单个核细胞中galectin-9 mRNA的表达值增高4倍(p=0.03)。
6.再障患者外周血单个核细胞中Foxp3的表达值显著低于正常对照(p=0.001)。
结论:
1.再障患者血清中细胞因子IFN-γ、IL-18、IL-23、IL-17浓度均显著高于正常。
2.再障患者TIM-3在蛋白水平及转录水平均显著高于正常,并与IFN-γ的表达呈正相关,进一步证实再障为Th1优势免疫应答。
3.再障患者galectin-9在转录水平显著高于正常,提示TIM-3-galectin-9途径的异常可能参与再障发病。
4.再障患者的外周血CD4~+CD25~+Foxp3~+调节性T细胞比例显著降低,且其特征性转录因子Foxp3在蛋白水平及转录水平均显著低于正常,提示再障患者免疫调节能力降低,外周免疫耐受异常。
第二部分抗IL-12受体β1亚基单克隆抗体对再生障碍性贫血患者Th1偏移的调节
目的:以再障患者来源的骨髓单个核细胞在抗CD3 mAb刺激下培养,观察不同浓度抗IL-12Rβ1 mAb的效应,采用ELISA检测细胞培养上清中IFN-γ的水平;采用荧光实时定量RT-PCR分析培养细胞IFN-γ、T-bet及GATA-3的mRNA表达;并用Western Blot检测培养细胞T-bet、GATA-3、STAT4及磷酸化的STAT4(phospho-STAT4,pSTAT4)的蛋白表达,初步判断抗IL-12Rβ1 mAb在体外纠正再障患者骨髓单个核细胞的Th1偏移状态的可能作用。
材料和方法:
1.病例选择:再障患者13例,其中SAA7例,NSAA6例。正常对照10例。无菌抽取患者髂后上棘骨髓8～10ml或胸骨骨髓约5ml,抽取正常对照骨髓5ml,肝素抗凝。
2.骨髓单个核细胞的培养
(1)初次细胞培养:分离来自10例再障患者及5例正常对照的骨髓单个核细胞,不同刺激条件下(未加任何初始刺激组/anti-CD3 mAb 5μg/ml组)培养72h。收集培养上清。
(2)不同因素对骨髓单个核细胞的影响:分离来自13例再障患者的骨髓单个核细胞,每例标本均随机分为anti-CD3 mAb(5μg/ml)组、anti-CD3mAb(5μg/ml)+anti-IL-12Rβ1 mAb(0.05μg/ml)组、anti-CD3 mAb(5μg/ml)+anti-IL-12Rβ1 mAb(0.5μg/ml)组及anti-CD3 mAb(5μg/ml)+anti-IL-12Rβ1 mAb(5μg/ml)组。另分离来自10例正常对照的BMMCs,仅给予anti-CD3 mAb(5μg/ml)作为刺激因素。收集细胞及培养上清。
3.ELISA检测细胞培养上清中IFN-γ浓度。
4.荧光实时定量RT-PCR检测体外培养的再障患者骨髓单个核细胞IFN-γ、T-bet及GATA-3的mRNA表达。
5.Western Blot检测体外培养的再障患者骨髓单个核细胞T-bet、GATA-3、STAT4及pSTAT4的蛋白表达。
6.统计学处理。
结果:
1.在没有任何刺激的条件下,多数正常对照骨髓单个核细胞产生IFN-γ量极低(18.64±11.95,pg/ml),而在anti-CD3 mAb刺激后产生IFN-γ显著增加(173.08±67.85,pg/ml,p＜0.001)。再障患者骨髓单个核细胞体外培养不需任何刺激即可产生IFN-γ(127.42±60.16,pg/ml),加入anti-CD3 mAb刺激后IFN-γ分泌显著增加(300.34±99.33,pg/ml,p=0.001)。
2.再障患者骨髓单个核细胞培养体系中加入不同浓度anti-IL-12Rβ1 mAb后,细胞培养上清中IFN-γ显著降低(差异界值均为P＜0.001),但仍高于正常对照(差异界值分别为p＜0.001,p=0.014,p=0.034)。
3.再障患者骨髓单个核细胞培养体系中加入不同浓度anti-IL-12Rβ1 mAb后,IFN-γ及T-bet在转录水平均有所下调(差异界值分别为IFN-γ:p=0.046,p=0.002,P＜0.001;T-bet:p=0.005,p＜0.001,P＜0.001)。GATA-3在转录水平无显著变化,但T-bet/GATA-3比值降低(差异界值均为p＜0.001)。
4.再障患者骨髓单个核细胞培养体系中加入anti-IL-12Rβ1 mAb后,T-bet蛋白表达显著降低(差异界值均为p＜0.001),GATA-3蛋白表达改变不显著,而T-bet/GATA-3比值降低(差异界值均为p＜0.001)。pSTAT4蛋白表达降低(差异界值分别为p=0.048,p＜0.001,p＜0.001),而STAT4蛋白表达变化不显著,pSTAT4/STAT4比值降低(差异界值分别为p=0.046,p＜0.001,p＜0.001)。
结论:
1.再障患者骨髓单个核细胞处于异常激活状态,不需初始刺激即可分泌IFN-γ。
2.Anti-IL-12Rβ1 mAb在转录水平及蛋白水平均可降低体外培养的再障患者骨髓单个核细胞IFN-γ的产生,此作用呈浓度依赖性。
3.Anti-IL-12Rβ1 mAb在转录水平及蛋白水平均可降低体外培养的再障患者骨髓单个核细胞Th1转录因子T-bet表达,但对GATA-3的表达影响不显著,并可显著降低T-bet/GATA-3比值,部分纠正Th1偏移,此作用呈浓度依赖性。
4.Anti-IL-12Rβ1 mAb对体外培养的再障患者骨髓单个核细胞转录因子STAT4的表达影响不显著,但可显著抑制STAT4磷酸化,降低pSTAT4/STAT4比值。此作用具有浓度依赖性。
The pathophysiology of acquired aplastic anemia(AA)can be characterized by a marked reduction in both the quality and quantity of hematopoietic stem cells resulting in pancytopenia.Pathophysiologically,acquired AA seems to be immune-mediated,causing an organ-specific destruction of bone marrow hematopoietic stem cells and progenitor cells through abnormal T cell activation in most patients.The most convicing evidence for the dominant role of the immune system in pathophysiology of AA was lately supported by the efficacy of immunesuppressive treatment in the majority of patients.Nevertheless,understanding of the initiating and perpetuating mechanisms in AA is still incomplete.The imbalance of Th1/Th2 plays an important role in the onset and developmentof AA.
Previous studies have also demonstrated endogenous stimulation in AA T cells and supported the Th1/Tc1 autoimmune basis of this complex disease.Aberrant type 1 immune responses have been linked to the pathogenesis of aplastic anemia,and cytokine drives a highly pathogenic T cell population involved in its initiation. Numerous studies have established IL-12 as an important factor for the differentiation ofnaive T cells into IFN-γ-producing Th1 cells,IL-23,a cytokine that shares the p40 subunit with IL-12,has since prompted reevaluation of the role of IL-12/Th1 response in autoimmunity.These cytokines play a pivotal role in the establishment and maintenance of autoimmune diseases and would be new therapeutic targets.
PARTⅠEXPRESSION OF TIM-3 AND ITS LIGAND IN APLASTIC ANEMIA PATIENTS
Objective:To investigate the Th1 shift in the cytokines and Th1 specific surface molecule in AA patients and to explore the immune mechanism of TIM-3 in aplastic anemia development.
Material and methods:
1.Bone marrow and peripheral blood samples were collected from 29 AA patients and 31 patients with non-hematopoietic diseases.
2.Bone marrow mononuclear cells and peripheral blood mononuclear cells were prepared by ficoll gradient centrifugation technique.
3.Concentration of IFN-γ,IL-18,IL-23 and IL-17 in sera from AA patients and controls were determined by ELISA.
4.The peripheral blood was incubated with different combination of cell surface antibodies.The analysis of the TIM-3 expression in CD3~+CD4~+(CD4~+ T cells), CD3~+CD8~+(CD8~+ T cells),CD14~+(monocytes),CD19~+(B cells), CD3~-CD16~+CD56~+(NK cells),and CD3~+CD16~+CD56~+(T cells with NK markers) cells were accomplished with flow cytometry.Intracellular staining was performed for analysis of CD4~+CD25~+Foxp3~+ regulatory T cells.The datas were analyzed using the CellQuest software.
5.Real-time quantitative RT-PCR was used for relative quantitation of mRNA in bone marrow mononuclear cells and peripheral blood mononuclear cells. Expression of TIM-3,IFN-γ,galectin-9 and Foxp3 transcripts were normalized respectively toβ-actin mRNA.
6.The results were expressed in mean±standard deviation(mean±s).Student's t-test and Spearman's rank test were performed.P value＜0.05 is considerated as significant.
Result:
1.The serum concentration of IFN-γ,IL-18,IL-23 and IL-17 all increased in AA patients compared with controls(IFN-γ:108.96±35.80 vs.42.41±39.36,pg/ml, p=0.002;IL-18:485.40±227.08 vs.71.59±73.91,pg/ml,p＜0.001;IL-23: 606.88±110.16 vs.213.52±143.10,pg/ml,p＜0.001;IL-17:238.05±173.28 vs. 32.38±29.19,pg/ml,p＜0.001,respectively).They are both higher in SAA than in NSAA(p=0.001,p=0.028,p=0.002,p=0.032,respectively).
2.The major cellular source of TIM-3 in peripheral blood in the controls was CD14~+ monocytes and NKT cells.There was remarkable elevation in TIM-3 protein as well as the frequency of TIM-3~+ cells in peripheral blood mononuclear cells from AA patients compared with controls(68.68±14.76 vs 41.66±15.19,p＜0.001; 51.45±10.95 vs 28.11±12.31,%,p＜0.001,respectively).In AA patients,the majority expressing TIM-3 protein was CD4~+ T cells,CD14~+ monocytes and CD8~+ T cells.
3.The frequency of CD4~+CD25~+Foxp3~+T cells in AA patients was much decreased compared with that from the controls(0.69±0.52 vs 2.24±0.16,%,p=0.002).The intracellular Foxp3 protein was also significantly reduced in AA patients (51.71±32.12 vs 100.14±60.24,p=0.006).
4.Compared with controls,the expression of TIM-3 and IFN-γmRNA was increased in peripheral blood mononuclear cells from AA patients by 3.17-fold and 4.71-fold respectively(both p＜0.001),and by 4.78-fold and 7.13-fold respectively in bone marrow mononuclear cells of AA patients(p=0.001,p＜0.001, respectively).Significant correlation was determined between the mRNA expression of TIM-3 and IFN-γin both peripheral blood mononuclear cells (r=0.806;p＜0.001)and bone marrow mononuclear cells(r=0.811;p=0.001)from AA patients.
5.The expression of galectin-9 transcript increased by 4.0-fold in peripheral blood mononuclear cells from AA patients than controls(p=0.03).
6.The expression of Foxp3 transcript significantly decreased in peripheral blood mononuclear cells from AA patients than controls(p=0.001).
Conclusion:
1.Overproduction of IFN-γ,IL-18,IL-23 and IL-17 was observed in sera from AA patients.
2.Realtime RT-PCR results revealed significantly higher mRNA expression of TIM-3 in peripheral blood mononuclear cells and bone marrow mononuclear cells from AA patients compared with controls,which well correlated with IFN-γmRNA.
3.Decreased number of regulatory T cell and low expression of Foxp3 were observed in AA patients.
4.High expression of galectin-9,the ligand of TIM-3,may be implicated in autoimmune marrow failure.
PARTⅡANTI-IL-12Rβ1 mAb REGULATES T-bet AND pSTAT4 EXPRESSION IN BMMCs FROM APLASTIC ANEMIA PATIENTS IN VITRO
Objective:To investigate the effect of anti-IL-12Rβ1 mAb on Th1 shift in bone marrow mononuclear cells from AA patients in vitro.
Material and methods:
1.Bone morrow samples were collected from 13 AA patients and 10 patients with non-hematopoietic diseases.
2.Bone marrow mononuclear cells were prepared by Ficoll gradient centrifugation technique.
(1)Freshly isolated bone marrow mononuclear cells from 10 AA patients and 5 controls were incubated for 72 hours in culture media with anti-CD3 mAb (5μg/ml)or without any stimulation.Supernatant was collected.
(2)Freshly isolated bone marrow mononuclear cells from 13 AA patients were cultured by stimulation with anti-CD3 mAb(5μg/ml)in the presence or absence of anti-IL-12Rβ1 mAb for 72 hours.Freshly isolated bone marrow mononuclear cells from 10 controls were cultured by stimulation with anti-CD3 mAb(5μg/ml) for 72 hours.Cell pellets and supernatant were collected.
3.The level of IFN-γin culture supernatant was determined by ELISA.
4.Real-time quantitative RT-PCR was used for relative quantitation of mRNA in bone marrow mononuclear cells.Expression of GATA-3,IFN-γand T-bet transcripts were normalized respectively toβ-actin mRNA.
5.Western blotting was used for determination of protein in bone marrow mononuclear cells.Expression of GATA-3,pSTAT4,STAT4 and T-bet was normalized respectively toβ-actin protein.
6.The results were expressed in mean±standard deviation(mean±s).One-way analysis of variance(ANOVA)or Kruskal-Wallis test were performed.P value＜0.05 is considerated as significant.
Result:
1.Bone marrow mononuclear cells from controls without any stimulation produced lower level of IFN-γin supernatants(18.64±11.95,pg/ml).IFN-γproduction was elevated by 9.29-fold by stimulation with anti-CD3 mAb(p＜0.001).Bone marrow mononuclear cells from AA patients without any stimulation produced increased levels of IFN-γcompared with controls(127.42±60.16,pg/ml,p＜0.001).IFN-γproduction was elevated by 2.36-fold by stimulation with anti-CD3 mAb (p=0.001).
2.Anti-IL-12Rβ1 mAb significantly decreased production of IFN-γin culture supernatant in a dose-dependent manner(all p＜0.001).
3.Anti-IL-12Rβ1 mAb significantly decreased expression of IFN-γand T-bet at transcript level in anti-CD3 mAb-stimulated bone marrow mononuclear cells from AA patients in a dose-dependent manner(p=0.046,p=0.002,p＜0.001 for IFN-γ; p=0.002,p＜0.001,p＜0.001 for T-bet,respectively).
4.Anti-IL-12Rβ1 mAb significantly decreased expression of T-bet and pSTAT4 at protein level in anti-CD3 mAb-stimulated bone marrow mononuclear cells from AA patients in a dose-dependent manner(all p＜0.001 for T-bet;p=0.048,p＜0.001, p＜0.001 for pSTAT4,respectively).
Conclusion:
1.There is aberrant activation of Th1 cell in AA resulting in overproduction of IFN-γwithout any prior stimulation.
2.Anti-IL-12Rβ1 mAb may significantly decrease expression of IFN-γat both transcript and protein levels in a dose-dependent manner in anti-CD3 mAb-stimulated bone marrow mononuclear cells from AA patients in vitro.
3.Anti-IL-12Rβ1 mAb may significantly decrease expression of T-bet at both transcript and protein levels in a dose-dependent manner in anti-CD3 mAb-stimulated bone marrow mononuclear cells from AA patients in vitro.
4.Anti-IL-12Rβ1 mAb may significantly decrease pSTAT4 at protein level in a dose-dependent manner in anti-CD3 mAb-stimulated bone marrow mononuclear cells from AA patients in vitro.
引文
1.Young NS.Acquired aplastic anemia.Ann Intern Med.2002;136(7):534-46.
2.Nakao S,Feng X,Sugimori C.Immune pathophysiology of aplastic anemia.Int J Hematol.2005;82(3):196-200
3.Risitano AM,Maciejewski JP,Green S,Plasilova M,Zeng W,Young NS.In-vivo dominant immune responses in aplastic anaemia:molecular tracking of putatively pathogenetic T-cell clones by TCR beta-CDR3 sequencing.Lancet.2004;364(9431):355-64.
4.Young NS.Immunosuppressive treatment of acquired aplastic anemia and immune-mediated bone marrow failure syndromes.Int J Hematol.2002;75(2):129-40.
5.Marsh J,Schrezenmeier H,Marin P,Ilhan O,Ljungman P,McCann S,Socie G,Tichelli A,Passweg J,Hows J,Raghavachar A,Locasciulli A,Bacigalupo A.Prospective randomized multicenter study comparing cyclosporin alone versus the combination of antithymocyte globulin and cyclosporin for treatment of patients with nonsevere aplastic anemia:a report from the European Blood and Marrow Transplant(EBMT)Severe Aplastic Anaemia Working Party.Blood.1999;93(7):2191-5.
6.龚非力主编.医学免疫学.第1版.北京:科学出版社,2000,304-5
7.Young NS,Abkowitz JL,Luzzatto L.New Insights into the Pathophysiology of Acquired Cytopenias.Hematology Am Soc Hematol Educ Program.2000:18-38
8.申蓉,徐从高,李丽珍,张锑,秦雪梅,李杰,赵川莉.再生障碍性贫血患者T淋巴细胞早期激活及可溶性肿瘤坏死因子受体的研究冲华血液学杂志,2004,25(4):209-12
9.Kanchan K,Loughran TP Jr.Antigen-driven clonal T cell expansion in disorders of hematopoiesis.Leuk Res.2003;27(4):305-12.
10.Lanzavecchia A,Sallusto F.Regulation of T cell immunity by dendritic cells.Cell.2001;106(3):263-6.
11.Garza KM,Chan SM,Suri R,Nguyen LT,Odermatt B,Schoenberger SP,Ohashi PS.Role of antigen-presenting cells in mediating tolerance and autoimmunity.J Exp Med.2000;191(11):2021-7.
12.何广胜,邵宗鸿,和虹,刘鸿,付蓉,白洁,施均,曹燕然,涂梅峰,孙娟,贾海荣.重型再 生障碍性贫血患者骨髓Ⅰ型树突细胞亚群的变化.中华血液学杂志,2004,25(11):649-52.
13.Zeng W,Kajigaya S,Chen G,Risitano AM,Nunez O,Young NS.Transcript profile of CD4+ and CD8+ T cells from the bone marrow of acquired aplastic anemia patients.Exp Hematol.2004;32(9):806-14.
14.Hara T,Ando K,Tsurumi H,Moriwaki H.Excessive production of tumor necrosis factor-alpha by bone marrow T lymphocytes is essential in causing bone marrow failure in patients with aplastic anemia.Eur J Haematol.2004;73(1):10-6.
15.Giannakoulas NC,Karakantza M,Theodorou GL,Pagoni M,Galanopoulos A,Kakagianni T,Kouraklis-Symeonidis A,Matsouka P,Maniatis A,Zoumbos NC.Clinical relevance of balance between type 1 and type 2 immune responses of lymphocyte subpopulations in aplastic anaemia patients.Br J Haematol.2004;124(1):97-105.
16.和虹,邵宗鸿,何广胜,刘鸿,施均,付蓉,赵明峰,白洁,贾海蓉,孙娟,崔振珠,储榆林,杨天楹,杨崇礼.Th1细胞在再生障碍性贫血发病机制中的作用.中华血液学杂志,2002,23(11):574-7.
17.Monney L,Sabatos CA,Gaglia JL,Ryu A,Waldner H,Chernova T,Manning S,Greenfield EA,Coyle AJ,Sobel RA,Freeman GJ,Kuchroo VK.Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease.Nature.2002;415(6871):536-41.
18.Sachez-Fueyo A,Tian J,Picarella D,Domenig C,Zheng XX,Sabatos CA,Manlongat N,Bender O,Kamradt T,Kuchroo VK,Gutierrez-Ramos JC,Coyle AJ,Strom TB.Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance.Nat Immunol.2003;4(11):1093-101.
19.Anderson AC,Anderson DE,Bregoli L,Hastings WD,Kassam N,Lei C,Chandwaskar R,Karman J,Su EW,Hirashima M,Brace JN,Kane LP,Kuchroo VK,Hafler DA.Promotion of tissue infiammation by the immune receptor Tim-3 expressed on innate immune cells.Science.2007;318(5853):1141-3.
20.Zhu C,Anderson AC,Schubart A,Xiong H,Imitola J,Khoury SJ,Zheng XX,Strom TB,Kuchroo VK.The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity.Nat Immunol.2005;6(12):1245-52.
21.Gately MK,Renzetti LM,Magram J,Stem AS,Adorini L,Gubler U,Presky DH.The interleukin-12/interleukin-12-receptor system:role in normal and pathologic immune responses.Annu Rev Immunol.1998;16:495-521.
22.张宁,徐永健,张珍祥.辅助性T细胞功能分化的分子机制.国外医学呼吸系统分册,2003,23(2):57-61
23.任翠爱,张茂宏,徐从高,张锑.再生障碍性贫血患者血浆IL-12水平的检测及临床意义.上海免疫学杂志,2000,20(4):252
24.孙晗笑,杨滨燕,李波,娄阁,吴长有.内源性IL-12决定人PBMCs产生干扰素γ的水平.中国免疫学杂志,2002,18(4):228-32
25.范艳莹,吴长有.Th2细胞因子和抗IL-12Rβ1mAb抑制由IL-23诱导PBMC IFN-γ的产生.中国免疫学杂志.2006,22(3):195-9
1.Monney L,Sabatos CA,Gaglia JL,Ryu A,Waldner H,Chemova T,Manning S,Greenfield EA,Coyle AJ,Sobel RA,Freeman GJ,Kuchroo VK.Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease.Nature.2002;415(6871):536-41.
2.Khademi M,Illes Z,Gielen AW,Marta M,Takazawa N,Baecher-Allan C,Brundin L,Hannerz J,Martin C,Harris RA,Hafler DA,Kuchroo VK,Olsson T,Piehl F,Wallstrom E.T Cell Ig- and mucin-domain-containing molecule-3(TIM-3)and TIM-1 molecules are differentially expressed on human Th1 and Th2 cells and in cerebrospinal fluid-derived mononuclear cells in multiple sclerosis.J Immunol.2004;172(11):7169-76.
3.Gielen AW,Lobell A,Lidman O,Khademi M,Olsson T,Piehl F.Expression of T cell immunoglobulin-and mucin-domain-containing molecules-1 and -3(TIM-1and -3)in the rat nervous and immune systems.J Neuroimmunol.2005;164(1-2):93-104.
4.Sanchez-Fueyo A,Tian J,Picarella D,Domenig C,Zheng XX,Sabatos CA,Manlongat N,Bender O,Kamradt T,Kuchroo VK,Gutierrez-Ramos JC,Coyle AJ,Strom TB.Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance.Nat Immunol.2003;4(11):1093-101.
5.Renesto PG,Ponciano VC,Cenedeze MA,Saraiva Camara NO,Pacheco-Silva A.High expression of Tim-3 mRNA in urinary cells from kidney transplant recipients with acute rejection.Am J Transplant.2007;7(6):1661-5.
6.黄金波,崔天盆,王琳,陈凤花,时杰,胡丽华.再生障碍性贫血患者Tim-3、IFN-γ及IL-4 mRNA的表达及其临床意义.中华血液学杂志,2006,27(12):813-6
7.张之南,沈悌,主编.血液病诊断及疗效标准.第2版.北京:科学出版社,1998.33-35.
8.Mosmann TR,Cherwinski H,Bond MW,Giedlin MA,Coffman RL.Two types of murine helper T cell clone.I.Definition according to profiles of lymphokine activities and secreted proteins.J Immunol.1986;136(7):2348-57.
9.Romagnani S.Human TH1 and TH2 subsets:doubt no more.Immunol Today.1991;12(8):256-7
10.Kamradt T,Mitchison NA.Tolerance and autoimmunity.N Engl J Med.2001;344(9):655-64.
11.Lanzavecchia A,Sallusto F.Regulation of T cell immunity by dendritic cells.Cell.2001;106(3):263-6.
12.Garza KM,Chan SM,Suri R,Nguyen LT,Odermatt B,Schoenberger SP,Ohashi PS Role of antigen-presenting cells in mediating tolerance and autoimmunity.J Exp Med.2000;191(11):2021-7.
13.何广胜,邵宗鸿,和虹,刘鸿,付蓉,白洁,施均,曹燕然,涂梅峰,孙娟,贾海荣.重型再生障碍性贫血患者骨髓I型树突细胞亚群的变化.中华血液学杂志.2004,25(11):649-52
14.傅晋翔.张勇.树突状细胞在再生障碍性贫血发病中的变化.中华微生物学和免疫学杂志.2007,27(5):473
15.唐晓文,邵景章,张学光,张毅,李建,郑列琳,谢炜,王爱青.再生障碍性贫血患者外周血T细胞亚群检测.中华血液学杂志,1997,18(4):205-6
16.王欣,张明珙,宋素琴,李杰,郭承山,宋强,赵川莉,王惠军,彭军,秦平.再生障碍性贫血患者细胞免疫功能与造血细胞因子的研究.中华血液学杂志,1998,19(4).181-3
17.Mentzel U,Vogt H,Rossol R,Geissler RG,Maurer A,Ganser A,Trommer WE,Hoelzer D.Analysis of lymphocyte subsets in patients with aplastic anemia before and during immunosuppressive therapy.Ann Hematol.1993;66(3):127-9.
18.Nistico A,Young NS.Gamma-Interferon gene expression in the bone marrow of patients with aplastic anemia.Ann Intern Med.1994;120(6):463-9.
19.Tsuda H,Yamasaki H.Type Ⅰ and type Ⅱ T-cell profiles in aplastic anemia and refractory anemia.Am J Hematol.2000;64(4):271-4.
20.Kook H,Zeng W,Guibin C,Kirby M,Young NS,Maciejewski JP.Increased cytotoxie T cells with effector phenotype in aplastic anemia and myelodysplasia.Exp Hematol.2001;29(11):1270-7.
21.Giannakoulas NC,Karakantza M,Theodorou GL,Pagoni M,Galanopoulos A,Kakagianni T,Kouraklis-Symeonidis A,Matsouka P,Maniatis A,Zoumbos NC.Clinical relevance of balance between type 1 and type 2 immune responses of lymphocyte subpopulations in aplastic anaemia patients.Br J Haematol.2004;124(1):97-105.
22.涂梅峰,邵宗鸿.淋巴细胞功能亢进与造血组织损伤,中华血液学杂志,2004,25(4):243-6
23.Zeng W,Kajigaya S,Chen G,Risitano AM,Nunez O,Young NS.Transcript profile of CD4+ and CD8+ T cells from the bone marrow of acquired aplastic anemia patients.Exp Hematol 2004;32:806-14
24.Sloand E,Kim S,Maciejewski JP,Tisdale J,Follmann D,Young NS.Intracellular interferon-gamma in circulating and marrow T cells detected by flow cytometry and the response to immunosuppressive therapy in patients with aplastic anemia.Blood.2002;100(4):1185-91.
25.Laver J,Castro-Malaspina H,Keman NA,Levick J,Evans RL,O'Reilly RJ,Moore MA.In vitro interferon-gamma production by cultured T-cells in severe aplastic anaemia:correlation with granulomonopoietic inhibition in patients who respond to anti-thymocyte globulin.Br J Haematol.1988;69(4):545-50.
26.Maciejewski JP,Hibbs JR,Anderson S,Katevas P,Young NS.Bone marrow and peripheral blood lymphocyte phenotype in patients with bone marrow failure.Exp Hematol.1994;22(11):1102-10.
27.Young NS.Pathophysiologic mechanisms in acquired aplastic anemia.Hematology Am Soc Hematol Educ Program.2006;72-7.
28.何广胜,邵宗鸿,和虹,刘鸿,白洁,施均,曹燕然,涂梅峰,孙娟,贾海蓉,杨崇礼.重型 再生障碍性贫血患者骨髓中辅助性T细胞亚群数量及功能的变化.中华血液学杂志,2004,25(10):613-6
29.Killick SB,Cox CV,Marsh JC,Gordon-Smith EC,Gibson FM.Mechanisms of bone marrow progenitor cell apoptosis in aplastic anaemia and the effect of anti-thymocyte globulin:examination of the role of the Fas-Fas-L interaction.Br J Haematol.2000;111(4):1164-9.
30.Maciejewski JP,Risitano A.Hematopoietic stem cells in aplastic anemia.Arch Med Res.2003;34(6):520-7.
31.张勇,傅晋翔.T淋巴细胞异常活化与再生障碍性贫血.江苏医药,2006,32(1):64-5
32.和虹,邵宗鸿,何广胜,刘鸿,施均,付蓉,赵明峰,白洁,贾海蓉,孙娟,崔振珠,储榆林,杨天楹,杨崇礼.Th1细胞在再生障碍性贫血发病机制中的作用.中华血液学杂志,2002,23:574-7.
33.Liblau RS,Singer SM,McDevitt HO.Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases.Immunol Today.1995;16(1):34-8.
34.Young NS.Hematopoietic cell destruction by immune mechanisms in acquired aplastic anemia.Semin Hematol.2000;37(1):3-14.
35.Ghayur T,Banerjee S,Hugunin M,Butler D,Herzog L,Carter A,Quintal L,Sekut L,Talanian R,Paskind M,Wong W,Kamen R,Tracey D,Allen H.Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production.Nature.1997;386(6625):619-23.
36.Gu Y,Kuida K,Tsutsui H,Ku G,Hsiao K,Fleming MA,Hayashi N,Higashino K,Okamura H,Nakanishi K,Kurimoto M,Tanimoto T,Flavell RA,Sato V,Harding MW,Livingston DJ,Su MS.Activation of interferon-gamma inducing factor mediated by interleukin-lbeta converting enzyme.Science.1997;275(5297):206-9.
37.Gracie JA,Robertson SE,Mclnnes IB.Interleukin-18.J Leukoc Biol.2003;73(2): 213-24.
38.Thomassen E,Bird TA,Renshaw BR,Kennedy MK,Sims JE.Binding of interleukin-18 to the interleukin-1 receptor homologous receptor IL-1Rrp1 leads to activation of signaling pathways similar to those used by interleukin-1.J Interferon Cytokine Res.1998;18(12):1077-88.
39.Furuya D,Yagihashi A,Yajima T,Kobayashi D,Orita K,Kurimoto M,Watanabe N.An immuno-polymerase chain reaction assay for human interleukin-18.J Immunol Methods.2000;238(1-2):173-80.
40.Kohno K,Kataoka J,Ohtsuki T,Suemoto Y,Okamoto I,Usui M,Ikeda M,Kurimoto M.IFN-gamma-inducing factor(IGIF)is a costimulatory factor on the activation of Th1 but not Th2 cells and exerts its effect independently of IL-12.J Immunol.1997;158(4):1541-50.
41.Yoshimoto T,Okamura H,Tagawa YI,Iwakura Y,Nakanishi K.Interleukin 18together with interleukin 12 inhibits IgE production by induction of interferon-gamma production from activated B cells.Proc Natl Acad Sci U S A.1997;94(8):3948-53.
42.Tomura M,Zhou XY,Maruo S,Ahn HJ,Hamaoka T,Okamura H,Nakanishi K,Tanimoto T,Kurimoto M,Fujiwara H.A critical role for IL-18 in the proliferation and activation of NK1.1+CD3-cells.J Immunol.1998;160(10):4738-46.
43.Tsutsui H,Nakanishi K,Matsui K,Higashino K,Okamura H,Miyazawa Y,Kaneda K.IFN-gamma-inducing factor up-regulates Fas ligand-mediated cytotoxic activity of murine natural killer cell clones.J Immunol.1996;157(9):3967-73.
44.Dao T,Ohashi K,Kayano T,Kurimoto M,Okamura H.Interferon-gamma-inducing factor,a novel cytokine,enhances Fas ligand-mediated cytotoxicity of murine T helper 1 cells.Cell Immunol.1996;173(2):230-5.
45.Ohtsuki T,MicaUef MJ,Kohno K,Tanimoto T,Ikeda M,Kurimoto M.Interleuldn 18 enhances Fas ligand expression and induces apoptosis in Fas-expressing human myelomonocytic KG-1 cells.Anticancer Res.1997;17(5A):3253-8.
46.Kayagaki N,Yamaguchi N,Nakayama M,Kawasaki A,Akiba H,Okumura K,Yagita H.Involvement of TNF-related apoptosis-inducing ligand in human CD4+T cell-mediated cytotoxicity.J Immunol.1999;162(5):2639-47.
47.Hyodo Y,Matsui K,Hayashi N,Tsutsui H,Kashiwamura S,Yamauchi H,Hiroishi K,Takeda K,Tagawa Y,Iwakura Y,Kayagaki N,Kurimoto M,Okamura H,Hada T,Yagita H,Akira S,Nakanishi K,Higashino K.IL-18 up-regulates perforin-mediated NK activity without increasing perforin messenger RNA expression by binding to constitutively expressed IL-18 receptor.J Immunol.1999;162(3):1662-8.
48.Kohka H,Yoshino T,Iwagaki H,Sakuma I,Tanimoto T,Matsuo Y,Kurimoto M,Orita K,Akagi T,Tanaka N.Interleukin-18/interferon-gamma-inducing factor,a novel cytokine,up-regulates ICAM-1(CD54)expression in KG-1 cells.J Leukoc Biol.1998;64(4):519-27.
49.高立芬.IL-18与免疫相关性疾病.国外医学免疫学分册.2001,24(3):165-8
50.Oppmann B,Lesley R,Blom B,Timans JC,Xu Y,Hunte B,Vega F,Yu N,Wang J,Singh K,Zonin F,Vaisberg E,Churakova T,Liu M,Gorman D,Wagner J,Zurawski S,Liu Y,Abrams JS,Moore KW,Rennick D,de Waal-Malefyt R,Hannum C,Bazan JF,Kastelein RA.Novel p19 protein engages IL-12p40 to form a cytokine,IL-23,with biological activities similar as well as distinct from IL-12.Immunity.2000;13(5):715-25.
51.Morelli AE,Zahorchak AF,Larregina AT,Colvin BL,Logar AJ,Takayama T,Falo LD,Thomson AW.Cytokine production by mouse myeloid dendritic cells in relation to differentiation and terminal maturation induced by lipopolysaccharide or CD40 ligation.Blood.2001;98(5):1512-23.
52.Frucht DM.IL-23:a cytokine that acts on memory T cells.Sci STKE.2002;2002(114):PE1.
53. Brombacher F, Kastelein RA, Alber G. Novel IL-12 family members shed light on the orchestration of Th1 responses. Trends Immunol. 2003;24(4):207-12.
54. Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B, Kleinschek MA, Owyang A, Mattson J, Blumenschein W, Murphy E, Sathe M, Cua DJ, Kastelein RA, Rennick D.IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006; 116(5): 1310-6.
55. Lankford CS, Frucht DM. A unique role for IL-23 in promoting cellular immunity.J Leukoc Biol. 2003; 73(1): 49-56.
56. Vaknin-Dembinsky A, Balashov K, Weiner HL.IL-23 is increased in dendritic cells in multiple sclerosis and down-regulation of IL-23 by antisense oligos increases dendritic cell IL-10 production. J Immunol. 2006;176(12):7768-74.
57. Belladonna ML, Renauld JC, Bianchi R, Vacca C, Fallarino F, Orabona C, Fioretti MC, Grohmann U, Puccetti P.IL-23 and IL-12 have overlapping, but distinct, effects on murine dendritic cells. J Immunol. 2002; 168(11 ):5448-54.
58. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD.Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421(6924):744-8.
59. Sugihara A, Okamoto H, Horio T. Effects of UVB on fascin expression in dendritic cells and Langerhans cells.J Dermatol Sci. 2005;40(3): 177-85.
60. Chen Z, Laurence A, Kanno Y, Pacher-Zavisin M, Zhu BM, Tato C, Yoshimura A, Hennighausen L, O'Shea JJ.Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc Natl Acad Sci U S A. 2006; 103(21): 8137-42.
61. Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, O'Shea JJ.Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol Rev. 2004; 202:139-56.
62. Kolls JK, Linden A.Interleukin-17 family members and inflammation. Immunity. 2004;21(4):467-76.
63. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ.IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201(2):233-40.
64. Gosset P, Tillie-Leblond I, Oudin S, Parmentier O, Wallaert B, Joseph M, Tonnel AB.Production of chemokines and proinflammatory and antiinflammatory cytokines by human alveolar macrophages activated by IgE receptors. J Allergy Clin Immunol. 1999; 103(2 Pt 1):289-97.
65. Stark MA, Huo Y, Burcin TL, Morris MA, Olson TS, Ley K.Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity. 2005; 22(3):285-94.
66. Yao Z, Spriggs MK, Derry JM, Strockbine L, Park LS, VandenBos T, Zappone JD, Painter SL, Armitage RJ. Molecular characterization of the human interleukin (IL)-17 receptor. Cytokine. 1997;9(11):794-800.
67. Molet S, Hamid Q, Davoine F, Nutku E, Taha R, Page N, Olivenstein R, Elias J, Chakir J.IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J Allergy Clin Immunol. 2001 ;108(3):430-8.
68. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C.A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6(11):1133-41.
69. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK.Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441(7090):235-8.
70. Moseley TA, Haudenschild DR, Rose L, Reddi AH. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev. 2003;14(2):155-74.
71. Nielsen OH, Kirman I, Rudiger N, Hendel J, Vainer B. Upregulation of interleukin-12 and -17 in active inflammatory bowel disease. Scand J Gastroenterol;2003;38(2):180-5
72.Komiyama Y,Nakae S,Matsuki T,Nambu A,Ishigame H,Kakuta S,Sudo K,Iwakura Y.IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis.J Immunol.2006;177(1):566-73.
73.Koenders MI,Lubberts E,van de Loo FA,Oppers-Walgreen B,van den Bersselaar L,Helsen MM,Kolls JK,Di Padova FE,Joosten LA,van den Berg WB.Interleukin-17 acts independently of TNF-alpha under arthritic conditions.2006;176(10):6262-9.
74.张鲁勤,葛晋源,郭玉琳,赵惠仁.再生障碍性贫血患者血浆细胞因子的测定.中华血液学杂志,2001,22(12):661-2
75.张岩,汪奇伟,何书.T细胞亚群及细胞因子网络与小儿再生障碍性贫血的相关性.中国综合临床,2006,22(2):138-9
76.Bonecchi R,Bianchi G,Bordignon PP,D'Ambrosio D,Lang R,Borsatti A,Sozzani S,Allavena P,Gray PA,Mantovani A,Sinigaglia F Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells(Thls)and Th2s.J Exp Med.1998;187(1):129-34..
77.Mclntire JJ,Umetsu SE,Akbari O,Potter M,Kuchroo VK,Barsh GS,Freeman GJ,Umetsu DT,DeKruyff RH.Identification of Tapr(an airway hyperreactivity regulatory locus)and the linked Tim gene family.Nat Immunol.2001;2(12):1109-16.
78.Kuchroo VK,Umetsu DT,DeKruyff RH,Freeman GJ.The TIM gene family:emerging roles in immunity and disease.Nat Rev Immunol.2003;3(6):454-62.
79.Mariat C,Sanchez-Fueyo A,Alexopoulos SP,Kenny J,Strom TB,Zheng XX.Regulation of T cell dependent immune responses by TIM family members.Philos Trans R Soc Lond B Biol Sci.2005;360(1461):1681-5.
80.Sui L,Zhang W,Chen Y,Zheng Y,Wan T,Zhang W,Yang Y,Fang G,Mao J,Cao X.Human membrane protein Tim-3 facilitates hepatitis A virus entry into target cells.Int J Mol Med.2006;17(6):1093-9.
81.Oaks MK,Hallett KM,Penwell RT,Stauber EC,Warren SJ,Tector AJ.A native soluble form of CTLA-4.Cell Immunol.2000;201(2):144-53.
82.Sabatos CA,Chakravarti S,Cha E,Schubart A,Sanchez-Fueyo A,Zheng XX,Coyle AJ,Strom TB,Freeman GJ,Kuchroo VK.Interaction of Tim-3 and Tim-3ligand regulates T helper type 1 responses and induction of peripheral tolerance.Nat Immunol.2003;4(11):1102-10.
83.Geng H,Zhang GM,Li D,Zhang H,Yuan Y,Zhu HG,Xiao H,Han LF,Feng ZH.Soluble form of T cell Ig mucin 3 is an inhibitory molecule in T cell-mediated immune response.J Immunol.2006;176(3):1411-20.
84.张胜桃,刘晓军,金霞,何培根,龚非力,杨东亮.TIM-3 mRNA在外周血单个核细胞不同细胞亚群及活化的T细胞上的表达.中华微生物学和免疫学杂志2006,26(5):442-5
85.Oikawa T,Kamimura Y,Akiba H,Yagita H,Okumura K,Takahashi H,Zeniya M,Tajiri H,Azuma M.Preferential involvement of Tim-3 in the regulation of hepatic CD8+ T cells in murine acute graft-versus-host disease.J lmmunol.2006;177(7):4281-7.
86.Wang F,He W,Zhou H,Yuan J,Wu K,Xu L,Chen ZK.The Tim-3 ligand galectin-9 negatively regulates CD8+ alloreactive T cell and prolongs survival of skin graft.Cell Immunol.2007;250(1-2):68-74.
87.Wang F,He W,Yuan J,Wu K,Zhou H,Zhang W,Chen ZK.Activation of Tim-3-Galectin-9 pathway improves survival of fully allogeneic skin grafts.Transpl Immunol.2008;19(1):12-9.
88.Chae SC,Park YR,Shim SC,Yoon KS,Chung HT.The polymorphisms of Th1cell surface gene Tim-3 are associated in a Korean population with rheumatoid arthritis.Immunol Lett.2004;95(1):91-5.
89.李际盛,刘奇迹,王频,李怀臣,魏春华,郭辰虹,龚瑶琴.中国山东汉族人群TIM-3基因启动子区域两单核苷酸多态与支气管哮喘的相关性。山东大学学报(医学版),2006,44(11):1159-63
90.张才成,吴健民,崔天盆,王平,潘世秀.湖北汉族人群TIM-3基因多态性与变应性哮喘的相关性.中华医学遗传学杂志.2006,23(1):74-7
91.张胜桃,刘晓军,何培根,雷小妹,李守新,胡绍先,龚非力,杨东亮.类风湿关节炎患者外周血CD4+T细胞TIM-3 mRNA的表达.中华风湿病学杂志.2006,10(1):30-2
92.Koguchi K,Anderson DE,Yang L,O'Connor KC,Kuchroo VK,Hafler DA.Dysregulated T cell expression of TIM3 in multiple sclerosis.J Exp Med.2006;203(6):1413-8.
93.Ponciano VC,Renesto PG,Nogueira E,Rangel EB,Cenedeze MA,Franco MF,Camara NO,Pacheco-Silva A.Tim-3 expression in human kidney allografts.Transpl Immunol.2007;17(3):215-22.
94.Zhu C,Anderson AC,Schubart A,Xiong H,Imitola J,Khoury SJ,Zheng XX,Strom TB,Kuchroo VK.The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity.Nat Immunol.2005;6(12):1245-52.
95.Asakura H,Kashio Y,Nakamura K,Seki M,Dai S,Shirato Y,Abedin MJ,Yoshida N,Nishi N,Imaizumi T,Saita N,Toyama Y,Takashima H,Nakamura T,Ohkawa M,Hirashima M.Selective eosinophil adhesion to fibroblast via IFN-gamma-induced galectin-9.J Immunol.2002;169(10):5912-8.
96.Dai SY,Nakagawa R,Itoh A,Murakami H,Kashio Y,Abe H,Katoh S,Kontani K,Kihara M,Zhang SL,Hata T,Nakamura T,Yamauchi A,Hirashima M.Galectin-9induces maturation of human monocyte-derived dendritic cells.J Immunol.2005;175(5):2974-81.
97.Anderson AC,Anderson DE,Bregoli L,Hastings WD,Kassam N,Lei C,Chandwaskar R,Karman J,Su EW,Hirashima M,Bruce JN,Kane LP,Kuchroo VK,Hafler DA.Promotion of tissue inflammation by the immune receptor Tim-3expressed on innate immune cells.Science.2007;318(5853):1141-3.
98.Hirashima M,Kashio Y,Nishi N,Yamauchi A,Imaizumi TA,Kageshita T,Saita N,Nakamura T.Galectin-9 in physiological and pathological conditions. Glycoconj J. 2004;19(7-9):593-600.
99. Kashio Y, Nakamura K, Abedin MJ, Seki M, Nishi N, Yoshida N, Nakamura T, Hirashima M. Galectin-9 induces apoptosis through the calcium-calpain-caspase-1 pathway. J Immunol. 2003;170(7):3631-6.
100.Wang Y, Meng J, Wang X, Liu S, Shu Q, Gao L, Ju Y, Zhang L, Sun W, Ma C.Expression of human TIM-1 and TIM-3 on lymphocytes from systemic lupus erythematosus patients. Scand J Immunol. 2008;67(1):63-70.
101.Dabbagh K, Lewis DB.Toll-like receptors and T-helper-1/T-helper-2 responses. Curr Opin Infect Dis.2003; 16(3): 199-204
102.Zeng W, Maciejewski JP, Chen G, Risitano AM, Kirby M, Kajigaya S, Young NS.Selective reduction of natural killer T cells in the bone marrow of aplastic anaemia. Br J Haematol.2002; 119(3): 803-9.
103.Selleri C, Sato T, Anderson S, Young NS, Maciejewski JP. Interferon-γ and tumor necrosis factor-alpha suppress both early and late stages of hematopoiesis and induce programmed cell death. J Cell Physiol.1995; 165(3): 538-46.
104.Philpott NJ, Scopes J, Marsh JC, Gordon-Smith EC, Gibson FM. Increased apoptosis in aplastic anemia bone marrow progenitor cells: possible pathophysiologic significance. Exp Hematol.1995; 23(14): 1642-8.
105.Maciejewski JP, Selleri C, Sato T, Anderson S, Young NS. Increased expression of Fas antigen on bone marrow CD34+ cells of patients with aplastic anaemia. Br J Haematol 1995; 91(1): 245-52.
106.Anderson AC, Anderson DE. TIM-3 in autoimmunity.Curr Opin Immunol. 2006; 18(6):665-9.
107.Frisancho-Kiss S, Nyland JF, Davis SE, Barrett MA, Gatewood SJ, Njoku DB, Cihakova D, Silbergeld EK, Rose NR, Fairweather D.Cutting edge: T cell Ig mucin-3 reduces inflammatory heart disease by increasing CTLA-4 during innate immunity. J Immunol. 2006; 176(11):6411-5.
108.Frisancho-Kiss S, Davis SE, Nyland JF, Frisancho JA, Cihakova D, Barrett MA, Rose NR,Fairweather D.Cutting edge:cross-regulation by TLR4 and T cell Ig mucin-3 determines sex differences in inflammatory heart disease.J Immunol.2007;178(11):6710-4.
109.隋潇徽,徐从高,李丽珍,张锑,于媛,彭军.CTLA-4Ig抑制再生障碍性贫血患者T淋巴细胞增殖及活化作用的体外研究.山东大学学报(医学版),2006,44(5):485-8
110.Roncarolo MG,Levings MK.The role of different subsets of T regulatory cells in controlling autoimmunity.Curr Opin Immunol.2000;12(6):676-83.
111.Shevach EM,McHugh RS,Piccirillo CA,Thornton AM.Control of T-cell activation by CD4+ CD25+ suppressor T cells.Immunol Rev.2001;182:58-67.
112.Sakaguchi S,Sakaguchi N,Asano M,Itoh M,Toda M.Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains(CD25).Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.J Immunol.1995;155(3):1151-64.
113.Hori S,Nomura T,Sakaguchi S.Control of regulatory T cell development by the transcription factor Foxp3.Science.2003;299(5609):1057-61.
114.Carrier Y,Yuan J,Kuchroo VK,Weiner HL.Th3 cells in peripheral tolerance.I.Induction of Foxp3-positive regulatory T cells by Th3 cells derived from TGF-beta T cell-transgenic mice.J Immunol.2007;178(1):179-85.
115.Shevach EM.Certified professionals:CD4(+)CD25(+)suppressor T cells.J Exp Med.2001;193(11):F41-6.
116.Paust S,Lu L,McCarty N,Cantor H.Engagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease.Proc Natl Acad Sci U S A.2004;101(28):10398-403.
117.Yagi H,Nomura T,Nakamura K,Yamazaki S,Kitawaki T,Hori S,Maeda M,Onodera M,Uchiyama T,Fujii S,Sakaguchi S.Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells.Int Immunol.2004;16(11):1643-56.
118.Khattri R,Kasprowicz D,Cox T,Mortrud M,Appleby MW,Brunkow ME,Ziegler SF,Ramsdell F.The amount of scurfin protein determines peripheral T cell number and responsiveness.J Immunol.2001;167(11):6312-20.
119.Kasprowicz DJ,Smallwood PS,Tyznik AJ,Ziegler SF.Scurfin(FoxP3)controls T-dependent immune responses in vivo through regulation of CD4+ T cell effector function.J Immunol.2003;171(3):1216-23.
120.Khattri R,Cox T,Yasayko SA,Ramsdell F.An essential role for Scurfin in CD4+CD25+ T regulatory cells.Nat Immunol.2003;4(4):337-42.
121.Fontenot JD,Gavin MA,Rudensky AY.Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.Nat Immunol.2003;4(4):330-6.
122.杨军,李成荣,祖莹,王国兵,李永柏.调节性T细胞在儿童过敏性紫癜发病机制中的作用初探.中华儿科杂志,2006,44(6):411-4
123.Mottonen M,Heikkinen J,Mustonen L,Isomaki P,Luukkainen R,Lassila O.CD4+ CD25+ T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis.Clin Exp Immunol.2005;140(2):360-7.
124.祖莹,李成荣,郑跃杰,邓继岿,付晓玲.CD4+CD25+调节性T细胞在儿童哮喘发病机制中的作用初探.中华医学杂志.2006,86(1):35-8
125.Lindley S,Dayan CM,Bishop A,Roep BO,Peakman M,Tree TI.Defective suppressor function in CD4(+)CD25(+)T-cells from patients with type 1diabetes.Diabetes.2005;54(1):92-9.
126.Viglietta V,Baecher-Allan C,Weiner HL,Hafler DA.Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis.J Exp Med.2004;199(7):971-9.
127.Suto A,Nakajima H,Kagami SI,Suzuki K,Saito Y,Iwamoto I.Role of CD4(+)CD25(+)regulatory T cells in T helper 2 cell-mediated allergic inflammation in the airways.Am J Respir Crit Care Med.2001;164(4):680-7.
128.Shi HZ,Qin XJ.CD4CD25 regulatory T lymphocytes in allergy and asthma.Allergy. 2005;60(8):986-95.
129.Solomou EE, Rezvani K, Mielke S, Malide D, Keyvanfar K, Visconte V, Kajigaya S, Barrett AJ, Young NS.Deficient CD4+ CD25+ FOXP3+ T regulatory cells in acquired aplastic anemia.Blood. 2007; 110(5): 1603-6.
1.Tsuda H,Yamasaki H.Type Ⅰ and type Ⅱ T-cell profiles in aplastic anemia and refractory anemia.Am J Hematol.2000;64(4):271-4.
2.Sloand E,Kim S,Maciejewski JP,Tisdale J,Follmann D,Young NS.Intracellular interferon-gamma in circulating and marrow T cells detected by flow cytometry and the response to immunosuppressive therapy in patients with aplastic anemia.Blood.2002;100(4):1185-91.
3.Murphy KM,Reiner SL.The lineage decisions of helper T cells.Nat Rev Immunol.2002;2(12):933-44.
4.Leonard WJ,O'Shea JJ.Jaks and STATs:biological implications.Annu Rev Immunol.1998;16:293-322.
5.Darnell JE Jr.STATs and gene regulation.Science.1997;277(5332):1630-5.
6.Farrar JD,Asnagli H,Murphy KM.T helper subset development:roles of instruction,selection,and transcription.J Clin Invest.2002;109(4):431-5.
7.Szabo SJ,Kim ST,Costa GL,Zhang X,Fathman CG,Glimcher LH.A novel transcription factor,T-bet,directs Th1 lineage commitment.Cell.2000;100(6):655-69.
8.张之南,沈悌,主编.血液病诊断及疗效标准.第2版.北京:科学出版社,1998.33-35.
9.Nakao S.Immune mechanism of aplastic anemia.Int J Hematol.1997;66(2):127-34.
10.Selleri C,Maciejewski JP,Sato T,Young NS.Interferon-gamma constitutively expressed in the stromal microenvironment of human marrow cultures mediates potent hematopoietic inhibition.Blood.1996;87(10):4149-57.
11.Shao Z,Chu Y,Zhang Y,Chen G,Zheng Y.Treatment of severe aplastic anemia with an immunosuppressive agent plus recombinant human granulocyte-macrophage colony-stimulating factor and erythropoietin.Am J Hematol.1998;59(3):185-91.
12.何广胜,邵宗鸿,张益枝,刘鸿,李克,宋鲁燕,郑以洲,陈桂彬,和虹,赵明峰,施均,张泓,储榆林,钱林生,杨天楹.序贯强化免疫抑制并用造血生长因子治疗重型再生障碍性贫血.中华血液学杂志.2001,22(4):176-81.
13.和虹,邵宗鸿.再生障碍性贫血T淋巴细胞研究进展.中华血液学杂志,1999,20(10):553-5.
14.王欣,张明珙,宋素琴,李杰,郭承山,宋强,赵川莉,王惠军,彭军,秦平.再生障碍性贫血患者细胞免疫功能与造血细胞因子的研究.中华血液学杂志,1998,19(4).181-3
15.黄云鹏,张伟华,张秀莲,范星火,李殿青.再生障碍性贫血患者外周血T细胞亚群及Th1/Th2细胞分析.山西医科大学学报,2005,36(4):443-5
16.唐晓文,邵景章,张学光,张毅,李建,郑列琳,谢炜,王爱青.再生障碍性贫血患者外周血T细胞亚群检测.中华血液学杂志,1997,18(4):205-6
17.Young NS.Hematopoietic cell destruction by immune mechanisms in acquired aplastic anemia.Semin Hematol.2000;37(1):3-14.
18.和虹,邵宗鸿,何广胜,刘鸿,施均,付蓉,赵明峰,白洁,贾海蓉,孙娟,崔振珠,储榆林,杨天楹,杨崇礼。Th1细胞在再生障碍性贫血发病机制中的作用.中华血液学杂志.2002,23(11):574-7
19.Hsu HC,Tsai WH,Chen LY,Hsu ML,Ho CH,Lin CK,Wang SY.Overpmduction of inhibitory hematopoietic cytokines by lipopolysaccharide-activated peripheral blood mononuclear cells in patients with aplastic anemia.Ann Hematol.1995;71(6):281-6
20.Laver J,Castro-Malaspina H,Kernan NA,Levick J,Evans RL,O'Reilly RJ,Moore MA.In vitro interferon-gamma production by cultured T-cells in severe aplastic anaemia:correlation with granulomonopoietic inhibition in patients who respond to anti-thymocyte globulin.Br J Haematol.1988;69(4):545-50.
21.Killick SB,Cox CV,Marsh JC,Gordon-Smith EC,Gibson FM.Mechanisms of bone marrow progenitor cell apoptosis in aplastic anaemia and the effect of anti-thymocyte globulin:examination of the role of the Fas-Fas-L interaction.Br J Haematol.2000;111(4):1164-9.
22.Maciejewski JP,Selleri C,Sato T,Anderson S,Young NS.Increased expression of Fas antigen on bone marrow CD34+ cells of patients with aplastic anaemia.Br J Haematol.1995;91(1):245-52.
23.Scopes J,Bagnara M,Gordon-Smith EC,Ball SE,Gibson FM.Haemopoietic progenitor cells are reduced in aplastic anaemia.Br J Haematol.1994;86(2):427-30.
24.Maciejewski JP,Selleri C,Sato T,Anderson S,Young NS.A severe and consistent deficit in marrow and circulating primitive hematopoietic cells(long-term culture-initiating cells)in acquired aplastic anemia.Blood.1996;88(6):1983-91.
25.Mosmann TR,Cherwinski H,Bond MW,Giedlin MA,Coffman RL.Two types of murine helper T cell clone.I.Definition according to profiles of lymphokine activities and secreted proteins.1986.J Immunol.2005;175(1):5-14.
26.Romagnani S.Human TH1 and TH2 subsets:doubt no more.Immunol Today.1991;12(8):256-7.
27.Ho IC,Hodge MR,Rooney JW,Glimcher LH.The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4.Cell.1996;85(7):973-83.
28.Nistico A,Young NS.Gamma-Interferon gene expression in the bone marrow of patients with aplastic anemia.Ann Intern Med.1994;120(6):463-9.
29.Kaito K,Otsubo H,Usui N,Kobayashi M.Th1/Th2 lymphocyte balance in patients with aplastic anemia.Rinsho Byori.2004;52(7):569-73.
30.张春青,王立军,张锑,秦雪梅.徐从高.获得性再生障碍性贫血患者Th1、Th2型T 细胞亚群的检测.中华血液学杂志,2006,27(11):777-8
31.Solomou EE,Keyvanfar K,Young NS.T-bet,a Th1 transcription factor,is up-regulated in T cells from patients with aplastic anemia.Blood.2006;107(10):3983-91.
32.张宁,徐永健,张珍祥.辅助性T细胞功能分化的分子机制.国外医学呼吸系统分册.2003,23(2):57-61
33.Gately MK,Renzetti LM,Magram J,Stern AS,Adorini L,Gubler U,Presky DH.The interleukin-12/interleukin-12-receptor system:role in normal and pathologic immune responses.Annu Rev Immunol.1998;16:495-521.
34.Nelms K,Keegan AD,Zamorano J,Ryan JJ,Paul WE.The IL-4 receptor:signaling mechanisms and biologic functions.Annu Rev Immunol.1999;17:701-38.
35.Trinchieri G.Interleukin-12:a cytokine at the interface of inflammation and immunity.Adv Immunol.1998;70:83-243.
36.Hikawa N,Ishikawa Y,Takenaka T.Interleukin-12 p40-homodimer production in sensory dorsal root ganglion neurons.Neuroscience.2004;129(1):75-83.
37.Macatonia SE,Hosken NA,Litton M,Vieira P,Hsieh CS,Culpepper JA,Wysocka M,Trinchieri G,Murphy KM,O'Garra A.Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells.J Immunol.1995;154(10):5071-9.
38.Trinchieri G.Interleukin-12:a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity.Annu Rev Immunol.1995;13:251-76.
39.Cassatella MA,Meda L,Gasperini S,D'Andrea A,Ma X,Trinchieri G.Interleukin-12 production by human polymorphonuclear leukocytes.Eur J Immunol.1995;25(1):1-5.
40.Ma X,Trinchieri G.Regulation of interleukin-12 production in antigen-presenting cells.Adv Immunol.2001;79:55-92.
41.Pallone F,Monteleone G.Interleukin 12 and Th1 responses in inflammatory bowel disease.Gut.1998;43(6):735-6.
42.van Boxel-Dezaire AH,Hoff SC,van Oosten BW,Verweij CL,Drager AM,Ader HJ,van Houwelingen JC,Barkhof F,Polman CH,Nagelkerken L.Decreased interleukin-10 and increased interleukin-12p40 mRNA are associated with disease activity and characterize different disease stages in multiple sclerosis.Ann Neurol.1999;45(6):695-703.
43.任翠爱,张茂宏,徐从高,张锑.再生障碍性贫血患者血浆IL-12水平的检测及临床意义.上海免疫学杂志.2000,20(4):252
44.Oppmann B,Lesley R,Blom B,Timans JC,Xu Y,Hunte B,Vega F,Yu N,Wang J,Singh K,Zonin F,Vaisberg E,Churakova T,Liu M,Gorman D,Wagner J,Zurawski S,Liu Y,Abrams JS,Moore KW,Rennick D,de Waal-Malefyt R,Hannum C,Bazan JF,Kastelein RA.Novel p19 protein engages IL-12p40 to form a cytokine,IL-23,with biological activities similar as well as distinct from IL-12.Immunity.2000;13(5):715-25.
45.Kolls JK,Linden A.Interleukin-17 family members and inflammation.Immunity.2004;21(4):467-76.
46.Watford WT,Hissong BD,Bream JH,Kanno Y,Muul L,O'Shea JJ.Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4.Immunol Rev. 2004;202:139-56.
47. Igarashi O, Yamane H, Imajoh-Ohmi S, Nariuchi H. IL-12 receptor (IL-12R) expression and accumulation of IL-12R beta 1 and IL-12R beta 2 mRNAs in CD4+ T cells by costimulation with B7-2 molecules.J Immunol. 1998; 160(4): 1638-46.
48. Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, Pflanz S, Zhang R, Singh KP, Vega F, To W, Wagner J, O'Farrell AM, McClanahan T, Zurawski S, Hannum C, Gorman D, Rennick DM, Kastelein RA, de Waal Malefyt R, Moore KW. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbetal and a novel cytokine receptor subunit, IL-23R.J Immunol. 2002; 168(11):5699-708.
49. Chua AO, Chizzonite R, Desai BB, Truitt TP, Nunes P, Minetti LJ, Warrier RR, Presky DH, Levine JF, Gately MK, Gubler U.Expression cloning of a human IL-12 receptor component. A new member of the cytokine receptor superfamily with strong homology to gpl30.J Immunol. 1994;153(1):128-36.
50. Zhang GX, Yu S, Gran B, Li J, Siglienti I, Chen X, Calida D, Ventura E, Kamoun M, Rostami A.Role of IL-12 receptor beta 1 in regulation of T cell response by APC in experimental autoimmune encephalomyelitis.J Immunol. 2003;171(9):4485-92.
51. Staretz-Haham O, Melamed R, Lifshitz M, Porat N, Fieschi C, Casanova JL, Levy J. Interleukin-12 receptor beta1 deficiency presenting as recurrent Salmonella infection.Clin Infect Dis. 2003;37(1): 137-40.
52. Caragol I, Raspall M, Fieschi C, Feinberg J, Larrosa MN, Hernandez M, Figueras C, Bertran JM, Casanova JL, Espanol T.Clinical tuberculosis in 2 of 3 siblings with interleukin-12 receptor betal deficiency.Clin Infect Dis. 2003;37(2):302-6.
53. Sanal O, Turkkani G, Gumruk F, Yel L, Secmeer G, Tezcan I, Kara A, Ersoy F.A case of interleukin-12 receptor beta-1 deficiency with recurrent leishmaniasis.Pediatr Infect Dis J.2007;26(4):366-8.
54.Wu CY,Warrier RR,Carvajal DM,Chua AO,Minetti LJ,Chizzonite R,Mongini PK,Stern AS,Gubler U,Presky DH,Gately MK.Biological function and distribution of human interleukin-12 receptor beta chain.Eur J Immunol.1996;26(2):345-50.
55.孙晗笑,杨滨燕,李波,娄阁,吴长有.内源性IL-12决定人PBMC产生干扰素γ的水平.中国免疫学杂志,2002,18(4):228-32
56.范艳莹,吴长有.Th2细胞因子和抗IL-12Rβ1mAb抑制由IL-23诱导PBMC IFN-γ的产生.中国免疫学杂志.2006,22(3):195-9
57.范艳莹,吴长有.IL-4、IL-10和抗IL-12受体β1 mAb抑制IL-23诱导正常人记忆T 细胞IFN-γ产生.免疫学杂志,2006,22(4):353-7
58.Lugo-Villarino G,Maldonado-Lopez R,Possemato R,Penaranda C,Glimcher LH.T-bet is required for optimal production of IFN-gamma and antigen-specific T cell activation by dendritic cells.Proc Natl Acad Sci U S A.2003;100(13):7749-54.
59.Agnello D,Lankford CS,Bream J,Morinobu A,Gadina M,O'Shea JJ,Frucht DM.Cytokines and transcription factors that regulate T helper cell differentiation:new players and new insights.J Clin Immunol.2003;23(3):147-61.
60.Strengell M,Matikainen S,Siren J,Lehtonen A,Foster D,Julkunen I,Sareneva T.IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells.J Immunol.2003;170(11):5464-9.
61.Liu N,Ohnishi N,Ni L,Akira S,Bacon KB.CpG directly induces T-bet expression and inhibits IgG1 and IgE switching in B cells.Nat Immunol.2003;4(7):687-93.
62.Usui T,Nishikomori R,Kitani A,Strober W.GATA-3 suppresses Th1development by downregulation of Stat4 and not through effects on IL-12Rbeta2chain or T-bet.Immunity.2003;18(3):415-28.
63.Hartenstein B,Teurich S,Hess J,Schenkel J,Schorpp-Kistner M,Angel P.Th2 cell-specific cytokine expression and allergen-induced airway inflammation depend on JunB.EMBO J.2002;21(23):6321-9.
64.Daynes RA,Enioutina EY,Jones DC.Role of redox imbalance in the molecular mechanisms responsible for immunosenescence.Antioxid Redox Signal.2003;5(5):537-48.
65.Chen CH,Seguin-Devaux C,Burke NA,Oriss TB,Watkins SC,Clipstone N,Ray A.Transforming growth factor beta blocks Tee kinase phosphorylation,Ca2+influx,and NFATc translocation causing inhibition of T cell differentiation.J Exp Med.2003;197(12):1689-99.
66.Park IK,Shultz LD,Letterio JJ,Gorham JD.TGF-betal inhibits T-bet induction by IFN-gamma in murine CD4+ T cells through the protein tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1.J Immunol.2005;175(9):5666-74.
67.Szabo SJ,Sullivan BM,Stemmann C,Satoskar AR,Sleckman BP,Glimcher LH.Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells.Science.2002;295(5553):338-42.
68.Rao A,Avni O.Molecular aspects of T-cell differentiation.Br Med Bull.2000;56(4):969-84.
69.Mullen AC,Hutchins AS,High FA,Lee HW,Sykes KJ,Chodosh LA,Reiner SL.Hlx is induced by and genetically interacts with T-bet to promote heritable T(H)1 gene induction.Nat Immunol.2002;3(7):652-8.
70.Ouyang W,Ranganath SH,Weindel K,Bhattacharya D,Murphy TL,Sha WC,Murphy KM.Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism.Immunity.1998;9(5):745-55.
71.Ouyang W,Lohning M,Gao Z,Assenmacher M,Ranganath S,Radbruch A,Murphy KM.Stato-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment.Immunity.2000;12(1):27-37.
72.Zheng W,Flavell RA.The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells.Cell.1997;89(4):587-96.
73.Lee HJ,Takemoto N,Kurata H,Kamogawa Y,Miyatake S,O'Garra A,Arai N.GATA-3 induces T helper cell type 2(Th2)cytokine expression and chromatin remodeling in committed Th1 cells.J Exp Med.2000;192(1):105-15.
74.Dong C,Flavell RA.Th1 and Th2 cells.Curr Opin Hematol.2001;8(1):47-51.
75.Glimcher LH,Murphy KM.Lineage commitment in the immune system:the T helper lymphocyte grows up.Genes Dev.2000;14(14):1693-711.
76.Zhang DH,Yang L,Ray A.Differential responsiveness of the IL-5 and IL-4 genes to transcription factor GATA-3.J Immunol.1998;161(8):3817-21.
77.Agarwal S,Avni O,Rao A.Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo.Immunity.2000;12(6):643-52.
78.Usui T,Preiss JC,Kanno Y,Yao ZJ,Bream JH,O'Shea JJ,Strober W.T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription.J Exp Med.2006;203(3):755-66.
79.张琦,董亮,李丽珍,于钦凤,陈明.以T-bet/GATA-3的比率作为评价哮喘患者Th1/Th2失衡指标的探讨.细胞与分子免疫学杂志,2005,21(1):118-20
80.Chakir H,Wang H,Lefebvre DE,Webb J,Scott FW.T-bet/GATA-3 ratio as a measure of the Th1/Th2 cytokine profile in mixed cell populations:predominant role of GATA-3.J Immunol Methods.2003;278(1-2):157-69.
81.魏海明,田志刚,许晓群,冯进波,肖伟.肺癌患者转录因子T-bet和GATA3的基因表达状况及药物干预研究.中华肿瘤杂志.2002,24(1):34-7
82.黄丽群,薛峰,沈小雁,郑捷.系统性红斑狼疮患者转录因子T-bet和GATA3基因的表达.中华皮肤科杂志,2004,37(12):724-6
83.Lit LC,Wong CK,Li EK,Tam LS,Lam CW,Lo YM.Elevated gene expression of Th1/Th2 associated transcription factors is correlated with disease activity in patients with systemic lupus erythematosus.J Rheumatol.2007;34(1):89-96.
84.Neurath MF,Weigmann B,Finotto S,Glickman J,Nieuwenhuis E,Iijima H,Mizoguchi A,Mizoguchi E,Mudter J,Galle PR,Bhan A,Autschbach F,Sullivan BM, Szabo SJ, Glimcher LH, Blumberg RS.The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease.J ExpMed.2002;195(9):1129-43.
85. Li B, Yang P, Zhou H, Zhang Z, Xie C, Lin X, Huang X, Kijlstra A.T-bet expression is upregulated in active Behcet's disease. Br J Ophthalmol. 2003 ;87(10): 1264-7.
86. Juedes AE, Rodrigo E, Togher L, Glimcher LH, von Herrath MGT-bet controls autoaggressive CD8 lymphocyte responses in type 1 diabetes.J Exp Med. 2004; 199(8): 1153-62.
87. Frisullo G, Angelucci F, Caggiula M, Nociti V, Iorio R, Patanella AK, Sancricca C, Mirabella M, Tonali PA, Batocchi AP.pSTAT1, pSTAT3, and T-bet expression in peripheral blood mononuclear cells from relapsing-remitting multiple sclerosis patients correlates with disease activity.J Neurosci Res. 2006;84(5): 1027-36.
88. Loyett-Racke AE, Rocchini AE, Choy J, Northrop SC, Hussain RZ, Ratts RB, Sikder D, Racke MK.Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes.Immunity. 2004;21 (5):719-31.
89. Peng SL, Szabo SJ, Glimcher LH. T-bet regulates IgG class switching and pathogenic autoantibody production. Proc Natl Acad Sci U S A. 2002;99(8): 5545-50.
90. Finotto S, Glimcher L.T cell directives for transcriptional regulation in asthma. Springer Semin Immunopathol. 2004;25(3-4):281-94.
91. Weigmann B, Neurath MF.T-bet as a possible therapeutic target in autoimmune disease. Expert Opin Ther Targets. 2002;6(6):619-22.
92. Turkson J, Jove R. STAT proteins: novel molecular targets for cancer drug discovery.Oncogene. 2000; 19(56):6613-26.
93. Bacon CM, McVicar DW, Ortaldo JR, Rees RC, O'Shea JJ, Johnston JA.Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL-2 and IL-12.J Exp Med. 1995;181(1):399-404.
94. Klein JL, Fickenscher H, Holliday JE, Biesinger B, Fleckenstein B. Herpesvirus saimiri immortalized gamma delta T cell line activated by IL-12. J Immunol. 1996;156(8):2754-60.
95. Jacobson NG, Szabo SJ, Giiler ML, Gorham JD, Murphy KM.Regulation of interleukin-12 signal transduction during T helper phenotype development. Res Immunol. 1995;146(7-8):446-56.
96. Jacobson NG, Szabo SJ, Weber-Nordt RM, Zhong Z, Schreiber RD, Darnell JE Jr, Murphy KM.Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4.J Exp Med. 1995;181(5):1755-62.
97. Ouyang W, Jacobson NG, Bhattacharya D, Gorham JD, Fenoglio D, Sha WC, Murphy TL, Murphy KM.The Ets transcription factor ERM is Th1-specific and induced by IL-12 through a Stat4-dependent pathway.Proc Natl Acad Sci U S A. 1999;96(7):3888-93.
98. Galon J, Sudarshan C, Ito S, Finbloom D, O'Shea JJ. IL-12 induces IFN regulating factor-1 (IRF-1) gene expression in human NK and T cells. J Immunol. 1999;162(12):7256-62.
99. Chitnis T, Najafian N, Benou C, Salama AD, Grusby MJ, Sayegh MH, Khoury SJ.Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis. J Clin Invest. 2001;108(5):739-47.
100.Verhagen CE, de Boer T, Smits HH, Verreck FA, Wierenga EA, Kurimoto M, Lammas DA, Kumararatne DS, Sanal O, Kroon FP, van Dissel JT, Sinigaglia F, Ottenhoff TH.Residual type 1 immunity in patients genetically deficient for interleukin 12 receptor beta1 (IL-12Rbeta1): evidence for an IL-12Rbeta1-independent pathway of IL-12 responsiveness in human T cells.J Exp Med. 2000;192(4):517-28.
1. Young NS. Acquired aplastic anemia. Ann Intern Med 2002; 136: 534-46.
2. Keohane EM. Acquired aplastic anemia. Clin Lab Sci 2004; 17: 165-71.
3. Nakao S. Immune mechanism of aplastic anemia. Int J Hematol 1997; 66: 127-34.
4. Brodsky RA, Jones RJ. Aplastic anaemia. Lancet 2005; 365: 1647-56.
5. Zeng W, Kajigaya S, Chen G, Risitano AM, Nunez O, Young NS. Transcript profile of CD4+ and CD8+ T cells from the bone marrow of acquired aplastic anemia patients. Exp Hematol 2004; 32: 806-14
6. Kagan WA, Ascensao JA, Pahwa RN, Hansen JA, Goldstein G, Valera EB, Incefy GS, Moore MA, Good RA. Aplastic anemia: presence in human bone marrow of cells that suppress myelopoiesis. Proc Natl Acad Sci U S A1976; 73: 2890-4.
7. Sullivan R, Quesenberry PJ, Parkman R, Zuckerman KS, Levey RH, Rappeport J, Ryan M. Aplastic anemia: lack of inhibitory effect of bone marrow lymphocytes on in vitro granulopoiesis. Blood 1980; 56: 625-32.
8. Young NS. Hematopoietic cell destruction by immune mechanisms in aquired aplastic anemia. Semin Hematol 2000; 37: 3-14
9. Zoumbos NC, Gascon P, Djeu JY, Young NS. Interferon is a mediator of hematopoietic suppression in aplastic anemia in vitro and possibly in vivo. Proc Natl Acad Sci U S A 1985; 82: 188-92.
10. Nistico A, Young NS. Gamma-Interferon gene expression in the bone marrow of patients with aplastic anemia. Ann Intern Med 1994; 120: 463-9
11. Selleri C, Sato T, Anderson S, Young NS, Maciejewski JP. Interferon-γ and tumor necrosis factor-alpha suppress both early and late stages of hematopoiesis and induce programmed cell death. J Cell Physiol 1995; 165: 538-46.
12. Philpott NJ, Scopes J, Marsh JC, Gordon-Smith EC, Gibson FM. Increased apoptosis in aplastic anemia bone marrow progenitor cells: possible pathophysiologic significance. Exp Hematol 1995; 23: 1642-8.
13. Maciejewski JP, Selleri C, Sato T, Anderson S, Young NS. Increased expression of Fas antigen on bone marrow CD34+ cells of patients with aplastic anaemia. Br J Haematol 1995; 91: 245-52.
14. Sato T, Selleri C, Anderson S, Young NS, Maciejewski JP. Expression and modulation of cellular receptors for interferon-γ, tumour necrosis factor, and Fas on human bone marrow CD34+ cells. Br J Haematol 1997; 97: 356-65.
15. Maciejewski JP, Hibbs JR, Anderson S, Katevas P, Young NS. Bone marrow and peripheral blood lymphocyte phenotype in patients with bone marrow failure. ExpHematol 1994; 22:1102-10.
16. Sloand E, Kim S, Maciejewski JP, Tisdale J, Follmann D, Young NS. Intracellular interferon-gamma in circulating and marrow T cells detected by flow cytometry and the response to immunosuppressive therapy in patients with aplastic anemia. Blood 2002; 100:1185-91.
17. Solomou EE, Keyvanfar K, Young NS. T-bet, a Thl transcription factor, is up-regulated in T cells from patients with aplastic anemia. Blood 2006; 107: 3983-91.
18. Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA, Freeman GJ, Kuchroo VK. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 2002; 415: 536-41.
19. Sanchez-Fueyo A, Tian J, Picarella D, Domenig C, Zheng XX, Sabatos CA, Manlongat N, Bender O, Kamradt T, Kuchroo VK, Gutierrez-Ramos JC, Coyle AJ, Strom TB. Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nat Immunol 2003; 4: 1093-101.
20. Sabatos CA, Chakravarti S, Cha E, Schubart A, Sanchez-Fueyo A, Zheng XX, Coyle AJ, Strom TB, Freeman GJ, Kuchroo VK. Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat Immunol 2003; 4: 1102-10.
21. Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol 2005; 6:1245-52.
22. Anderson AC, Anderson DE, Bregoli L, Hastings WD, Kassam N, Lei C, Chandwaskar R, Karman J, Su EW, Hirashima M, Bruce JN, Kane LP, Kuchroo VK, Hafler DA.Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science 2007; 318: 1141-3.
23. Kaufman DW, Kelly JP, Jurgelon JM, Anderson T, Issaragrisil S, Wiholm BE, Young NS, Leaverton P, Levy M, Shapiro S. Drugs in the aetiology of agranulocytosis and aplastic anaemia. Eur J Haematol 1996; Suppl 60: 23-30.
24. Camitta BM, Thomas ED, Nathan DG, Santos G., Gordon-Smith EC, Gale RP, Rappeport JM, Storb R. Severe aplastic anemia: a prospective study of the effect of early marrow transplantation on acute mortality. Blood 1976; 48:63-70.
25. Asakura H, Kashio Y, Nakamura K, Seki M, Dai S, Shirato Y, Abedin MJ, Yoshida N, Nishi N, Imaizumi T, Saita N, Toyama Y, Takashima H, Nakamura T., Ohkawa M, Hirashima M. Selective eosinophil adhesion to fibroblast via IFN-gamma-induced galectin-9. J Immunol 2002; 169: 5912-8.
26. Khademi M, Illes Z, Gielen AW, Marta M, Takazawa N, Baecher-Allan C, Brundin L, Hannerz J, Martin C, Harris RA, Hafler DA, Kuchroo VK, Olsson T., Piehl F, Wallstrom E. T Cell Ig- and mucin-domain-containing molecule-3 (TIM-3) and TIM-1 molecules are differentially expressed on human Th1 and Th2 cells and in cerebrospinal fluid-derived mononuclear cells in multiple sclerosis. J Immunol 2004; 172: 7169-76.
27. Baratelli F, Lin Y, Zhu L, Yang SC, Heuze-Vourc'h N, Zeng G, Reckamp K, Dohadwala M, Sharma S, Dubinett SM. Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4+ T cells. J Immunol 2005; 175:1483-90.
28. Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+CD25high regulatory cells in human peripheral blood. J Immunol 2001; 167:1245-53.
29. Wing K, Ekmark A, Karlsson H, Rudin A, Suri-Payer E. Characterization of human CD25+ CD4+ T cells in thymus, cord and adult blood. Immunology 2002; 106: 190-9.
30. Ponciano VC, Renesto PG, Nogueira E, Rangel EB, Cenedeze MA, Franco MF, Camara NO, Pacheco-Silva A. Tim-3 expression in human kidney allografts. Transpl Immunol 2007; 17: 215-22.
31. Renesto PG, Ponciano VC, Cenedeze MA, Saraiva Camara NO, Pacheco-Silva A. High expression of Tim-3 mRNA in urinary cells from kidney transplant recipients with acute rejection. Am J Transplant 2007; 7:1661-5.
32. He GS, Shao ZH, He H, Liu H, Fu R, Bai J, Shi J, Cao YR, Tu MF, Sun J, Jia HR. Changes of subsets of DC1 in the bone marrow of severe aplastic anemia patients. Zhonghua Xue Ye Xue Za Zhi 2004; 25: 649-52.
33. Tu MF, Shao ZH, Liu H, He GS, Shi J, Bai J, Cao YR, Wang HQ, Xing LM, Cui ZZ. Study on the peripheral blood dendritic cells subtypes and the expression of co-stimulating molecules on dendritic cells and B cells in severe aplastic anemia patients. Zhonghua Xue Ye Xue Za Zhi 2006; 27:611-5.
34. Hirashima M, Kashio Y, Nishi N, Yamauchi A, Imaizumi TA, Kageshita T, Saita N, Nakamura T. Galectin-9 in physiological and pathological conditions. Glycoconj J 2004; 19: 593-600.
35. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003; 4: 330-6.
36. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299: 1057-61.
37. Solomou EE, Rezvani K, Mielke S, Malide D, Keyvanfar K, Visconte V, Kajigaya S, Barrett AJ, Young NS. Deficient CD4+ CD25+ FOXP3+ T regulatory cells in acquired aplastic anemia. Blood 2007; 110:1603-6.
38. Dabbagh K, Lewis DB.Toll-like receptors and T-helper-1/T-helper-2 responses. Curr Opin Infect Dis 2003; 16:199-204.
39. Zeng W, Maciejewski JP, Chen G, Risitano AM, Kirby M, Kajigaya S, Young NS.Selective reduction of natural killer T cells in the bone marrow of aplastic anaemia. Br J Haematol 2002; 119: 803-9.
40. Chen Y, Langrish CL, McKenzie B, Joyce-Shaikh B, Stumhofer JS, McClanahan T, Blumenschein W, Churakovsa T, Low J, Presta L, Hunter CA, Kastelein RA, Cua DJ. Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J Clin Invest 2006,116: 1317-26.
41. Nielsen OH, Kirman I, Rudiger N, Hendel J, Vainer B. Upregulation of interleukin-12 and -17 in active inflammatory bowel disease. Scand J Gastroenterol 2003;38:180-5.
42.Komiyama Y,Nakae S,Matsuki T,Nambu A,Ishigame H,Kakuta S,Sudo K,Iwakura Y.IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis.J Immunol 2006;177:566-73.
43.Koenders MI,Lubberts E,van de Loo FA,Oppers-Walgreen B,van den Bersselaar L,Helsen MM,Kolls JK,Di Padova FE,Joosten LA,van den Berg WB.Interleukin-17 acts independently of TNF-alpha under arthritic conditions.J Immunol 2006;176:6262-9.
44.Anderson AC,Anderson DE.TIM-3 in autoimmunity.Curr Opin Immunol 2006;18:665-9.
45.Kolls JK,Linden A.Intedeukin-17 family members and inflammation.Immunity 2004;21:467-76.
1.Mosmann TR,Cherwinski H,Bond MW,Giedlin MA,Coffman RL.Two types of murine helper T cell clone.I.Definition according to profiles of lymphokine activities and secreted proteins.J Immunol.1986 Apr 1;136(7):2348-57.
2. Romagnani S.The Thl/Th2 paradigm.Immunol Today. 1997 Jun;18(6):263-6.
3. Abbas AK, Murphy KM, Sher A.Functional diversity of helper T lymphocytes. Nature. 1996 Oct 31;383(6603):787-93.
4. Seder RA, Paul WE. Acquisition of lymphokine-producing phenotype by CD4+ T cells.Annu Rev Immunol. 1994;12:635-73.
5. Constant SL, Bottomly K. Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Annu Rev Immunol. 1997; 15:297-322.
6. O'Garra A. Cytokines induce the development of functionally heterogeneous T helper cell subsets.Immunity. 1998 Mar;8(3):275-83.
7. Kaplan MH, Schindler U, Smiley ST, Grusby MJ.Stat6 is required for mediating responses to IL-4 and for development of Th2 cells.Immunity. 1996 Mar;4(3):313-9.
8. Kaplan MH, Sun YL, Hoey T, Grusby MJ. Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice.Nature. 1996 Jul 11;382(6587): 174-7.
9. Thierfelder WE, van Deursen JM, Yamamoto K, Tripp RA, Sarawar SR, Carson RT, Sangster MY, Vignali DA, Doherty PC, Grosveld GC, Ihle JN. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells.Nature. 1996 Jul 11;382(6587):171-4.
10. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH.A novel transcription factor, T-bet, directs Thl lineage commitment. Cell. 2000 Mar 17;100(6):655-69.
11. Ann HJ, Maruo S, Tomura M, Mu J, Hamaoka T, Nakanishi K, Clark S, Kurimoto M, Okamura H, Fujiwara H.A mechanism underlying synergy between IL-12 and IFN-gamma-inducing factor in enhanced production of IFN-gamma.J Immunol. 1997 Sep 1;159(5):2125-31.
12. Nakahira M, Ann HJ, Park WR, Gao P, Tomura M, Park CS, Hamaoka T, Ohta T, Kurimoto M, Fujiwara H.Synergy of IL-12 and IL-18 for IFN-gamma gene expression: IL-12-induced STAT4 contributes to IFN-gamma promoter activation by up-regulating the binding activity of IL-18-induced activator protein 1.J Immunol.2002 Feb 1;168(3):1146-53.
13.Trinchieri G.Interleukin-12:a cytokine at the interface of inflammation and immunity.Adv Immunol.1998;70:83-243.
14.Shevach EM,Chang JT,Segal BM.The critical role of IL-12 and the IL-12R beta 2 subunit in the generation of pathogenic autoreactive Th1 cells.Springer Semin Immunopathol.1999;21(3):249-62.
15.Mullen AC,High FA,Hutchins AS,Lee HW,Villarino AV,Livingston DM,Kung AL,Cereb N,Yao TP,Yang SY,Reiner SL.Role of T-bet in commitment of TH1cells before IL-12-dependent selection.Science.2001 Jun 8;292(5523):1907-10.
16.Presky DH,Yang H,Minetti LJ,Chua AO,Nabavi N,Wu CY,Gately MK,Gubler U.A functional interleukin 12 receptor complex is composed of two beta-type cytokine receptor subunits.Proc Natl Acad Sci U S A.1996 Nov 26;93(24):14002-7.
17.Gately MK,Renzetti LM,Magram J,Stern AS,Adorini L,Gubler U,Presky DH.The interleukin-12/interleukin-12-receptor system:role in normal and pathologic immune responses.Annu Rev Immunol.1998;16:495-521.
18.Wu C,Ferrante J,Gately MK,Magram J.Characterization of IL-12 receptor betal chain(IL-12Rbetal)-deficient mice:IL-12Rbetal is an essential component of the functional mouse IL-12 receptor.J Immunol.1997 Aug 15;159(4):1658-65.
19.Oppmann B,Lesley R,Blom B,Timans JC,Xu Y,Hunte B,Vega F,Yu N,Wang J,Singh K,Zonin F,Vaisberg E,Churakova T,Liu M,Gorman D,Wagner J,Zurawski S,Liu Y,Abrams JS,Moore KW,Rennick D,de Waal-Malefyt R,Hannum C,Bazan JF,Kastelein RA.Novel p19 protein engages IL-12p40 to form a cytokine,IL-23,with biological activities similar as well as distinct from IL-12.Immunity.2000 Nov;13(5):715-25.
20.Frucht DM.IL-23:a cytokine that acts on memory T cells.Sci STKE.2002 Jan 8;2002(114):PE1.
21.Lankford CS,Frucht DM.A unique role for IL-23 in promoting cellular immunity.J Leukoc Biol.2003 Jan;73(1):49-56.
22.Cleary AM,Tu W,Enright A,Giffon T,Dewaal-Malefyt R,Gutierrez K,Lewis DB.Impaired accumulation and function of memory CD4 T cells in human IL-12 receptor beta 1 deficiency.J Immunol. 2003 Jan l;170(1):597-603.
23. Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL.Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem. 2003 Jan 17;278(3):1910-4.
24. Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, Pflanz S, Zhang R, Singh KP, Vega F, To W, Wagner J, O'Farrell AM, McClanahan T, Zurawski S, Hannum C, Gorman D, Rennick DM, Kastelein RA, de Waal Malefyt R, Moore KW. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol. 2002 Jun 1;168(11):5699-708.
25. Zhang GX, Yu S, Gran B, Li J, Siglienti I, Chen X, Calida D, Ventura E, Kamoun M, Rostami A.Role of IL-12 receptor beta 1 in regulation of T cell response by APC in experimental autoimmune encephalomyelitis. J Immunol. 2003 Nov l;171(9):4485-92.
26. Young NS. Acquired aplastic anemia. Ann Intern Med. 2002 Apr 2;136(7):534-46.
27. Young NS, Maciejewski J.The pathophysiology of acquired aplastic anemia.N Engl J Med. 1997 May 8;336(19):1365-72.
28. Young NS. Gamma interferon and aplastic anemia.Blood. 1987 Jul;70(1):337-9.
29. Zoumbos NC, Gascon P, Djeu JY, Young NS.Interferon is a mediator of hematopoietic suppression in aplastic anemia in vitro and possibly in vivo.Proc Natl Acad Sci U S A. 1985 Jan;82(1):188-92.
30. Giannakoulas NC, Karakantza M, Theodorou GL, Pagoni M, Galanopoulos A, Kakagianni T, Kouraklis-Symeonidis A, Matsouka P, Maniatis A, Zoumbos NC.Clinical relevance of balance between type 1 and type 2 immune responses of lymphocyte subpopulations in aplastic anaemia patients. Br J Haematol. 2004 Jan;124(1):97-105.
31. Sloand E, Kim S, Maciejewski JP, Tisdale J, Follmann D, Young NS.Intracellular interferon-gamma in circulating and marrow T cells detected by flow cytometry and the response to immunosuppressive therapy in patients with aplastic anemia.Blood. 2002 Aug 15; 100(4): 1185-91.
32. Zoumbos NC, Djeu JY, Young NS. Interferon is the suppressor of hematopoiesis generated by stimulated lymphocytes in vitro. J Immunol. 1984 Aug;133(2):769-74.
33. Solomou EE, Keyvanfar K, Young NS.T-bet, a Th1 transcription factor, is up-regulated in T cells from patients with aplastic anemia.Blood. 2006 May 15;107(10):3983-91.
34. Young NS, Leonard E, Platanias L. Lymphocytes and lymphokines in aplastic anemia: pathogenic role and implications for pathogenesis. Blood Cells. 1987;13(1-2):87-100.
35. Kaufman DW, Kelly JP, Jurgelon JM, Anderson T, Issaragrisil S, Wiholm BE, Young NS, Leaverton P, Levy M, Shapiro S. Drugs in the aetiology of agranulocytosis and aplastic anaemia. Eur J Haematol 1996; Suppl 60: 23-30.
36. Camitta BM, Thomas ED, Nathan DG, Santos G, Gordon-Smith EC, Gale RP, Rappeport JM, Storb R. Severe aplastic anemia: a prospective study of the effect of early marrow transplantation on acute mortality. Blood 1976; 48:63-70.
37. Solomou EE, Juang YT, Tsokos GC. Protein kinase C-theta participates in the activation of cyclic AMP-responsive element-binding protein and its subsequent binding to the -180 site of the IL-2 promoter in normal human T lymphocytes. J Immunol. 2001 May l;166(9):5665-74.
38. Caspi RR.IL-12 in autoimmunity.Clin Immunol Immunopathol. 1998 Jul;88(1):4-13.
39. Wu CY, Wang K, McDyer JF, Seder RA.Prostaglandin E2 and dexamethasone inhibit IL-12 receptor expression and IL-12 responsiveness.J Immunol. 1998 Sep 15;161(6):2723-30.
40. Wu CY, Warner RR, Carvajal DM, Chua AO, Minetti LJ, Chizzonite R, Mongini PK, Stern AS, Gubler U, Presky DH, Gately MK.Biological function and distribution of human interleukin-12 receptor beta chain.Eur J Immunol. 1996 Feb;26(2):345-50.
41. Bacigalupo A, Podesta M, Mingari MC, Moretta L, Van Lint MT, Marmont A.Immune suppression of hematopoiesis in aplastic anemia: activity of T-gamma lymphocytes.J Immunol. 1980 Oct; 125(4): 1449-53.
42. Gu Y, Zhang J, Peng J, Hu X, Xu C.Elevated expression of IL-12 and IL-23 in patients with aplastic anemia.Int J Lab Hematol. 2008.[article in press]
43. Rengarajan J, Szabo SJ, Glimcher LH. Transcriptional regulation of Thl/Th2 polarization.Immunol Today. 2000 Oct;21(10):479-83.
44. Finotto S, Glimcher L.T cell directives for transcriptional regulation in asthma.Springer Semin Immunopathol. 2004 Feb;25(3-4):281-94.
45. Hatton RD, Weaver CT.Immunology. T-bet or not T-bet. Science. 2003 Nov 7;302(5647):993-4.
46. Finotto S, Neurath MF, Glickman JN, Qin S, Lehr HA, Green FH, Ackerman K, Haley K, Galle PR, Szabo SJ, Drazen JM, De Sanctis GT, Glimcher LH.Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Science. 2002 Jan 11;295(5553):336-8.
47. Zhang DH, Cohn L, Ray P, Bottomly K, Ray A.Transcription factor GATA-3 is differentially expressed in murine Thl and Th2 cells and controls Th2-speciflc expression of the interleukin-5 gene. J Biol Chem. 1997 Aug 22;272(34):21597-603.
48. Ouyang W, Ranganath SH, Weindel K, Bhattacharya D, Murphy TL, Sha WC, Murphy KM.Inhibition of Thl development mediated by GATA-3 through an IL-4-independent mechanism. Immunity. 1998 Nov;9(5):745-55.
49. Bacon CM, McVicar DW, Ortaldo JR, Rees RC, O'Shea JJ, Johnston JA.Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL-2 and IL-12. J Exp Med. 1995 Jan 1;181(1):399-404.
50. Jacobson NG, Szabo SJ, Weber-Nordt RM, Zhong Z, Schreiber RD, Darnell JE Jr, Murphy KM.Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4. J Exp Med. 1995 May 1;181(5):1755-62.
51. Bacon CM, Petricoin EF 3rd, Ortaldo JR, Rees RC, Lamer AC, Johnston JA, O'Shea JJ.Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes. Proc Natl Acad Sci U S A. 1995 Aug l;92(16):7307-11.
52. Cho SS, Bacon CM, Sudarshan C, Rees RC, Finbloom D, Pine R, O'Shea JJ.Activation of STAT4 by IL-12 and IFN-alpha: evidence for the involvement of ligand-induced tyrosine and serine phosphorylation. J Immunol. 1996 Dec 1;157(11):4781-9.
53. Morinobu A, Gadina M, Strober W, Visconti R, Foraace A, Montagna C, Feldman GM, Nishikomori R, O'Shea JJ. STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12281-6.
2.Nakao S,Feng X,Sugimori C.Immune pathophysiology of aplastic anemia.Int J Hematol.2005;82(3):196-200
3.Risitano AM,Maciejewski JP,Green S,Plasilova M,Zeng W,Young NS.In-vivo dominant immune responses in aplastic anaemia:molecular tracking of putatively pathogenetic T-cell clones by TCR beta-CDR3 sequencing.Lancet.2004;364(9431):355-64.
4.Young NS.Immunosuppressive treatment of acquired aplastic anemia and immune-mediated bone marrow failure syndromes.Int J Hematol.2002;75(2):129-40.
5.Marsh J,Schrezenmeier H,Marin P,Ilhan O,Ljungman P,McCann S,Socie G,Tichelli A,Passweg J,Hows J,Raghavachar A,Locasciulli A,Bacigalupo A.Prospective randomized multicenter study comparing cyclosporin alone versus the combination of antithymocyte globulin and cyclosporin for treatment of patients with nonsevere aplastic anemia:a report from the European Blood and Marrow Transplant(EBMT)Severe Aplastic Anaemia Working Party.Blood.1999;93(7):2191-5.
6.龚非力主编.医学免疫学.第1版.北京:科学出版社,2000,304-5
7.Young NS,Abkowitz JL,Luzzatto L.New Insights into the Pathophysiology of Acquired Cytopenias.Hematology Am Soc Hematol Educ Program.2000:18-38
8.申蓉,徐从高,李丽珍,张锑,秦雪梅,李杰,赵川莉.再生障碍性贫血患者T淋巴细胞早期激活及可溶性肿瘤坏死因子受体的研究冲华血液学杂志,2004,25(4):209-12
9.Kanchan K,Loughran TP Jr.Antigen-driven clonal T cell expansion in disorders of hematopoiesis.Leuk Res.2003;27(4):305-12.
10.Lanzavecchia A,Sallusto F.Regulation of T cell immunity by dendritic cells.Cell.2001;106(3):263-6.
11.Garza KM,Chan SM,Suri R,Nguyen LT,Odermatt B,Schoenberger SP,Ohashi PS.Role of antigen-presenting cells in mediating tolerance and autoimmunity.J Exp Med.2000;191(11):2021-7.
12.何广胜,邵宗鸿,和虹,刘鸿,付蓉,白洁,施均,曹燕然,涂梅峰,孙娟,贾海荣.重型再 生障碍性贫血患者骨髓Ⅰ型树突细胞亚群的变化.中华血液学杂志,2004,25(11):649-52.
13.Zeng W,Kajigaya S,Chen G,Risitano AM,Nunez O,Young NS.Transcript profile of CD4+ and CD8+ T cells from the bone marrow of acquired aplastic anemia patients.Exp Hematol.2004;32(9):806-14.
14.Hara T,Ando K,Tsurumi H,Moriwaki H.Excessive production of tumor necrosis factor-alpha by bone marrow T lymphocytes is essential in causing bone marrow failure in patients with aplastic anemia.Eur J Haematol.2004;73(1):10-6.
15.Giannakoulas NC,Karakantza M,Theodorou GL,Pagoni M,Galanopoulos A,Kakagianni T,Kouraklis-Symeonidis A,Matsouka P,Maniatis A,Zoumbos NC.Clinical relevance of balance between type 1 and type 2 immune responses of lymphocyte subpopulations in aplastic anaemia patients.Br J Haematol.2004;124(1):97-105.
16.和虹,邵宗鸿,何广胜,刘鸿,施均,付蓉,赵明峰,白洁,贾海蓉,孙娟,崔振珠,储榆林,杨天楹,杨崇礼.Th1细胞在再生障碍性贫血发病机制中的作用.中华血液学杂志,2002,23(11):574-7.
17.Monney L,Sabatos CA,Gaglia JL,Ryu A,Waldner H,Chernova T,Manning S,Greenfield EA,Coyle AJ,Sobel RA,Freeman GJ,Kuchroo VK.Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease.Nature.2002;415(6871):536-41.
18.Sachez-Fueyo A,Tian J,Picarella D,Domenig C,Zheng XX,Sabatos CA,Manlongat N,Bender O,Kamradt T,Kuchroo VK,Gutierrez-Ramos JC,Coyle AJ,Strom TB.Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance.Nat Immunol.2003;4(11):1093-101.
19.Anderson AC,Anderson DE,Bregoli L,Hastings WD,Kassam N,Lei C,Chandwaskar R,Karman J,Su EW,Hirashima M,Brace JN,Kane LP,Kuchroo VK,Hafler DA.Promotion of tissue infiammation by the immune receptor Tim-3 expressed on innate immune cells.Science.2007;318(5853):1141-3.
20.Zhu C,Anderson AC,Schubart A,Xiong H,Imitola J,Khoury SJ,Zheng XX,Strom TB,Kuchroo VK.The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity.Nat Immunol.2005;6(12):1245-52.
21.Gately MK,Renzetti LM,Magram J,Stem AS,Adorini L,Gubler U,Presky DH.The interleukin-12/interleukin-12-receptor system:role in normal and pathologic immune responses.Annu Rev Immunol.1998;16:495-521.
22.张宁,徐永健,张珍祥.辅助性T细胞功能分化的分子机制.国外医学呼吸系统分册,2003,23(2):57-61
23.任翠爱,张茂宏,徐从高,张锑.再生障碍性贫血患者血浆IL-12水平的检测及临床意义.上海免疫学杂志,2000,20(4):252
24.孙晗笑,杨滨燕,李波,娄阁,吴长有.内源性IL-12决定人PBMCs产生干扰素γ的水平.中国免疫学杂志,2002,18(4):228-32
25.范艳莹,吴长有.Th2细胞因子和抗IL-12Rβ1mAb抑制由IL-23诱导PBMC IFN-γ的产生.中国免疫学杂志.2006,22(3):195-9
1.Monney L,Sabatos CA,Gaglia JL,Ryu A,Waldner H,Chemova T,Manning S,Greenfield EA,Coyle AJ,Sobel RA,Freeman GJ,Kuchroo VK.Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease.Nature.2002;415(6871):536-41.
2.Khademi M,Illes Z,Gielen AW,Marta M,Takazawa N,Baecher-Allan C,Brundin L,Hannerz J,Martin C,Harris RA,Hafler DA,Kuchroo VK,Olsson T,Piehl F,Wallstrom E.T Cell Ig- and mucin-domain-containing molecule-3(TIM-3)and TIM-1 molecules are differentially expressed on human Th1 and Th2 cells and in cerebrospinal fluid-derived mononuclear cells in multiple sclerosis.J Immunol.2004;172(11):7169-76.
3.Gielen AW,Lobell A,Lidman O,Khademi M,Olsson T,Piehl F.Expression of T cell immunoglobulin-and mucin-domain-containing molecules-1 and -3(TIM-1and -3)in the rat nervous and immune systems.J Neuroimmunol.2005;164(1-2):93-104.
4.Sanchez-Fueyo A,Tian J,Picarella D,Domenig C,Zheng XX,Sabatos CA,Manlongat N,Bender O,Kamradt T,Kuchroo VK,Gutierrez-Ramos JC,Coyle AJ,Strom TB.Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance.Nat Immunol.2003;4(11):1093-101.
5.Renesto PG,Ponciano VC,Cenedeze MA,Saraiva Camara NO,Pacheco-Silva A.High expression of Tim-3 mRNA in urinary cells from kidney transplant recipients with acute rejection.Am J Transplant.2007;7(6):1661-5.
6.黄金波,崔天盆,王琳,陈凤花,时杰,胡丽华.再生障碍性贫血患者Tim-3、IFN-γ及IL-4 mRNA的表达及其临床意义.中华血液学杂志,2006,27(12):813-6
7.张之南,沈悌,主编.血液病诊断及疗效标准.第2版.北京:科学出版社,1998.33-35.
8.Mosmann TR,Cherwinski H,Bond MW,Giedlin MA,Coffman RL.Two types of murine helper T cell clone.I.Definition according to profiles of lymphokine activities and secreted proteins.J Immunol.1986;136(7):2348-57.
9.Romagnani S.Human TH1 and TH2 subsets:doubt no more.Immunol Today.1991;12(8):256-7
10.Kamradt T,Mitchison NA.Tolerance and autoimmunity.N Engl J Med.2001;344(9):655-64.
11.Lanzavecchia A,Sallusto F.Regulation of T cell immunity by dendritic cells.Cell.2001;106(3):263-6.
12.Garza KM,Chan SM,Suri R,Nguyen LT,Odermatt B,Schoenberger SP,Ohashi PS Role of antigen-presenting cells in mediating tolerance and autoimmunity.J Exp Med.2000;191(11):2021-7.
13.何广胜,邵宗鸿,和虹,刘鸿,付蓉,白洁,施均,曹燕然,涂梅峰,孙娟,贾海荣.重型再生障碍性贫血患者骨髓I型树突细胞亚群的变化.中华血液学杂志.2004,25(11):649-52
14.傅晋翔.张勇.树突状细胞在再生障碍性贫血发病中的变化.中华微生物学和免疫学杂志.2007,27(5):473
15.唐晓文,邵景章,张学光,张毅,李建,郑列琳,谢炜,王爱青.再生障碍性贫血患者外周血T细胞亚群检测.中华血液学杂志,1997,18(4):205-6
16.王欣,张明珙,宋素琴,李杰,郭承山,宋强,赵川莉,王惠军,彭军,秦平.再生障碍性贫血患者细胞免疫功能与造血细胞因子的研究.中华血液学杂志,1998,19(4).181-3
17.Mentzel U,Vogt H,Rossol R,Geissler RG,Maurer A,Ganser A,Trommer WE,Hoelzer D.Analysis of lymphocyte subsets in patients with aplastic anemia before and during immunosuppressive therapy.Ann Hematol.1993;66(3):127-9.
18.Nistico A,Young NS.Gamma-Interferon gene expression in the bone marrow of patients with aplastic anemia.Ann Intern Med.1994;120(6):463-9.
19.Tsuda H,Yamasaki H.Type Ⅰ and type Ⅱ T-cell profiles in aplastic anemia and refractory anemia.Am J Hematol.2000;64(4):271-4.
20.Kook H,Zeng W,Guibin C,Kirby M,Young NS,Maciejewski JP.Increased cytotoxie T cells with effector phenotype in aplastic anemia and myelodysplasia.Exp Hematol.2001;29(11):1270-7.
21.Giannakoulas NC,Karakantza M,Theodorou GL,Pagoni M,Galanopoulos A,Kakagianni T,Kouraklis-Symeonidis A,Matsouka P,Maniatis A,Zoumbos NC.Clinical relevance of balance between type 1 and type 2 immune responses of lymphocyte subpopulations in aplastic anaemia patients.Br J Haematol.2004;124(1):97-105.
22.涂梅峰,邵宗鸿.淋巴细胞功能亢进与造血组织损伤,中华血液学杂志,2004,25(4):243-6
23.Zeng W,Kajigaya S,Chen G,Risitano AM,Nunez O,Young NS.Transcript profile of CD4+ and CD8+ T cells from the bone marrow of acquired aplastic anemia patients.Exp Hematol 2004;32:806-14
24.Sloand E,Kim S,Maciejewski JP,Tisdale J,Follmann D,Young NS.Intracellular interferon-gamma in circulating and marrow T cells detected by flow cytometry and the response to immunosuppressive therapy in patients with aplastic anemia.Blood.2002;100(4):1185-91.
25.Laver J,Castro-Malaspina H,Keman NA,Levick J,Evans RL,O'Reilly RJ,Moore MA.In vitro interferon-gamma production by cultured T-cells in severe aplastic anaemia:correlation with granulomonopoietic inhibition in patients who respond to anti-thymocyte globulin.Br J Haematol.1988;69(4):545-50.
26.Maciejewski JP,Hibbs JR,Anderson S,Katevas P,Young NS.Bone marrow and peripheral blood lymphocyte phenotype in patients with bone marrow failure.Exp Hematol.1994;22(11):1102-10.
27.Young NS.Pathophysiologic mechanisms in acquired aplastic anemia.Hematology Am Soc Hematol Educ Program.2006;72-7.
28.何广胜,邵宗鸿,和虹,刘鸿,白洁,施均,曹燕然,涂梅峰,孙娟,贾海蓉,杨崇礼.重型 再生障碍性贫血患者骨髓中辅助性T细胞亚群数量及功能的变化.中华血液学杂志,2004,25(10):613-6
29.Killick SB,Cox CV,Marsh JC,Gordon-Smith EC,Gibson FM.Mechanisms of bone marrow progenitor cell apoptosis in aplastic anaemia and the effect of anti-thymocyte globulin:examination of the role of the Fas-Fas-L interaction.Br J Haematol.2000;111(4):1164-9.
30.Maciejewski JP,Risitano A.Hematopoietic stem cells in aplastic anemia.Arch Med Res.2003;34(6):520-7.
31.张勇,傅晋翔.T淋巴细胞异常活化与再生障碍性贫血.江苏医药,2006,32(1):64-5
32.和虹,邵宗鸿,何广胜,刘鸿,施均,付蓉,赵明峰,白洁,贾海蓉,孙娟,崔振珠,储榆林,杨天楹,杨崇礼.Th1细胞在再生障碍性贫血发病机制中的作用.中华血液学杂志,2002,23:574-7.
33.Liblau RS,Singer SM,McDevitt HO.Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases.Immunol Today.1995;16(1):34-8.
34.Young NS.Hematopoietic cell destruction by immune mechanisms in acquired aplastic anemia.Semin Hematol.2000;37(1):3-14.
35.Ghayur T,Banerjee S,Hugunin M,Butler D,Herzog L,Carter A,Quintal L,Sekut L,Talanian R,Paskind M,Wong W,Kamen R,Tracey D,Allen H.Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production.Nature.1997;386(6625):619-23.
36.Gu Y,Kuida K,Tsutsui H,Ku G,Hsiao K,Fleming MA,Hayashi N,Higashino K,Okamura H,Nakanishi K,Kurimoto M,Tanimoto T,Flavell RA,Sato V,Harding MW,Livingston DJ,Su MS.Activation of interferon-gamma inducing factor mediated by interleukin-lbeta converting enzyme.Science.1997;275(5297):206-9.
37.Gracie JA,Robertson SE,Mclnnes IB.Interleukin-18.J Leukoc Biol.2003;73(2): 213-24.
38.Thomassen E,Bird TA,Renshaw BR,Kennedy MK,Sims JE.Binding of interleukin-18 to the interleukin-1 receptor homologous receptor IL-1Rrp1 leads to activation of signaling pathways similar to those used by interleukin-1.J Interferon Cytokine Res.1998;18(12):1077-88.
39.Furuya D,Yagihashi A,Yajima T,Kobayashi D,Orita K,Kurimoto M,Watanabe N.An immuno-polymerase chain reaction assay for human interleukin-18.J Immunol Methods.2000;238(1-2):173-80.
40.Kohno K,Kataoka J,Ohtsuki T,Suemoto Y,Okamoto I,Usui M,Ikeda M,Kurimoto M.IFN-gamma-inducing factor(IGIF)is a costimulatory factor on the activation of Th1 but not Th2 cells and exerts its effect independently of IL-12.J Immunol.1997;158(4):1541-50.
41.Yoshimoto T,Okamura H,Tagawa YI,Iwakura Y,Nakanishi K.Interleukin 18together with interleukin 12 inhibits IgE production by induction of interferon-gamma production from activated B cells.Proc Natl Acad Sci U S A.1997;94(8):3948-53.
42.Tomura M,Zhou XY,Maruo S,Ahn HJ,Hamaoka T,Okamura H,Nakanishi K,Tanimoto T,Kurimoto M,Fujiwara H.A critical role for IL-18 in the proliferation and activation of NK1.1+CD3-cells.J Immunol.1998;160(10):4738-46.
43.Tsutsui H,Nakanishi K,Matsui K,Higashino K,Okamura H,Miyazawa Y,Kaneda K.IFN-gamma-inducing factor up-regulates Fas ligand-mediated cytotoxic activity of murine natural killer cell clones.J Immunol.1996;157(9):3967-73.
44.Dao T,Ohashi K,Kayano T,Kurimoto M,Okamura H.Interferon-gamma-inducing factor,a novel cytokine,enhances Fas ligand-mediated cytotoxicity of murine T helper 1 cells.Cell Immunol.1996;173(2):230-5.
45.Ohtsuki T,MicaUef MJ,Kohno K,Tanimoto T,Ikeda M,Kurimoto M.Interleuldn 18 enhances Fas ligand expression and induces apoptosis in Fas-expressing human myelomonocytic KG-1 cells.Anticancer Res.1997;17(5A):3253-8.
46.Kayagaki N,Yamaguchi N,Nakayama M,Kawasaki A,Akiba H,Okumura K,Yagita H.Involvement of TNF-related apoptosis-inducing ligand in human CD4+T cell-mediated cytotoxicity.J Immunol.1999;162(5):2639-47.
47.Hyodo Y,Matsui K,Hayashi N,Tsutsui H,Kashiwamura S,Yamauchi H,Hiroishi K,Takeda K,Tagawa Y,Iwakura Y,Kayagaki N,Kurimoto M,Okamura H,Hada T,Yagita H,Akira S,Nakanishi K,Higashino K.IL-18 up-regulates perforin-mediated NK activity without increasing perforin messenger RNA expression by binding to constitutively expressed IL-18 receptor.J Immunol.1999;162(3):1662-8.
48.Kohka H,Yoshino T,Iwagaki H,Sakuma I,Tanimoto T,Matsuo Y,Kurimoto M,Orita K,Akagi T,Tanaka N.Interleukin-18/interferon-gamma-inducing factor,a novel cytokine,up-regulates ICAM-1(CD54)expression in KG-1 cells.J Leukoc Biol.1998;64(4):519-27.
49.高立芬.IL-18与免疫相关性疾病.国外医学免疫学分册.2001,24(3):165-8
50.Oppmann B,Lesley R,Blom B,Timans JC,Xu Y,Hunte B,Vega F,Yu N,Wang J,Singh K,Zonin F,Vaisberg E,Churakova T,Liu M,Gorman D,Wagner J,Zurawski S,Liu Y,Abrams JS,Moore KW,Rennick D,de Waal-Malefyt R,Hannum C,Bazan JF,Kastelein RA.Novel p19 protein engages IL-12p40 to form a cytokine,IL-23,with biological activities similar as well as distinct from IL-12.Immunity.2000;13(5):715-25.
51.Morelli AE,Zahorchak AF,Larregina AT,Colvin BL,Logar AJ,Takayama T,Falo LD,Thomson AW.Cytokine production by mouse myeloid dendritic cells in relation to differentiation and terminal maturation induced by lipopolysaccharide or CD40 ligation.Blood.2001;98(5):1512-23.
52.Frucht DM.IL-23:a cytokine that acts on memory T cells.Sci STKE.2002;2002(114):PE1.
53. Brombacher F, Kastelein RA, Alber G. Novel IL-12 family members shed light on the orchestration of Th1 responses. Trends Immunol. 2003;24(4):207-12.
54. Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B, Kleinschek MA, Owyang A, Mattson J, Blumenschein W, Murphy E, Sathe M, Cua DJ, Kastelein RA, Rennick D.IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006; 116(5): 1310-6.
55. Lankford CS, Frucht DM. A unique role for IL-23 in promoting cellular immunity.J Leukoc Biol. 2003; 73(1): 49-56.
56. Vaknin-Dembinsky A, Balashov K, Weiner HL.IL-23 is increased in dendritic cells in multiple sclerosis and down-regulation of IL-23 by antisense oligos increases dendritic cell IL-10 production. J Immunol. 2006;176(12):7768-74.
57. Belladonna ML, Renauld JC, Bianchi R, Vacca C, Fallarino F, Orabona C, Fioretti MC, Grohmann U, Puccetti P.IL-23 and IL-12 have overlapping, but distinct, effects on murine dendritic cells. J Immunol. 2002; 168(11 ):5448-54.
58. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD.Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421(6924):744-8.
59. Sugihara A, Okamoto H, Horio T. Effects of UVB on fascin expression in dendritic cells and Langerhans cells.J Dermatol Sci. 2005;40(3): 177-85.
60. Chen Z, Laurence A, Kanno Y, Pacher-Zavisin M, Zhu BM, Tato C, Yoshimura A, Hennighausen L, O'Shea JJ.Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc Natl Acad Sci U S A. 2006; 103(21): 8137-42.
61. Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, O'Shea JJ.Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol Rev. 2004; 202:139-56.
62. Kolls JK, Linden A.Interleukin-17 family members and inflammation. Immunity. 2004;21(4):467-76.
63. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ.IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201(2):233-40.
64. Gosset P, Tillie-Leblond I, Oudin S, Parmentier O, Wallaert B, Joseph M, Tonnel AB.Production of chemokines and proinflammatory and antiinflammatory cytokines by human alveolar macrophages activated by IgE receptors. J Allergy Clin Immunol. 1999; 103(2 Pt 1):289-97.
65. Stark MA, Huo Y, Burcin TL, Morris MA, Olson TS, Ley K.Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity. 2005; 22(3):285-94.
66. Yao Z, Spriggs MK, Derry JM, Strockbine L, Park LS, VandenBos T, Zappone JD, Painter SL, Armitage RJ. Molecular characterization of the human interleukin (IL)-17 receptor. Cytokine. 1997;9(11):794-800.
67. Molet S, Hamid Q, Davoine F, Nutku E, Taha R, Page N, Olivenstein R, Elias J, Chakir J.IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J Allergy Clin Immunol. 2001 ;108(3):430-8.
68. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C.A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6(11):1133-41.
69. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK.Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441(7090):235-8.
70. Moseley TA, Haudenschild DR, Rose L, Reddi AH. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev. 2003;14(2):155-74.
71. Nielsen OH, Kirman I, Rudiger N, Hendel J, Vainer B. Upregulation of interleukin-12 and -17 in active inflammatory bowel disease. Scand J Gastroenterol;2003;38(2):180-5
72.Komiyama Y,Nakae S,Matsuki T,Nambu A,Ishigame H,Kakuta S,Sudo K,Iwakura Y.IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis.J Immunol.2006;177(1):566-73.
73.Koenders MI,Lubberts E,van de Loo FA,Oppers-Walgreen B,van den Bersselaar L,Helsen MM,Kolls JK,Di Padova FE,Joosten LA,van den Berg WB.Interleukin-17 acts independently of TNF-alpha under arthritic conditions.2006;176(10):6262-9.
74.张鲁勤,葛晋源,郭玉琳,赵惠仁.再生障碍性贫血患者血浆细胞因子的测定.中华血液学杂志,2001,22(12):661-2
75.张岩,汪奇伟,何书.T细胞亚群及细胞因子网络与小儿再生障碍性贫血的相关性.中国综合临床,2006,22(2):138-9
76.Bonecchi R,Bianchi G,Bordignon PP,D'Ambrosio D,Lang R,Borsatti A,Sozzani S,Allavena P,Gray PA,Mantovani A,Sinigaglia F Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells(Thls)and Th2s.J Exp Med.1998;187(1):129-34..
77.Mclntire JJ,Umetsu SE,Akbari O,Potter M,Kuchroo VK,Barsh GS,Freeman GJ,Umetsu DT,DeKruyff RH.Identification of Tapr(an airway hyperreactivity regulatory locus)and the linked Tim gene family.Nat Immunol.2001;2(12):1109-16.
78.Kuchroo VK,Umetsu DT,DeKruyff RH,Freeman GJ.The TIM gene family:emerging roles in immunity and disease.Nat Rev Immunol.2003;3(6):454-62.
79.Mariat C,Sanchez-Fueyo A,Alexopoulos SP,Kenny J,Strom TB,Zheng XX.Regulation of T cell dependent immune responses by TIM family members.Philos Trans R Soc Lond B Biol Sci.2005;360(1461):1681-5.
80.Sui L,Zhang W,Chen Y,Zheng Y,Wan T,Zhang W,Yang Y,Fang G,Mao J,Cao X.Human membrane protein Tim-3 facilitates hepatitis A virus entry into target cells.Int J Mol Med.2006;17(6):1093-9.
81.Oaks MK,Hallett KM,Penwell RT,Stauber EC,Warren SJ,Tector AJ.A native soluble form of CTLA-4.Cell Immunol.2000;201(2):144-53.
82.Sabatos CA,Chakravarti S,Cha E,Schubart A,Sanchez-Fueyo A,Zheng XX,Coyle AJ,Strom TB,Freeman GJ,Kuchroo VK.Interaction of Tim-3 and Tim-3ligand regulates T helper type 1 responses and induction of peripheral tolerance.Nat Immunol.2003;4(11):1102-10.
83.Geng H,Zhang GM,Li D,Zhang H,Yuan Y,Zhu HG,Xiao H,Han LF,Feng ZH.Soluble form of T cell Ig mucin 3 is an inhibitory molecule in T cell-mediated immune response.J Immunol.2006;176(3):1411-20.
84.张胜桃,刘晓军,金霞,何培根,龚非力,杨东亮.TIM-3 mRNA在外周血单个核细胞不同细胞亚群及活化的T细胞上的表达.中华微生物学和免疫学杂志2006,26(5):442-5
85.Oikawa T,Kamimura Y,Akiba H,Yagita H,Okumura K,Takahashi H,Zeniya M,Tajiri H,Azuma M.Preferential involvement of Tim-3 in the regulation of hepatic CD8+ T cells in murine acute graft-versus-host disease.J lmmunol.2006;177(7):4281-7.
86.Wang F,He W,Zhou H,Yuan J,Wu K,Xu L,Chen ZK.The Tim-3 ligand galectin-9 negatively regulates CD8+ alloreactive T cell and prolongs survival of skin graft.Cell Immunol.2007;250(1-2):68-74.
87.Wang F,He W,Yuan J,Wu K,Zhou H,Zhang W,Chen ZK.Activation of Tim-3-Galectin-9 pathway improves survival of fully allogeneic skin grafts.Transpl Immunol.2008;19(1):12-9.
88.Chae SC,Park YR,Shim SC,Yoon KS,Chung HT.The polymorphisms of Th1cell surface gene Tim-3 are associated in a Korean population with rheumatoid arthritis.Immunol Lett.2004;95(1):91-5.
89.李际盛,刘奇迹,王频,李怀臣,魏春华,郭辰虹,龚瑶琴.中国山东汉族人群TIM-3基因启动子区域两单核苷酸多态与支气管哮喘的相关性。山东大学学报(医学版),2006,44(11):1159-63
90.张才成,吴健民,崔天盆,王平,潘世秀.湖北汉族人群TIM-3基因多态性与变应性哮喘的相关性.中华医学遗传学杂志.2006,23(1):74-7
91.张胜桃,刘晓军,何培根,雷小妹,李守新,胡绍先,龚非力,杨东亮.类风湿关节炎患者外周血CD4+T细胞TIM-3 mRNA的表达.中华风湿病学杂志.2006,10(1):30-2
92.Koguchi K,Anderson DE,Yang L,O'Connor KC,Kuchroo VK,Hafler DA.Dysregulated T cell expression of TIM3 in multiple sclerosis.J Exp Med.2006;203(6):1413-8.
93.Ponciano VC,Renesto PG,Nogueira E,Rangel EB,Cenedeze MA,Franco MF,Camara NO,Pacheco-Silva A.Tim-3 expression in human kidney allografts.Transpl Immunol.2007;17(3):215-22.
94.Zhu C,Anderson AC,Schubart A,Xiong H,Imitola J,Khoury SJ,Zheng XX,Strom TB,Kuchroo VK.The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity.Nat Immunol.2005;6(12):1245-52.
95.Asakura H,Kashio Y,Nakamura K,Seki M,Dai S,Shirato Y,Abedin MJ,Yoshida N,Nishi N,Imaizumi T,Saita N,Toyama Y,Takashima H,Nakamura T,Ohkawa M,Hirashima M.Selective eosinophil adhesion to fibroblast via IFN-gamma-induced galectin-9.J Immunol.2002;169(10):5912-8.
96.Dai SY,Nakagawa R,Itoh A,Murakami H,Kashio Y,Abe H,Katoh S,Kontani K,Kihara M,Zhang SL,Hata T,Nakamura T,Yamauchi A,Hirashima M.Galectin-9induces maturation of human monocyte-derived dendritic cells.J Immunol.2005;175(5):2974-81.
97.Anderson AC,Anderson DE,Bregoli L,Hastings WD,Kassam N,Lei C,Chandwaskar R,Karman J,Su EW,Hirashima M,Bruce JN,Kane LP,Kuchroo VK,Hafler DA.Promotion of tissue inflammation by the immune receptor Tim-3expressed on innate immune cells.Science.2007;318(5853):1141-3.
98.Hirashima M,Kashio Y,Nishi N,Yamauchi A,Imaizumi TA,Kageshita T,Saita N,Nakamura T.Galectin-9 in physiological and pathological conditions. Glycoconj J. 2004;19(7-9):593-600.
99. Kashio Y, Nakamura K, Abedin MJ, Seki M, Nishi N, Yoshida N, Nakamura T, Hirashima M. Galectin-9 induces apoptosis through the calcium-calpain-caspase-1 pathway. J Immunol. 2003;170(7):3631-6.
100.Wang Y, Meng J, Wang X, Liu S, Shu Q, Gao L, Ju Y, Zhang L, Sun W, Ma C.Expression of human TIM-1 and TIM-3 on lymphocytes from systemic lupus erythematosus patients. Scand J Immunol. 2008;67(1):63-70.
101.Dabbagh K, Lewis DB.Toll-like receptors and T-helper-1/T-helper-2 responses. Curr Opin Infect Dis.2003; 16(3): 199-204
102.Zeng W, Maciejewski JP, Chen G, Risitano AM, Kirby M, Kajigaya S, Young NS.Selective reduction of natural killer T cells in the bone marrow of aplastic anaemia. Br J Haematol.2002; 119(3): 803-9.
103.Selleri C, Sato T, Anderson S, Young NS, Maciejewski JP. Interferon-γ and tumor necrosis factor-alpha suppress both early and late stages of hematopoiesis and induce programmed cell death. J Cell Physiol.1995; 165(3): 538-46.
104.Philpott NJ, Scopes J, Marsh JC, Gordon-Smith EC, Gibson FM. Increased apoptosis in aplastic anemia bone marrow progenitor cells: possible pathophysiologic significance. Exp Hematol.1995; 23(14): 1642-8.
105.Maciejewski JP, Selleri C, Sato T, Anderson S, Young NS. Increased expression of Fas antigen on bone marrow CD34+ cells of patients with aplastic anaemia. Br J Haematol 1995; 91(1): 245-52.
106.Anderson AC, Anderson DE. TIM-3 in autoimmunity.Curr Opin Immunol. 2006; 18(6):665-9.
107.Frisancho-Kiss S, Nyland JF, Davis SE, Barrett MA, Gatewood SJ, Njoku DB, Cihakova D, Silbergeld EK, Rose NR, Fairweather D.Cutting edge: T cell Ig mucin-3 reduces inflammatory heart disease by increasing CTLA-4 during innate immunity. J Immunol. 2006; 176(11):6411-5.
108.Frisancho-Kiss S, Davis SE, Nyland JF, Frisancho JA, Cihakova D, Barrett MA, Rose NR,Fairweather D.Cutting edge:cross-regulation by TLR4 and T cell Ig mucin-3 determines sex differences in inflammatory heart disease.J Immunol.2007;178(11):6710-4.
109.隋潇徽,徐从高,李丽珍,张锑,于媛,彭军.CTLA-4Ig抑制再生障碍性贫血患者T淋巴细胞增殖及活化作用的体外研究.山东大学学报(医学版),2006,44(5):485-8
110.Roncarolo MG,Levings MK.The role of different subsets of T regulatory cells in controlling autoimmunity.Curr Opin Immunol.2000;12(6):676-83.
111.Shevach EM,McHugh RS,Piccirillo CA,Thornton AM.Control of T-cell activation by CD4+ CD25+ suppressor T cells.Immunol Rev.2001;182:58-67.
112.Sakaguchi S,Sakaguchi N,Asano M,Itoh M,Toda M.Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains(CD25).Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.J Immunol.1995;155(3):1151-64.
113.Hori S,Nomura T,Sakaguchi S.Control of regulatory T cell development by the transcription factor Foxp3.Science.2003;299(5609):1057-61.
114.Carrier Y,Yuan J,Kuchroo VK,Weiner HL.Th3 cells in peripheral tolerance.I.Induction of Foxp3-positive regulatory T cells by Th3 cells derived from TGF-beta T cell-transgenic mice.J Immunol.2007;178(1):179-85.
115.Shevach EM.Certified professionals:CD4(+)CD25(+)suppressor T cells.J Exp Med.2001;193(11):F41-6.
116.Paust S,Lu L,McCarty N,Cantor H.Engagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease.Proc Natl Acad Sci U S A.2004;101(28):10398-403.
117.Yagi H,Nomura T,Nakamura K,Yamazaki S,Kitawaki T,Hori S,Maeda M,Onodera M,Uchiyama T,Fujii S,Sakaguchi S.Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells.Int Immunol.2004;16(11):1643-56.
118.Khattri R,Kasprowicz D,Cox T,Mortrud M,Appleby MW,Brunkow ME,Ziegler SF,Ramsdell F.The amount of scurfin protein determines peripheral T cell number and responsiveness.J Immunol.2001;167(11):6312-20.
119.Kasprowicz DJ,Smallwood PS,Tyznik AJ,Ziegler SF.Scurfin(FoxP3)controls T-dependent immune responses in vivo through regulation of CD4+ T cell effector function.J Immunol.2003;171(3):1216-23.
120.Khattri R,Cox T,Yasayko SA,Ramsdell F.An essential role for Scurfin in CD4+CD25+ T regulatory cells.Nat Immunol.2003;4(4):337-42.
121.Fontenot JD,Gavin MA,Rudensky AY.Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.Nat Immunol.2003;4(4):330-6.
122.杨军,李成荣,祖莹,王国兵,李永柏.调节性T细胞在儿童过敏性紫癜发病机制中的作用初探.中华儿科杂志,2006,44(6):411-4
123.Mottonen M,Heikkinen J,Mustonen L,Isomaki P,Luukkainen R,Lassila O.CD4+ CD25+ T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis.Clin Exp Immunol.2005;140(2):360-7.
124.祖莹,李成荣,郑跃杰,邓继岿,付晓玲.CD4+CD25+调节性T细胞在儿童哮喘发病机制中的作用初探.中华医学杂志.2006,86(1):35-8
125.Lindley S,Dayan CM,Bishop A,Roep BO,Peakman M,Tree TI.Defective suppressor function in CD4(+)CD25(+)T-cells from patients with type 1diabetes.Diabetes.2005;54(1):92-9.
126.Viglietta V,Baecher-Allan C,Weiner HL,Hafler DA.Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis.J Exp Med.2004;199(7):971-9.
127.Suto A,Nakajima H,Kagami SI,Suzuki K,Saito Y,Iwamoto I.Role of CD4(+)CD25(+)regulatory T cells in T helper 2 cell-mediated allergic inflammation in the airways.Am J Respir Crit Care Med.2001;164(4):680-7.
128.Shi HZ,Qin XJ.CD4CD25 regulatory T lymphocytes in allergy and asthma.Allergy. 2005;60(8):986-95.
129.Solomou EE, Rezvani K, Mielke S, Malide D, Keyvanfar K, Visconte V, Kajigaya S, Barrett AJ, Young NS.Deficient CD4+ CD25+ FOXP3+ T regulatory cells in acquired aplastic anemia.Blood. 2007; 110(5): 1603-6.
1.Tsuda H,Yamasaki H.Type Ⅰ and type Ⅱ T-cell profiles in aplastic anemia and refractory anemia.Am J Hematol.2000;64(4):271-4.
2.Sloand E,Kim S,Maciejewski JP,Tisdale J,Follmann D,Young NS.Intracellular interferon-gamma in circulating and marrow T cells detected by flow cytometry and the response to immunosuppressive therapy in patients with aplastic anemia.Blood.2002;100(4):1185-91.
3.Murphy KM,Reiner SL.The lineage decisions of helper T cells.Nat Rev Immunol.2002;2(12):933-44.
4.Leonard WJ,O'Shea JJ.Jaks and STATs:biological implications.Annu Rev Immunol.1998;16:293-322.
5.Darnell JE Jr.STATs and gene regulation.Science.1997;277(5332):1630-5.
6.Farrar JD,Asnagli H,Murphy KM.T helper subset development:roles of instruction,selection,and transcription.J Clin Invest.2002;109(4):431-5.
7.Szabo SJ,Kim ST,Costa GL,Zhang X,Fathman CG,Glimcher LH.A novel transcription factor,T-bet,directs Th1 lineage commitment.Cell.2000;100(6):655-69.
8.张之南,沈悌,主编.血液病诊断及疗效标准.第2版.北京:科学出版社,1998.33-35.
9.Nakao S.Immune mechanism of aplastic anemia.Int J Hematol.1997;66(2):127-34.
10.Selleri C,Maciejewski JP,Sato T,Young NS.Interferon-gamma constitutively expressed in the stromal microenvironment of human marrow cultures mediates potent hematopoietic inhibition.Blood.1996;87(10):4149-57.
11.Shao Z,Chu Y,Zhang Y,Chen G,Zheng Y.Treatment of severe aplastic anemia with an immunosuppressive agent plus recombinant human granulocyte-macrophage colony-stimulating factor and erythropoietin.Am J Hematol.1998;59(3):185-91.
12.何广胜,邵宗鸿,张益枝,刘鸿,李克,宋鲁燕,郑以洲,陈桂彬,和虹,赵明峰,施均,张泓,储榆林,钱林生,杨天楹.序贯强化免疫抑制并用造血生长因子治疗重型再生障碍性贫血.中华血液学杂志.2001,22(4):176-81.
13.和虹,邵宗鸿.再生障碍性贫血T淋巴细胞研究进展.中华血液学杂志,1999,20(10):553-5.
14.王欣,张明珙,宋素琴,李杰,郭承山,宋强,赵川莉,王惠军,彭军,秦平.再生障碍性贫血患者细胞免疫功能与造血细胞因子的研究.中华血液学杂志,1998,19(4).181-3
15.黄云鹏,张伟华,张秀莲,范星火,李殿青.再生障碍性贫血患者外周血T细胞亚群及Th1/Th2细胞分析.山西医科大学学报,2005,36(4):443-5
16.唐晓文,邵景章,张学光,张毅,李建,郑列琳,谢炜,王爱青.再生障碍性贫血患者外周血T细胞亚群检测.中华血液学杂志,1997,18(4):205-6
17.Young NS.Hematopoietic cell destruction by immune mechanisms in acquired aplastic anemia.Semin Hematol.2000;37(1):3-14.
18.和虹,邵宗鸿,何广胜,刘鸿,施均,付蓉,赵明峰,白洁,贾海蓉,孙娟,崔振珠,储榆林,杨天楹,杨崇礼。Th1细胞在再生障碍性贫血发病机制中的作用.中华血液学杂志.2002,23(11):574-7
19.Hsu HC,Tsai WH,Chen LY,Hsu ML,Ho CH,Lin CK,Wang SY.Overpmduction of inhibitory hematopoietic cytokines by lipopolysaccharide-activated peripheral blood mononuclear cells in patients with aplastic anemia.Ann Hematol.1995;71(6):281-6
20.Laver J,Castro-Malaspina H,Kernan NA,Levick J,Evans RL,O'Reilly RJ,Moore MA.In vitro interferon-gamma production by cultured T-cells in severe aplastic anaemia:correlation with granulomonopoietic inhibition in patients who respond to anti-thymocyte globulin.Br J Haematol.1988;69(4):545-50.
21.Killick SB,Cox CV,Marsh JC,Gordon-Smith EC,Gibson FM.Mechanisms of bone marrow progenitor cell apoptosis in aplastic anaemia and the effect of anti-thymocyte globulin:examination of the role of the Fas-Fas-L interaction.Br J Haematol.2000;111(4):1164-9.
22.Maciejewski JP,Selleri C,Sato T,Anderson S,Young NS.Increased expression of Fas antigen on bone marrow CD34+ cells of patients with aplastic anaemia.Br J Haematol.1995;91(1):245-52.
23.Scopes J,Bagnara M,Gordon-Smith EC,Ball SE,Gibson FM.Haemopoietic progenitor cells are reduced in aplastic anaemia.Br J Haematol.1994;86(2):427-30.
24.Maciejewski JP,Selleri C,Sato T,Anderson S,Young NS.A severe and consistent deficit in marrow and circulating primitive hematopoietic cells(long-term culture-initiating cells)in acquired aplastic anemia.Blood.1996;88(6):1983-91.
25.Mosmann TR,Cherwinski H,Bond MW,Giedlin MA,Coffman RL.Two types of murine helper T cell clone.I.Definition according to profiles of lymphokine activities and secreted proteins.1986.J Immunol.2005;175(1):5-14.
26.Romagnani S.Human TH1 and TH2 subsets:doubt no more.Immunol Today.1991;12(8):256-7.
27.Ho IC,Hodge MR,Rooney JW,Glimcher LH.The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4.Cell.1996;85(7):973-83.
28.Nistico A,Young NS.Gamma-Interferon gene expression in the bone marrow of patients with aplastic anemia.Ann Intern Med.1994;120(6):463-9.
29.Kaito K,Otsubo H,Usui N,Kobayashi M.Th1/Th2 lymphocyte balance in patients with aplastic anemia.Rinsho Byori.2004;52(7):569-73.
30.张春青,王立军,张锑,秦雪梅.徐从高.获得性再生障碍性贫血患者Th1、Th2型T 细胞亚群的检测.中华血液学杂志,2006,27(11):777-8
31.Solomou EE,Keyvanfar K,Young NS.T-bet,a Th1 transcription factor,is up-regulated in T cells from patients with aplastic anemia.Blood.2006;107(10):3983-91.
32.张宁,徐永健,张珍祥.辅助性T细胞功能分化的分子机制.国外医学呼吸系统分册.2003,23(2):57-61
33.Gately MK,Renzetti LM,Magram J,Stern AS,Adorini L,Gubler U,Presky DH.The interleukin-12/interleukin-12-receptor system:role in normal and pathologic immune responses.Annu Rev Immunol.1998;16:495-521.
34.Nelms K,Keegan AD,Zamorano J,Ryan JJ,Paul WE.The IL-4 receptor:signaling mechanisms and biologic functions.Annu Rev Immunol.1999;17:701-38.
35.Trinchieri G.Interleukin-12:a cytokine at the interface of inflammation and immunity.Adv Immunol.1998;70:83-243.
36.Hikawa N,Ishikawa Y,Takenaka T.Interleukin-12 p40-homodimer production in sensory dorsal root ganglion neurons.Neuroscience.2004;129(1):75-83.
37.Macatonia SE,Hosken NA,Litton M,Vieira P,Hsieh CS,Culpepper JA,Wysocka M,Trinchieri G,Murphy KM,O'Garra A.Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells.J Immunol.1995;154(10):5071-9.
38.Trinchieri G.Interleukin-12:a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity.Annu Rev Immunol.1995;13:251-76.
39.Cassatella MA,Meda L,Gasperini S,D'Andrea A,Ma X,Trinchieri G.Interleukin-12 production by human polymorphonuclear leukocytes.Eur J Immunol.1995;25(1):1-5.
40.Ma X,Trinchieri G.Regulation of interleukin-12 production in antigen-presenting cells.Adv Immunol.2001;79:55-92.
41.Pallone F,Monteleone G.Interleukin 12 and Th1 responses in inflammatory bowel disease.Gut.1998;43(6):735-6.
42.van Boxel-Dezaire AH,Hoff SC,van Oosten BW,Verweij CL,Drager AM,Ader HJ,van Houwelingen JC,Barkhof F,Polman CH,Nagelkerken L.Decreased interleukin-10 and increased interleukin-12p40 mRNA are associated with disease activity and characterize different disease stages in multiple sclerosis.Ann Neurol.1999;45(6):695-703.
43.任翠爱,张茂宏,徐从高,张锑.再生障碍性贫血患者血浆IL-12水平的检测及临床意义.上海免疫学杂志.2000,20(4):252
44.Oppmann B,Lesley R,Blom B,Timans JC,Xu Y,Hunte B,Vega F,Yu N,Wang J,Singh K,Zonin F,Vaisberg E,Churakova T,Liu M,Gorman D,Wagner J,Zurawski S,Liu Y,Abrams JS,Moore KW,Rennick D,de Waal-Malefyt R,Hannum C,Bazan JF,Kastelein RA.Novel p19 protein engages IL-12p40 to form a cytokine,IL-23,with biological activities similar as well as distinct from IL-12.Immunity.2000;13(5):715-25.
45.Kolls JK,Linden A.Interleukin-17 family members and inflammation.Immunity.2004;21(4):467-76.
46.Watford WT,Hissong BD,Bream JH,Kanno Y,Muul L,O'Shea JJ.Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4.Immunol Rev. 2004;202:139-56.
47. Igarashi O, Yamane H, Imajoh-Ohmi S, Nariuchi H. IL-12 receptor (IL-12R) expression and accumulation of IL-12R beta 1 and IL-12R beta 2 mRNAs in CD4+ T cells by costimulation with B7-2 molecules.J Immunol. 1998; 160(4): 1638-46.
48. Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, Pflanz S, Zhang R, Singh KP, Vega F, To W, Wagner J, O'Farrell AM, McClanahan T, Zurawski S, Hannum C, Gorman D, Rennick DM, Kastelein RA, de Waal Malefyt R, Moore KW. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbetal and a novel cytokine receptor subunit, IL-23R.J Immunol. 2002; 168(11):5699-708.
49. Chua AO, Chizzonite R, Desai BB, Truitt TP, Nunes P, Minetti LJ, Warrier RR, Presky DH, Levine JF, Gately MK, Gubler U.Expression cloning of a human IL-12 receptor component. A new member of the cytokine receptor superfamily with strong homology to gpl30.J Immunol. 1994;153(1):128-36.
50. Zhang GX, Yu S, Gran B, Li J, Siglienti I, Chen X, Calida D, Ventura E, Kamoun M, Rostami A.Role of IL-12 receptor beta 1 in regulation of T cell response by APC in experimental autoimmune encephalomyelitis.J Immunol. 2003;171(9):4485-92.
51. Staretz-Haham O, Melamed R, Lifshitz M, Porat N, Fieschi C, Casanova JL, Levy J. Interleukin-12 receptor beta1 deficiency presenting as recurrent Salmonella infection.Clin Infect Dis. 2003;37(1): 137-40.
52. Caragol I, Raspall M, Fieschi C, Feinberg J, Larrosa MN, Hernandez M, Figueras C, Bertran JM, Casanova JL, Espanol T.Clinical tuberculosis in 2 of 3 siblings with interleukin-12 receptor betal deficiency.Clin Infect Dis. 2003;37(2):302-6.
53. Sanal O, Turkkani G, Gumruk F, Yel L, Secmeer G, Tezcan I, Kara A, Ersoy F.A case of interleukin-12 receptor beta-1 deficiency with recurrent leishmaniasis.Pediatr Infect Dis J.2007;26(4):366-8.
54.Wu CY,Warrier RR,Carvajal DM,Chua AO,Minetti LJ,Chizzonite R,Mongini PK,Stern AS,Gubler U,Presky DH,Gately MK.Biological function and distribution of human interleukin-12 receptor beta chain.Eur J Immunol.1996;26(2):345-50.
55.孙晗笑,杨滨燕,李波,娄阁,吴长有.内源性IL-12决定人PBMC产生干扰素γ的水平.中国免疫学杂志,2002,18(4):228-32
56.范艳莹,吴长有.Th2细胞因子和抗IL-12Rβ1mAb抑制由IL-23诱导PBMC IFN-γ的产生.中国免疫学杂志.2006,22(3):195-9
57.范艳莹,吴长有.IL-4、IL-10和抗IL-12受体β1 mAb抑制IL-23诱导正常人记忆T 细胞IFN-γ产生.免疫学杂志,2006,22(4):353-7
58.Lugo-Villarino G,Maldonado-Lopez R,Possemato R,Penaranda C,Glimcher LH.T-bet is required for optimal production of IFN-gamma and antigen-specific T cell activation by dendritic cells.Proc Natl Acad Sci U S A.2003;100(13):7749-54.
59.Agnello D,Lankford CS,Bream J,Morinobu A,Gadina M,O'Shea JJ,Frucht DM.Cytokines and transcription factors that regulate T helper cell differentiation:new players and new insights.J Clin Immunol.2003;23(3):147-61.
60.Strengell M,Matikainen S,Siren J,Lehtonen A,Foster D,Julkunen I,Sareneva T.IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells.J Immunol.2003;170(11):5464-9.
61.Liu N,Ohnishi N,Ni L,Akira S,Bacon KB.CpG directly induces T-bet expression and inhibits IgG1 and IgE switching in B cells.Nat Immunol.2003;4(7):687-93.
62.Usui T,Nishikomori R,Kitani A,Strober W.GATA-3 suppresses Th1development by downregulation of Stat4 and not through effects on IL-12Rbeta2chain or T-bet.Immunity.2003;18(3):415-28.
63.Hartenstein B,Teurich S,Hess J,Schenkel J,Schorpp-Kistner M,Angel P.Th2 cell-specific cytokine expression and allergen-induced airway inflammation depend on JunB.EMBO J.2002;21(23):6321-9.
64.Daynes RA,Enioutina EY,Jones DC.Role of redox imbalance in the molecular mechanisms responsible for immunosenescence.Antioxid Redox Signal.2003;5(5):537-48.
65.Chen CH,Seguin-Devaux C,Burke NA,Oriss TB,Watkins SC,Clipstone N,Ray A.Transforming growth factor beta blocks Tee kinase phosphorylation,Ca2+influx,and NFATc translocation causing inhibition of T cell differentiation.J Exp Med.2003;197(12):1689-99.
66.Park IK,Shultz LD,Letterio JJ,Gorham JD.TGF-betal inhibits T-bet induction by IFN-gamma in murine CD4+ T cells through the protein tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1.J Immunol.2005;175(9):5666-74.
67.Szabo SJ,Sullivan BM,Stemmann C,Satoskar AR,Sleckman BP,Glimcher LH.Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells.Science.2002;295(5553):338-42.
68.Rao A,Avni O.Molecular aspects of T-cell differentiation.Br Med Bull.2000;56(4):969-84.
69.Mullen AC,Hutchins AS,High FA,Lee HW,Sykes KJ,Chodosh LA,Reiner SL.Hlx is induced by and genetically interacts with T-bet to promote heritable T(H)1 gene induction.Nat Immunol.2002;3(7):652-8.
70.Ouyang W,Ranganath SH,Weindel K,Bhattacharya D,Murphy TL,Sha WC,Murphy KM.Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism.Immunity.1998;9(5):745-55.
71.Ouyang W,Lohning M,Gao Z,Assenmacher M,Ranganath S,Radbruch A,Murphy KM.Stato-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment.Immunity.2000;12(1):27-37.
72.Zheng W,Flavell RA.The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells.Cell.1997;89(4):587-96.
73.Lee HJ,Takemoto N,Kurata H,Kamogawa Y,Miyatake S,O'Garra A,Arai N.GATA-3 induces T helper cell type 2(Th2)cytokine expression and chromatin remodeling in committed Th1 cells.J Exp Med.2000;192(1):105-15.
74.Dong C,Flavell RA.Th1 and Th2 cells.Curr Opin Hematol.2001;8(1):47-51.
75.Glimcher LH,Murphy KM.Lineage commitment in the immune system:the T helper lymphocyte grows up.Genes Dev.2000;14(14):1693-711.
76.Zhang DH,Yang L,Ray A.Differential responsiveness of the IL-5 and IL-4 genes to transcription factor GATA-3.J Immunol.1998;161(8):3817-21.
77.Agarwal S,Avni O,Rao A.Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo.Immunity.2000;12(6):643-52.
78.Usui T,Preiss JC,Kanno Y,Yao ZJ,Bream JH,O'Shea JJ,Strober W.T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription.J Exp Med.2006;203(3):755-66.
79.张琦,董亮,李丽珍,于钦凤,陈明.以T-bet/GATA-3的比率作为评价哮喘患者Th1/Th2失衡指标的探讨.细胞与分子免疫学杂志,2005,21(1):118-20
80.Chakir H,Wang H,Lefebvre DE,Webb J,Scott FW.T-bet/GATA-3 ratio as a measure of the Th1/Th2 cytokine profile in mixed cell populations:predominant role of GATA-3.J Immunol Methods.2003;278(1-2):157-69.
81.魏海明,田志刚,许晓群,冯进波,肖伟.肺癌患者转录因子T-bet和GATA3的基因表达状况及药物干预研究.中华肿瘤杂志.2002,24(1):34-7
82.黄丽群,薛峰,沈小雁,郑捷.系统性红斑狼疮患者转录因子T-bet和GATA3基因的表达.中华皮肤科杂志,2004,37(12):724-6
83.Lit LC,Wong CK,Li EK,Tam LS,Lam CW,Lo YM.Elevated gene expression of Th1/Th2 associated transcription factors is correlated with disease activity in patients with systemic lupus erythematosus.J Rheumatol.2007;34(1):89-96.
84.Neurath MF,Weigmann B,Finotto S,Glickman J,Nieuwenhuis E,Iijima H,Mizoguchi A,Mizoguchi E,Mudter J,Galle PR,Bhan A,Autschbach F,Sullivan BM, Szabo SJ, Glimcher LH, Blumberg RS.The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease.J ExpMed.2002;195(9):1129-43.
85. Li B, Yang P, Zhou H, Zhang Z, Xie C, Lin X, Huang X, Kijlstra A.T-bet expression is upregulated in active Behcet's disease. Br J Ophthalmol. 2003 ;87(10): 1264-7.
86. Juedes AE, Rodrigo E, Togher L, Glimcher LH, von Herrath MGT-bet controls autoaggressive CD8 lymphocyte responses in type 1 diabetes.J Exp Med. 2004; 199(8): 1153-62.
87. Frisullo G, Angelucci F, Caggiula M, Nociti V, Iorio R, Patanella AK, Sancricca C, Mirabella M, Tonali PA, Batocchi AP.pSTAT1, pSTAT3, and T-bet expression in peripheral blood mononuclear cells from relapsing-remitting multiple sclerosis patients correlates with disease activity.J Neurosci Res. 2006;84(5): 1027-36.
88. Loyett-Racke AE, Rocchini AE, Choy J, Northrop SC, Hussain RZ, Ratts RB, Sikder D, Racke MK.Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes.Immunity. 2004;21 (5):719-31.
89. Peng SL, Szabo SJ, Glimcher LH. T-bet regulates IgG class switching and pathogenic autoantibody production. Proc Natl Acad Sci U S A. 2002;99(8): 5545-50.
90. Finotto S, Glimcher L.T cell directives for transcriptional regulation in asthma. Springer Semin Immunopathol. 2004;25(3-4):281-94.
91. Weigmann B, Neurath MF.T-bet as a possible therapeutic target in autoimmune disease. Expert Opin Ther Targets. 2002;6(6):619-22.
92. Turkson J, Jove R. STAT proteins: novel molecular targets for cancer drug discovery.Oncogene. 2000; 19(56):6613-26.
93. Bacon CM, McVicar DW, Ortaldo JR, Rees RC, O'Shea JJ, Johnston JA.Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL-2 and IL-12.J Exp Med. 1995;181(1):399-404.
94. Klein JL, Fickenscher H, Holliday JE, Biesinger B, Fleckenstein B. Herpesvirus saimiri immortalized gamma delta T cell line activated by IL-12. J Immunol. 1996;156(8):2754-60.
95. Jacobson NG, Szabo SJ, Giiler ML, Gorham JD, Murphy KM.Regulation of interleukin-12 signal transduction during T helper phenotype development. Res Immunol. 1995;146(7-8):446-56.
96. Jacobson NG, Szabo SJ, Weber-Nordt RM, Zhong Z, Schreiber RD, Darnell JE Jr, Murphy KM.Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4.J Exp Med. 1995;181(5):1755-62.
97. Ouyang W, Jacobson NG, Bhattacharya D, Gorham JD, Fenoglio D, Sha WC, Murphy TL, Murphy KM.The Ets transcription factor ERM is Th1-specific and induced by IL-12 through a Stat4-dependent pathway.Proc Natl Acad Sci U S A. 1999;96(7):3888-93.
98. Galon J, Sudarshan C, Ito S, Finbloom D, O'Shea JJ. IL-12 induces IFN regulating factor-1 (IRF-1) gene expression in human NK and T cells. J Immunol. 1999;162(12):7256-62.
99. Chitnis T, Najafian N, Benou C, Salama AD, Grusby MJ, Sayegh MH, Khoury SJ.Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis. J Clin Invest. 2001;108(5):739-47.
100.Verhagen CE, de Boer T, Smits HH, Verreck FA, Wierenga EA, Kurimoto M, Lammas DA, Kumararatne DS, Sanal O, Kroon FP, van Dissel JT, Sinigaglia F, Ottenhoff TH.Residual type 1 immunity in patients genetically deficient for interleukin 12 receptor beta1 (IL-12Rbeta1): evidence for an IL-12Rbeta1-independent pathway of IL-12 responsiveness in human T cells.J Exp Med. 2000;192(4):517-28.
1. Young NS. Acquired aplastic anemia. Ann Intern Med 2002; 136: 534-46.
2. Keohane EM. Acquired aplastic anemia. Clin Lab Sci 2004; 17: 165-71.
3. Nakao S. Immune mechanism of aplastic anemia. Int J Hematol 1997; 66: 127-34.
4. Brodsky RA, Jones RJ. Aplastic anaemia. Lancet 2005; 365: 1647-56.
5. Zeng W, Kajigaya S, Chen G, Risitano AM, Nunez O, Young NS. Transcript profile of CD4+ and CD8+ T cells from the bone marrow of acquired aplastic anemia patients. Exp Hematol 2004; 32: 806-14
6. Kagan WA, Ascensao JA, Pahwa RN, Hansen JA, Goldstein G, Valera EB, Incefy GS, Moore MA, Good RA. Aplastic anemia: presence in human bone marrow of cells that suppress myelopoiesis. Proc Natl Acad Sci U S A1976; 73: 2890-4.
7. Sullivan R, Quesenberry PJ, Parkman R, Zuckerman KS, Levey RH, Rappeport J, Ryan M. Aplastic anemia: lack of inhibitory effect of bone marrow lymphocytes on in vitro granulopoiesis. Blood 1980; 56: 625-32.
8. Young NS. Hematopoietic cell destruction by immune mechanisms in aquired aplastic anemia. Semin Hematol 2000; 37: 3-14
9. Zoumbos NC, Gascon P, Djeu JY, Young NS. Interferon is a mediator of hematopoietic suppression in aplastic anemia in vitro and possibly in vivo. Proc Natl Acad Sci U S A 1985; 82: 188-92.
10. Nistico A, Young NS. Gamma-Interferon gene expression in the bone marrow of patients with aplastic anemia. Ann Intern Med 1994; 120: 463-9
11. Selleri C, Sato T, Anderson S, Young NS, Maciejewski JP. Interferon-γ and tumor necrosis factor-alpha suppress both early and late stages of hematopoiesis and induce programmed cell death. J Cell Physiol 1995; 165: 538-46.
12. Philpott NJ, Scopes J, Marsh JC, Gordon-Smith EC, Gibson FM. Increased apoptosis in aplastic anemia bone marrow progenitor cells: possible pathophysiologic significance. Exp Hematol 1995; 23: 1642-8.
13. Maciejewski JP, Selleri C, Sato T, Anderson S, Young NS. Increased expression of Fas antigen on bone marrow CD34+ cells of patients with aplastic anaemia. Br J Haematol 1995; 91: 245-52.
14. Sato T, Selleri C, Anderson S, Young NS, Maciejewski JP. Expression and modulation of cellular receptors for interferon-γ, tumour necrosis factor, and Fas on human bone marrow CD34+ cells. Br J Haematol 1997; 97: 356-65.
15. Maciejewski JP, Hibbs JR, Anderson S, Katevas P, Young NS. Bone marrow and peripheral blood lymphocyte phenotype in patients with bone marrow failure. ExpHematol 1994; 22:1102-10.
16. Sloand E, Kim S, Maciejewski JP, Tisdale J, Follmann D, Young NS. Intracellular interferon-gamma in circulating and marrow T cells detected by flow cytometry and the response to immunosuppressive therapy in patients with aplastic anemia. Blood 2002; 100:1185-91.
17. Solomou EE, Keyvanfar K, Young NS. T-bet, a Thl transcription factor, is up-regulated in T cells from patients with aplastic anemia. Blood 2006; 107: 3983-91.
18. Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA, Freeman GJ, Kuchroo VK. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 2002; 415: 536-41.
19. Sanchez-Fueyo A, Tian J, Picarella D, Domenig C, Zheng XX, Sabatos CA, Manlongat N, Bender O, Kamradt T, Kuchroo VK, Gutierrez-Ramos JC, Coyle AJ, Strom TB. Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nat Immunol 2003; 4: 1093-101.
20. Sabatos CA, Chakravarti S, Cha E, Schubart A, Sanchez-Fueyo A, Zheng XX, Coyle AJ, Strom TB, Freeman GJ, Kuchroo VK. Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat Immunol 2003; 4: 1102-10.
21. Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol 2005; 6:1245-52.
22. Anderson AC, Anderson DE, Bregoli L, Hastings WD, Kassam N, Lei C, Chandwaskar R, Karman J, Su EW, Hirashima M, Bruce JN, Kane LP, Kuchroo VK, Hafler DA.Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science 2007; 318: 1141-3.
23. Kaufman DW, Kelly JP, Jurgelon JM, Anderson T, Issaragrisil S, Wiholm BE, Young NS, Leaverton P, Levy M, Shapiro S. Drugs in the aetiology of agranulocytosis and aplastic anaemia. Eur J Haematol 1996; Suppl 60: 23-30.
24. Camitta BM, Thomas ED, Nathan DG, Santos G., Gordon-Smith EC, Gale RP, Rappeport JM, Storb R. Severe aplastic anemia: a prospective study of the effect of early marrow transplantation on acute mortality. Blood 1976; 48:63-70.
25. Asakura H, Kashio Y, Nakamura K, Seki M, Dai S, Shirato Y, Abedin MJ, Yoshida N, Nishi N, Imaizumi T, Saita N, Toyama Y, Takashima H, Nakamura T., Ohkawa M, Hirashima M. Selective eosinophil adhesion to fibroblast via IFN-gamma-induced galectin-9. J Immunol 2002; 169: 5912-8.
26. Khademi M, Illes Z, Gielen AW, Marta M, Takazawa N, Baecher-Allan C, Brundin L, Hannerz J, Martin C, Harris RA, Hafler DA, Kuchroo VK, Olsson T., Piehl F, Wallstrom E. T Cell Ig- and mucin-domain-containing molecule-3 (TIM-3) and TIM-1 molecules are differentially expressed on human Th1 and Th2 cells and in cerebrospinal fluid-derived mononuclear cells in multiple sclerosis. J Immunol 2004; 172: 7169-76.
27. Baratelli F, Lin Y, Zhu L, Yang SC, Heuze-Vourc'h N, Zeng G, Reckamp K, Dohadwala M, Sharma S, Dubinett SM. Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4+ T cells. J Immunol 2005; 175:1483-90.
28. Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+CD25high regulatory cells in human peripheral blood. J Immunol 2001; 167:1245-53.
29. Wing K, Ekmark A, Karlsson H, Rudin A, Suri-Payer E. Characterization of human CD25+ CD4+ T cells in thymus, cord and adult blood. Immunology 2002; 106: 190-9.
30. Ponciano VC, Renesto PG, Nogueira E, Rangel EB, Cenedeze MA, Franco MF, Camara NO, Pacheco-Silva A. Tim-3 expression in human kidney allografts. Transpl Immunol 2007; 17: 215-22.
31. Renesto PG, Ponciano VC, Cenedeze MA, Saraiva Camara NO, Pacheco-Silva A. High expression of Tim-3 mRNA in urinary cells from kidney transplant recipients with acute rejection. Am J Transplant 2007; 7:1661-5.
32. He GS, Shao ZH, He H, Liu H, Fu R, Bai J, Shi J, Cao YR, Tu MF, Sun J, Jia HR. Changes of subsets of DC1 in the bone marrow of severe aplastic anemia patients. Zhonghua Xue Ye Xue Za Zhi 2004; 25: 649-52.
33. Tu MF, Shao ZH, Liu H, He GS, Shi J, Bai J, Cao YR, Wang HQ, Xing LM, Cui ZZ. Study on the peripheral blood dendritic cells subtypes and the expression of co-stimulating molecules on dendritic cells and B cells in severe aplastic anemia patients. Zhonghua Xue Ye Xue Za Zhi 2006; 27:611-5.
34. Hirashima M, Kashio Y, Nishi N, Yamauchi A, Imaizumi TA, Kageshita T, Saita N, Nakamura T. Galectin-9 in physiological and pathological conditions. Glycoconj J 2004; 19: 593-600.
35. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003; 4: 330-6.
36. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299: 1057-61.
37. Solomou EE, Rezvani K, Mielke S, Malide D, Keyvanfar K, Visconte V, Kajigaya S, Barrett AJ, Young NS. Deficient CD4+ CD25+ FOXP3+ T regulatory cells in acquired aplastic anemia. Blood 2007; 110:1603-6.
38. Dabbagh K, Lewis DB.Toll-like receptors and T-helper-1/T-helper-2 responses. Curr Opin Infect Dis 2003; 16:199-204.
39. Zeng W, Maciejewski JP, Chen G, Risitano AM, Kirby M, Kajigaya S, Young NS.Selective reduction of natural killer T cells in the bone marrow of aplastic anaemia. Br J Haematol 2002; 119: 803-9.
40. Chen Y, Langrish CL, McKenzie B, Joyce-Shaikh B, Stumhofer JS, McClanahan T, Blumenschein W, Churakovsa T, Low J, Presta L, Hunter CA, Kastelein RA, Cua DJ. Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J Clin Invest 2006,116: 1317-26.
41. Nielsen OH, Kirman I, Rudiger N, Hendel J, Vainer B. Upregulation of interleukin-12 and -17 in active inflammatory bowel disease. Scand J Gastroenterol 2003;38:180-5.
42.Komiyama Y,Nakae S,Matsuki T,Nambu A,Ishigame H,Kakuta S,Sudo K,Iwakura Y.IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis.J Immunol 2006;177:566-73.
43.Koenders MI,Lubberts E,van de Loo FA,Oppers-Walgreen B,van den Bersselaar L,Helsen MM,Kolls JK,Di Padova FE,Joosten LA,van den Berg WB.Interleukin-17 acts independently of TNF-alpha under arthritic conditions.J Immunol 2006;176:6262-9.
44.Anderson AC,Anderson DE.TIM-3 in autoimmunity.Curr Opin Immunol 2006;18:665-9.
45.Kolls JK,Linden A.Intedeukin-17 family members and inflammation.Immunity 2004;21:467-76.
1.Mosmann TR,Cherwinski H,Bond MW,Giedlin MA,Coffman RL.Two types of murine helper T cell clone.I.Definition according to profiles of lymphokine activities and secreted proteins.J Immunol.1986 Apr 1;136(7):2348-57.
2. Romagnani S.The Thl/Th2 paradigm.Immunol Today. 1997 Jun;18(6):263-6.
3. Abbas AK, Murphy KM, Sher A.Functional diversity of helper T lymphocytes. Nature. 1996 Oct 31;383(6603):787-93.
4. Seder RA, Paul WE. Acquisition of lymphokine-producing phenotype by CD4+ T cells.Annu Rev Immunol. 1994;12:635-73.
5. Constant SL, Bottomly K. Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Annu Rev Immunol. 1997; 15:297-322.
6. O'Garra A. Cytokines induce the development of functionally heterogeneous T helper cell subsets.Immunity. 1998 Mar;8(3):275-83.
7. Kaplan MH, Schindler U, Smiley ST, Grusby MJ.Stat6 is required for mediating responses to IL-4 and for development of Th2 cells.Immunity. 1996 Mar;4(3):313-9.
8. Kaplan MH, Sun YL, Hoey T, Grusby MJ. Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice.Nature. 1996 Jul 11;382(6587): 174-7.
9. Thierfelder WE, van Deursen JM, Yamamoto K, Tripp RA, Sarawar SR, Carson RT, Sangster MY, Vignali DA, Doherty PC, Grosveld GC, Ihle JN. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells.Nature. 1996 Jul 11;382(6587):171-4.
10. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH.A novel transcription factor, T-bet, directs Thl lineage commitment. Cell. 2000 Mar 17;100(6):655-69.
11. Ann HJ, Maruo S, Tomura M, Mu J, Hamaoka T, Nakanishi K, Clark S, Kurimoto M, Okamura H, Fujiwara H.A mechanism underlying synergy between IL-12 and IFN-gamma-inducing factor in enhanced production of IFN-gamma.J Immunol. 1997 Sep 1;159(5):2125-31.
12. Nakahira M, Ann HJ, Park WR, Gao P, Tomura M, Park CS, Hamaoka T, Ohta T, Kurimoto M, Fujiwara H.Synergy of IL-12 and IL-18 for IFN-gamma gene expression: IL-12-induced STAT4 contributes to IFN-gamma promoter activation by up-regulating the binding activity of IL-18-induced activator protein 1.J Immunol.2002 Feb 1;168(3):1146-53.
13.Trinchieri G.Interleukin-12:a cytokine at the interface of inflammation and immunity.Adv Immunol.1998;70:83-243.
14.Shevach EM,Chang JT,Segal BM.The critical role of IL-12 and the IL-12R beta 2 subunit in the generation of pathogenic autoreactive Th1 cells.Springer Semin Immunopathol.1999;21(3):249-62.
15.Mullen AC,High FA,Hutchins AS,Lee HW,Villarino AV,Livingston DM,Kung AL,Cereb N,Yao TP,Yang SY,Reiner SL.Role of T-bet in commitment of TH1cells before IL-12-dependent selection.Science.2001 Jun 8;292(5523):1907-10.
16.Presky DH,Yang H,Minetti LJ,Chua AO,Nabavi N,Wu CY,Gately MK,Gubler U.A functional interleukin 12 receptor complex is composed of two beta-type cytokine receptor subunits.Proc Natl Acad Sci U S A.1996 Nov 26;93(24):14002-7.
17.Gately MK,Renzetti LM,Magram J,Stern AS,Adorini L,Gubler U,Presky DH.The interleukin-12/interleukin-12-receptor system:role in normal and pathologic immune responses.Annu Rev Immunol.1998;16:495-521.
18.Wu C,Ferrante J,Gately MK,Magram J.Characterization of IL-12 receptor betal chain(IL-12Rbetal)-deficient mice:IL-12Rbetal is an essential component of the functional mouse IL-12 receptor.J Immunol.1997 Aug 15;159(4):1658-65.
19.Oppmann B,Lesley R,Blom B,Timans JC,Xu Y,Hunte B,Vega F,Yu N,Wang J,Singh K,Zonin F,Vaisberg E,Churakova T,Liu M,Gorman D,Wagner J,Zurawski S,Liu Y,Abrams JS,Moore KW,Rennick D,de Waal-Malefyt R,Hannum C,Bazan JF,Kastelein RA.Novel p19 protein engages IL-12p40 to form a cytokine,IL-23,with biological activities similar as well as distinct from IL-12.Immunity.2000 Nov;13(5):715-25.
20.Frucht DM.IL-23:a cytokine that acts on memory T cells.Sci STKE.2002 Jan 8;2002(114):PE1.
21.Lankford CS,Frucht DM.A unique role for IL-23 in promoting cellular immunity.J Leukoc Biol.2003 Jan;73(1):49-56.
22.Cleary AM,Tu W,Enright A,Giffon T,Dewaal-Malefyt R,Gutierrez K,Lewis DB.Impaired accumulation and function of memory CD4 T cells in human IL-12 receptor beta 1 deficiency.J Immunol. 2003 Jan l;170(1):597-603.
23. Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL.Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem. 2003 Jan 17;278(3):1910-4.
24. Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, Pflanz S, Zhang R, Singh KP, Vega F, To W, Wagner J, O'Farrell AM, McClanahan T, Zurawski S, Hannum C, Gorman D, Rennick DM, Kastelein RA, de Waal Malefyt R, Moore KW. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol. 2002 Jun 1;168(11):5699-708.
25. Zhang GX, Yu S, Gran B, Li J, Siglienti I, Chen X, Calida D, Ventura E, Kamoun M, Rostami A.Role of IL-12 receptor beta 1 in regulation of T cell response by APC in experimental autoimmune encephalomyelitis. J Immunol. 2003 Nov l;171(9):4485-92.
26. Young NS. Acquired aplastic anemia. Ann Intern Med. 2002 Apr 2;136(7):534-46.
27. Young NS, Maciejewski J.The pathophysiology of acquired aplastic anemia.N Engl J Med. 1997 May 8;336(19):1365-72.
28. Young NS. Gamma interferon and aplastic anemia.Blood. 1987 Jul;70(1):337-9.
29. Zoumbos NC, Gascon P, Djeu JY, Young NS.Interferon is a mediator of hematopoietic suppression in aplastic anemia in vitro and possibly in vivo.Proc Natl Acad Sci U S A. 1985 Jan;82(1):188-92.
30. Giannakoulas NC, Karakantza M, Theodorou GL, Pagoni M, Galanopoulos A, Kakagianni T, Kouraklis-Symeonidis A, Matsouka P, Maniatis A, Zoumbos NC.Clinical relevance of balance between type 1 and type 2 immune responses of lymphocyte subpopulations in aplastic anaemia patients. Br J Haematol. 2004 Jan;124(1):97-105.
31. Sloand E, Kim S, Maciejewski JP, Tisdale J, Follmann D, Young NS.Intracellular interferon-gamma in circulating and marrow T cells detected by flow cytometry and the response to immunosuppressive therapy in patients with aplastic anemia.Blood. 2002 Aug 15; 100(4): 1185-91.
32. Zoumbos NC, Djeu JY, Young NS. Interferon is the suppressor of hematopoiesis generated by stimulated lymphocytes in vitro. J Immunol. 1984 Aug;133(2):769-74.
33. Solomou EE, Keyvanfar K, Young NS.T-bet, a Th1 transcription factor, is up-regulated in T cells from patients with aplastic anemia.Blood. 2006 May 15;107(10):3983-91.
34. Young NS, Leonard E, Platanias L. Lymphocytes and lymphokines in aplastic anemia: pathogenic role and implications for pathogenesis. Blood Cells. 1987;13(1-2):87-100.
35. Kaufman DW, Kelly JP, Jurgelon JM, Anderson T, Issaragrisil S, Wiholm BE, Young NS, Leaverton P, Levy M, Shapiro S. Drugs in the aetiology of agranulocytosis and aplastic anaemia. Eur J Haematol 1996; Suppl 60: 23-30.
36. Camitta BM, Thomas ED, Nathan DG, Santos G, Gordon-Smith EC, Gale RP, Rappeport JM, Storb R. Severe aplastic anemia: a prospective study of the effect of early marrow transplantation on acute mortality. Blood 1976; 48:63-70.
37. Solomou EE, Juang YT, Tsokos GC. Protein kinase C-theta participates in the activation of cyclic AMP-responsive element-binding protein and its subsequent binding to the -180 site of the IL-2 promoter in normal human T lymphocytes. J Immunol. 2001 May l;166(9):5665-74.
38. Caspi RR.IL-12 in autoimmunity.Clin Immunol Immunopathol. 1998 Jul;88(1):4-13.
39. Wu CY, Wang K, McDyer JF, Seder RA.Prostaglandin E2 and dexamethasone inhibit IL-12 receptor expression and IL-12 responsiveness.J Immunol. 1998 Sep 15;161(6):2723-30.
40. Wu CY, Warner RR, Carvajal DM, Chua AO, Minetti LJ, Chizzonite R, Mongini PK, Stern AS, Gubler U, Presky DH, Gately MK.Biological function and distribution of human interleukin-12 receptor beta chain.Eur J Immunol. 1996 Feb;26(2):345-50.
41. Bacigalupo A, Podesta M, Mingari MC, Moretta L, Van Lint MT, Marmont A.Immune suppression of hematopoiesis in aplastic anemia: activity of T-gamma lymphocytes.J Immunol. 1980 Oct; 125(4): 1449-53.
42. Gu Y, Zhang J, Peng J, Hu X, Xu C.Elevated expression of IL-12 and IL-23 in patients with aplastic anemia.Int J Lab Hematol. 2008.[article in press]
43. Rengarajan J, Szabo SJ, Glimcher LH. Transcriptional regulation of Thl/Th2 polarization.Immunol Today. 2000 Oct;21(10):479-83.
44. Finotto S, Glimcher L.T cell directives for transcriptional regulation in asthma.Springer Semin Immunopathol. 2004 Feb;25(3-4):281-94.
45. Hatton RD, Weaver CT.Immunology. T-bet or not T-bet. Science. 2003 Nov 7;302(5647):993-4.
46. Finotto S, Neurath MF, Glickman JN, Qin S, Lehr HA, Green FH, Ackerman K, Haley K, Galle PR, Szabo SJ, Drazen JM, De Sanctis GT, Glimcher LH.Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Science. 2002 Jan 11;295(5553):336-8.
47. Zhang DH, Cohn L, Ray P, Bottomly K, Ray A.Transcription factor GATA-3 is differentially expressed in murine Thl and Th2 cells and controls Th2-speciflc expression of the interleukin-5 gene. J Biol Chem. 1997 Aug 22;272(34):21597-603.
48. Ouyang W, Ranganath SH, Weindel K, Bhattacharya D, Murphy TL, Sha WC, Murphy KM.Inhibition of Thl development mediated by GATA-3 through an IL-4-independent mechanism. Immunity. 1998 Nov;9(5):745-55.
49. Bacon CM, McVicar DW, Ortaldo JR, Rees RC, O'Shea JJ, Johnston JA.Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL-2 and IL-12. J Exp Med. 1995 Jan 1;181(1):399-404.
50. Jacobson NG, Szabo SJ, Weber-Nordt RM, Zhong Z, Schreiber RD, Darnell JE Jr, Murphy KM.Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4. J Exp Med. 1995 May 1;181(5):1755-62.
51. Bacon CM, Petricoin EF 3rd, Ortaldo JR, Rees RC, Lamer AC, Johnston JA, O'Shea JJ.Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes. Proc Natl Acad Sci U S A. 1995 Aug l;92(16):7307-11.
52. Cho SS, Bacon CM, Sudarshan C, Rees RC, Finbloom D, Pine R, O'Shea JJ.Activation of STAT4 by IL-12 and IFN-alpha: evidence for the involvement of ligand-induced tyrosine and serine phosphorylation. J Immunol. 1996 Dec 1;157(11):4781-9.
53. Morinobu A, Gadina M, Strober W, Visconti R, Foraace A, Montagna C, Feldman GM, Nishikomori R, O'Shea JJ. STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12281-6.