血必净注射液对系统性红斑狼疮小鼠免疫功能的影响及意义
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摘要
目的:通过系统性红斑狼疮(SLE)动物模型,探讨树突细胞在SLE发病机制中的作用。观察血必净对系统性红斑狼疮动物免疫功能及脏器损害的可能保护效应。阐明血必净对系统性红斑狼疮(SLE)动物模型免疫功能的影响及调节机制。
方法:采用系统性红斑狼疮动物模型,清洁级EB病毒膜抗原BLLF1基因转基因小鼠,雌性, 8-10周龄,体重30-40g。8周龄、10周龄分别给予6.4ml/kg血必净腹腔内注射。实验分组:分为4组,10只昆明小鼠设为(1)正常对照组(n=10);SLE模型小鼠按照不同周龄编号,然后按照随机数字表将小鼠随机平均分为3组(2)模型组(n=10),(3)SLE 8周龄治疗组(n=10),(4)SLE 10周龄治疗组(n=10)。实验一:血必净治疗14天后无菌取血及肾脏。分离血清,-20℃贮存。甲醛固定肾脏,进行组织病理学检查。实验二:血必净治疗14天后,断颈处死小鼠后,钝性分离脾脏,一部分用于提取DC和T淋巴细胞,另一部分置于液氮冻存。采用MiniMACS免疫磁性分离系统进行DC的分离纯化。T淋巴细胞,利用B细胞和单核细胞具有易粘附于尼龙纤维表面的特性分离。流式细胞术检测细胞免疫表型,MTT法检测脾T淋巴细胞增殖,荧光定量PCR和酶联免疫吸附试验检测目的基因表达水平以及血清、细胞孵育上清及组织匀浆液的细胞因子。
结果:实验一:(1)模型组小鼠血清抗dsDNA抗体的滴度与正常对照组比较,明显增高。血必净治疗能显著降低SLE小鼠的抗dsDNA抗体的滴度。(2)狼疮小鼠肾脏的组织病理主要表现为增生性肾小球肾炎。肾小球系膜细胞和系膜基质增生,嗜复红蛋白沉积,新月体形成。血必净治疗能明显减轻狼疮鼠肾脏组织的损伤。与正常对照进行比较,模型组小鼠血中Cr、BUN含量显著升高(P <0.01)。血必净治疗可明显降低动物血中Cr、BUN含量,与模型组比较,有统计学意义(P <0.01),与正常对照进行比较,无统计学差异。实验二:(1)孵育24小时后,模型组动物脾脏DC表面共刺激分子CD80表达明显升高,与正常对照组比较有统计学显著差异(P < 0.01),CD86和MHCII弱表达。8周龄及10周龄治疗组脾脏DC表面共刺激分子CD80的表达仍维持在较高水平,与模型组比较无统计学差异,CD86和MHCII的表达与模型组比较明显升高,与模型组比较有统计学差异(P <0.05)。表明血必净治疗可以使SLE小鼠脾脏DC表面共刺激分子的表达升高。(2)将DC与T淋巴细胞按照不同比例(1:100、1:150、1:200)相互作用3天和5天后,与正常对照组比较,模型组小鼠T淋巴细胞增殖活性受到抑制,给予血必净治疗后增殖抑制效应减轻。(3)与正常对照组比较,模型组IL-4、TNF-a的含量显著升高(P<0.01),而IL-2、IFN-γ及IL-12的水平明显降低(P<0.01)。动物脾脏组织及T淋巴细胞IL-2的基因表达显著下降,而TNF-a基因表达则明显升高(P<0. 01~0.05)。血必净治疗后,与模型组比较,狼疮鼠IL-4、TNF-a的含量显著降低(P<0. 01~0.05),而IL-2、IFN-γ及IL-12的水平明显升高(P<0.01~0.05),IL-2的基因表达显著升高,TNF-a基因表达明显降低,具有统计学差异。
结论:树突细胞在系统性红斑狼疮疾病的发展过程中具有重要的作用,DC向成熟发展,但表型表达异常,存在功能障碍,从而介导T淋巴细胞增殖反应低,并向Th2漂移。血必净治疗能够保护动物的脏器损害,改善DC的功能障碍,促进Th1的增殖和发育,将Th2细胞转化为Th1细胞,改变Th1 /Th2的比例和机体的免疫应答类型,对系统性红斑狼疮的免疫功能产生影响。
Objective: Systemic lupus erythematosus(SLE)is a multifactorial autoimmune disease characterized by breakdown of self-tolerance,autoantibody production,aberrant formation of immune complexes(IC),and inflammation of multiple organs.Dendritic cells (DCs) are functionally abnormal in systemic lupus erythematosus (SLE). The present study was performed to identify a protective role for Xuebijing administration in systemic lupus erythematosus (SLE)-prone BLLF1 mice. To observe the effect of Xuebijing on DC to T lymphocyte and its potential mechanisms in SLE.
Methods: A widely used model for in systemic lupus erythematosus (SLE)-prone BLLF1 mice was used in these studies. Ten normal female mice and thirty BLLF1 female mice were divided into four groups as follows: normal control group (10 mice), model control group (10 mice), SLE (8w) with Xuebijing treatment group (10 mice), and SLE(10w)Xuebijing treatment group (10 mice). Xuebijing 6.4ml/kg was given via dorsal penile vein in Xuebijing treatment group. In the first experiment,.animals of all groups were sacrificed, and blood, kidney samples were harvested aseptically to determine. In the second experiment spleen was divided into two parts as following: one part was used to procure DC by MACS microbeads and T cell by using column of nylon wool, and the other part was used to detect gene and protein expression levels of various cytokines. Cells were cultured and phenotypes were analyzed by flow cytometry. The contents of cytokines released into supernatants were also determined. Gene expression was measured by real-time quantitative PCR as the internal standard. All cytokines in supernatant and tissue were determined by ELISA kits for mice.
Result: 1.Mice demonstrated characteristic alterations of serum immune parameters, the levels of anti-dsDNA antibodies in model control group were significantly higher than the normal group. Treatment with Xuebijing could inhibit the expression levels of anti-dsDNA antibodies.Conventional histological staining of kidneys showed abnormalities in BLLF1 mice at ages 8-10 weeks. Prominent mononuclear cell infiltrating was also observed, with predominantly perivascular localization in the cortex and medulla of the kidneys. In contrast, minimal histopathologic abnormalities can be observed in Xuebijing treatment group. The serum Crand CRE and BUN levels were significantly elevated in SLE, and treatment with Xuebijing could inhibit these increase to different extent.
2.In the model control group, DC expressed strongly enhanced levels of CD80 and slightly enhanced levels of CD86 and MHC classⅡcompared with DC from normal mice. Treatment with Xuebijing could significantly up-regulated the expression levels of CD80, CD86 and MHC classⅡof DC. Splenic T lymphocyte proliferative response to ConA, were suppressed on days 3 and 5 after cultured in the presence of DC to T lymphocyte ratios in 1:100, 1:150 and 1:200 in the model control group, Xuebijing treatment could restore T cell proliferative activity. In the model control group, with marked production of interferon-γ, interleukin-2, TNF-alpha and interleukin-4 in supernatants, the levels of IL-4 and TNF-αincreased significantly ,but the levels of IL-2, and IFN-γand IL-12decreased markedly, The gene expression levels of IL-2 were also decreased and TNF-alpha were increased. Xuebijing treatment could significantly inhibite increase of IL-4, TNF-αand decrease of IL-2, IFN-γand IL-12.
Conclusion: Dendritic cells play an important role in the development of SLE. The splenic DC express abnormally, and further induce suppression of T lymphocyte immune function and drifting to Th2 in SLE. Xuebijing treatment might influence the polarization of T cells in animals in SLE and induced Th cells to drift to Th1 cells. Xuebijihg has a potential therapeutic for suppressing immune dysfunction and ameliorating multiple organ injury in SLE.
方法:采用系统性红斑狼疮动物模型,清洁级EB病毒膜抗原BLLF1基因转基因小鼠,雌性, 8-10周龄,体重30-40g。8周龄、10周龄分别给予6.4ml/kg血必净腹腔内注射。实验分组:分为4组,10只昆明小鼠设为(1)正常对照组(n=10);SLE模型小鼠按照不同周龄编号,然后按照随机数字表将小鼠随机平均分为3组(2)模型组(n=10),(3)SLE 8周龄治疗组(n=10),(4)SLE 10周龄治疗组(n=10)。实验一:血必净治疗14天后无菌取血及肾脏。分离血清,-20℃贮存。甲醛固定肾脏,进行组织病理学检查。实验二:血必净治疗14天后,断颈处死小鼠后,钝性分离脾脏,一部分用于提取DC和T淋巴细胞,另一部分置于液氮冻存。采用MiniMACS免疫磁性分离系统进行DC的分离纯化。T淋巴细胞,利用B细胞和单核细胞具有易粘附于尼龙纤维表面的特性分离。流式细胞术检测细胞免疫表型,MTT法检测脾T淋巴细胞增殖,荧光定量PCR和酶联免疫吸附试验检测目的基因表达水平以及血清、细胞孵育上清及组织匀浆液的细胞因子。
结果:实验一:(1)模型组小鼠血清抗dsDNA抗体的滴度与正常对照组比较,明显增高。血必净治疗能显著降低SLE小鼠的抗dsDNA抗体的滴度。(2)狼疮小鼠肾脏的组织病理主要表现为增生性肾小球肾炎。肾小球系膜细胞和系膜基质增生,嗜复红蛋白沉积,新月体形成。血必净治疗能明显减轻狼疮鼠肾脏组织的损伤。与正常对照进行比较,模型组小鼠血中Cr、BUN含量显著升高(P <0.01)。血必净治疗可明显降低动物血中Cr、BUN含量,与模型组比较,有统计学意义(P <0.01),与正常对照进行比较,无统计学差异。实验二:(1)孵育24小时后,模型组动物脾脏DC表面共刺激分子CD80表达明显升高,与正常对照组比较有统计学显著差异(P < 0.01),CD86和MHCII弱表达。8周龄及10周龄治疗组脾脏DC表面共刺激分子CD80的表达仍维持在较高水平,与模型组比较无统计学差异,CD86和MHCII的表达与模型组比较明显升高,与模型组比较有统计学差异(P <0.05)。表明血必净治疗可以使SLE小鼠脾脏DC表面共刺激分子的表达升高。(2)将DC与T淋巴细胞按照不同比例(1:100、1:150、1:200)相互作用3天和5天后,与正常对照组比较,模型组小鼠T淋巴细胞增殖活性受到抑制,给予血必净治疗后增殖抑制效应减轻。(3)与正常对照组比较,模型组IL-4、TNF-a的含量显著升高(P<0.01),而IL-2、IFN-γ及IL-12的水平明显降低(P<0.01)。动物脾脏组织及T淋巴细胞IL-2的基因表达显著下降,而TNF-a基因表达则明显升高(P<0. 01~0.05)。血必净治疗后,与模型组比较,狼疮鼠IL-4、TNF-a的含量显著降低(P<0. 01~0.05),而IL-2、IFN-γ及IL-12的水平明显升高(P<0.01~0.05),IL-2的基因表达显著升高,TNF-a基因表达明显降低,具有统计学差异。
结论:树突细胞在系统性红斑狼疮疾病的发展过程中具有重要的作用,DC向成熟发展,但表型表达异常,存在功能障碍,从而介导T淋巴细胞增殖反应低,并向Th2漂移。血必净治疗能够保护动物的脏器损害,改善DC的功能障碍,促进Th1的增殖和发育,将Th2细胞转化为Th1细胞,改变Th1 /Th2的比例和机体的免疫应答类型,对系统性红斑狼疮的免疫功能产生影响。
Objective: Systemic lupus erythematosus(SLE)is a multifactorial autoimmune disease characterized by breakdown of self-tolerance,autoantibody production,aberrant formation of immune complexes(IC),and inflammation of multiple organs.Dendritic cells (DCs) are functionally abnormal in systemic lupus erythematosus (SLE). The present study was performed to identify a protective role for Xuebijing administration in systemic lupus erythematosus (SLE)-prone BLLF1 mice. To observe the effect of Xuebijing on DC to T lymphocyte and its potential mechanisms in SLE.
Methods: A widely used model for in systemic lupus erythematosus (SLE)-prone BLLF1 mice was used in these studies. Ten normal female mice and thirty BLLF1 female mice were divided into four groups as follows: normal control group (10 mice), model control group (10 mice), SLE (8w) with Xuebijing treatment group (10 mice), and SLE(10w)Xuebijing treatment group (10 mice). Xuebijing 6.4ml/kg was given via dorsal penile vein in Xuebijing treatment group. In the first experiment,.animals of all groups were sacrificed, and blood, kidney samples were harvested aseptically to determine. In the second experiment spleen was divided into two parts as following: one part was used to procure DC by MACS microbeads and T cell by using column of nylon wool, and the other part was used to detect gene and protein expression levels of various cytokines. Cells were cultured and phenotypes were analyzed by flow cytometry. The contents of cytokines released into supernatants were also determined. Gene expression was measured by real-time quantitative PCR as the internal standard. All cytokines in supernatant and tissue were determined by ELISA kits for mice.
Result: 1.Mice demonstrated characteristic alterations of serum immune parameters, the levels of anti-dsDNA antibodies in model control group were significantly higher than the normal group. Treatment with Xuebijing could inhibit the expression levels of anti-dsDNA antibodies.Conventional histological staining of kidneys showed abnormalities in BLLF1 mice at ages 8-10 weeks. Prominent mononuclear cell infiltrating was also observed, with predominantly perivascular localization in the cortex and medulla of the kidneys. In contrast, minimal histopathologic abnormalities can be observed in Xuebijing treatment group. The serum Crand CRE and BUN levels were significantly elevated in SLE, and treatment with Xuebijing could inhibit these increase to different extent.
2.In the model control group, DC expressed strongly enhanced levels of CD80 and slightly enhanced levels of CD86 and MHC classⅡcompared with DC from normal mice. Treatment with Xuebijing could significantly up-regulated the expression levels of CD80, CD86 and MHC classⅡof DC. Splenic T lymphocyte proliferative response to ConA, were suppressed on days 3 and 5 after cultured in the presence of DC to T lymphocyte ratios in 1:100, 1:150 and 1:200 in the model control group, Xuebijing treatment could restore T cell proliferative activity. In the model control group, with marked production of interferon-γ, interleukin-2, TNF-alpha and interleukin-4 in supernatants, the levels of IL-4 and TNF-αincreased significantly ,but the levels of IL-2, and IFN-γand IL-12decreased markedly, The gene expression levels of IL-2 were also decreased and TNF-alpha were increased. Xuebijing treatment could significantly inhibite increase of IL-4, TNF-αand decrease of IL-2, IFN-γand IL-12.
Conclusion: Dendritic cells play an important role in the development of SLE. The splenic DC express abnormally, and further induce suppression of T lymphocyte immune function and drifting to Th2 in SLE. Xuebijing treatment might influence the polarization of T cells in animals in SLE and induced Th cells to drift to Th1 cells. Xuebijihg has a potential therapeutic for suppressing immune dysfunction and ameliorating multiple organ injury in SLE.
引文
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52. Baker SJ, Reddy EP. Transducers of life and death: TNF receptor superfamily and associated proteins. Oncogene, 1996, 12:1-9.
53.蒋建新,姚咏明,郑江,主编.细菌内毒素基础与临床.第1版.北京:人民军医出版社, 2004. 363-371.
54. Erickson SL, de Savage FJ, Kikly K, et al. Decreased sensitivity to tumor-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice. Nature, 1994, 372:560-563.
55. Tartaglia LA, Pennica D, Goeddel DV. Ligand passing: The 75-kd tumor necrosis factor receptor recruit TNF for signaling by the 55-kd TNF receptor. J Biol Chem, 1993, 268:18542-18548.
56. Soares MP, Muniappan A, Kaczmarek, et al. Adenovirus mediated ezperssion of a dominant negative mutant of p65/Rela inhibit proinflammatory gene expression in endothelial cells. J Immunol, 1998, 161:4572-4582
57. Wang CY, Mayo MW, Korneluk RG, et al. NF-κB antiapoptosis: Induction of TRAF1 and TRAF2 and c-IPA1 and cIAP2 to suppress caspase-8 activation. Science 1998, 281:1680-1683.
58 Radvanyi LG, Banerjee A, Weir M, et al. Low levels of interferon-alpha induce CD86 (B7.2) expression and accelerates dendritic cell maturation from human peripheral blood mononuclear cells. Scand J Immunol, 1999, 50(5):499-509.
59 Luft T, Pang KC, Thomas E, et al. Type I IFNs enhance the terminal differentiation of dendritic cells. J Immunol, 1998, 161(4):1947-1953.
60 Le Bon A, Etchart N, Rossmann C, et al. Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon. Nat Immunol, 2003, 4(10):1009- 1015.
61 Buelens C, Bartholome EJ, Amraoui Z, et al. Interleukin-3 and interferon beta cooperate to induce differentiation of monocytes into dendritic cells with potent helper T-cell stimulatory properties. Blood, 2002, 99(3):993-998.
62 Wu X, Hou W, Sun S, et al. Novel function of IFN-gamma: negative regulation of dendritic cell migration and T cell priming. J Immunol, 2006, 177(2):934-943.
63 Banyer JL, Halliday DC, Thomson SA, et al. Combinations of IFN-gamma and IL-4 induce distinct profiles of dendritic cell-associated immunoregulatory properties. Genes Immun, 2003, 4(6):427-440.
64. Tracy KJ, Cerami A. Tumor necrosis factor: a pleiotropic cytokine and therapeutic target. Annu Rev Med, 1994, 45:491-503.
65. Hanlon WA, Stolk J, Davies P, et al. rTNF alpha facilitates human polymer- phonuclear leukocyte adherence to fibrinogen matrices with mobilization of specific and tertiary but not azurophilic granule markers. J Leukoc Biol, 1991, 50:43-48.
66. Deguchi Y, Kishimoto S. Tumour necrosis factor/cachectin plays a key role in autoimmune pulmonary inflammation in lupus-prone mice. Clin Exp Immunol, 1991, 85: 392-395.
67. Tracey KJ; Cerami A. Tumor necrosis factor in the malnutrition (cachexia) of infection and cancer.. Am J Trop Med Hyg,1992, 47: 2-7
68. Schofield L, Vivas L, Hackett F. Neutralizing monoclonal antibodies to gly- cosylphosphatidylinositol, the dominant TNF-alpha-inducing toxin of plasmodium falciparum: prospects for the immunotherapy of severe malaria. Ann Trop Med Parasitol, 1993, 87: 617-626.
69. Tracey KJ, Cerami A. Tumor necrosis factor, other cytokines and disease.Annu Rev Cell Biol, 1993, 9:317-343.
70. Fiers W. Tumor necrosis: characterization at the molecular, celluar and in vivo level. FEBS Lett, 1991, 285:199-212.
71. Baker SJ, Reddy EP. Transducers of life and death: TNF receptorsuperfamily and associated proteins. Oncogene, 1996, 12:1-9.
72.蒋建新,姚咏明,郑江,主编.细菌内毒素基础与临床.第1版.北京:人民军医出版社, 2004. 363-371.
73. Erickson SL, de Savage FJ, Kikly K, et al. Decreased sensitivity to tumor-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice. Nature, 1994, 372:560-563.
74. Tartaglia LA, Pennica D, Goeddel DV. Ligand passing: The 75-kd tumor necrosis factor receptor recruit TNF for signaling by the 55-kd TNF receptor. J Biol Chem, 1993, 268:18542-18548.
75. Soares MP, Muniappan A, Kaczmarek, et al. Adenovirus mediated ezperssion of a dominant negative mutant of p65/Rela inhibit proinflammatory gene expression in endothelial cells. J Immunol, 1998, 161:4572-4582
76. Wang CY, Mayo MW, Korneluk RG, et al. NF-κB antiapoptosis: Induction of TRAF1 and TRAF2 and c-IPA1 and cIAP2 to suppress caspase-8 activation. Science 1998, 281:1680-1683.
77. Matsuguchi T, Musikacharoen T, Ogawa T, et al. Gene expressions of Toll-like receptor 2, but not Toll-like receptor 4, is induced by LPS and inflammatory cytokines in mouse macrophages. J Immunol, 2000, 165: 5767-5772.
78. Semenzato G.Tumor necrosis factor:a cytokines with multiple biological activities [J].Br J Cancer,1990,61:354.
79. Hassuneh MR,Nagarkatti PS,Nagarkatti M.Evidence for the articipation of interleukin-2(IL-2) and IL-4 in the regulation of antonomous growth and tumorigenesis of trans-formed cells of lymphoid origin [J].Blood,1997,89:610.
80. Matesarz F,Fedetz M,Colladoromero M,et al.Allelic expression and interleukin-2 polymorphis in multiple sclerosis [J].J Neuroimmunol,2001,119:101-105.
81.Banyer JL, Halliday DC, Thomson SA, et al. Combinations of IFN-gamma and IL-4 induce distinct profiles of dendritic cell-associated immunoregulatory properties. Genes Immun, 2003, 4(6):427-440.
82 utz MB, Schnare M, Menges M, et al. Differential functions of IL-4 receptor types I and II for dendritic cell maturation and IL-12 production and their dependency on GM-CSF. J Immunol, 2002, 169(7):3574-3580
83 Roy KC, Bandyopadhyay G, Rakshit S, et al. IL-4 alone without the involvement of GM-CSF transforms human peripheral blood monocytes to a CD1a (dim), CD83(+) myeloid dendritic cell subset. J Cell Sci, 2004, 117(Pt 16):3435-3445.
84 Klimp AH, de Vries EG, Scherphof GL, et al. A potential role of macrophage activation in the treatment of cancer. Crit Rev Oncol Hematol, 2002, 44(2):143-161.
85 Syme R, Gluck S. Generation of dendritic cells: role of cytokines and potential clinical applications. Transfus Apher Sci, 2001, 24(2):117-124.
86 Hochrein H, O'Keeffe M, Luft T, et al. Interleukin (IL)-4 is a major regulatory cytokine governing bioactive IL-12 production by mouse and human dendritic cells. J Exp Med, 2000, 192(6):823-833.
87 Bertorelli G, Bocchino V, Zhou X, et al. Dendritic cell number is related to IL-4 expression in the airways of atopic asthmatic subjects. Allergy, 2000, 55(5):449-454.
88 Rogge L,Barberis-Maino L,Biffl M,et al.Selective expression of an interleukin-12 receptor component by human T help 1 cells[J]. J Expmed,1997,185:825-831.
89 Gabrielsson S, Soderlund A. Influence of atopic heredity on IL-4, IL-12 and IFN-gamma-producting cells in vitro activated cord blood mononuclear cells[J]. Clin Exp Immunol 2001,126(3):390-396.
90 Tyrrell-Price J, Lydyard PM. The effect of interleukin-10 and of interleukin-12 on the in vitro production of anti-double stranded DNA antibodies from patients with systemic lupus erythematosus[J]. Clin Exp Immunol 2001,124(1):118-125.
91. WEENING JJ, D'AGATI VD, SCHWARTZ MM, et a1.The classification of glo- merulonephritis in systemic lupus erythematosus revisited[J]. J Am Soc Nephrol, 2004,15(2):241-50.
92. WEENING JJ, D'AGATI VD, SCHWARTZ MM, et a1.The classification of glomerulonephritis in systemic lupus erythematosus revisited[J]. Kidney Int, 20 04 ,65(2):521-30.
93姚咏明,柴家科,林洪远,主编.现代脓毒症理论与实践.第1版.北京:科学出版社, 2005. 1112-1152.
94 U C C, LIAO M H, CHEN S J, et al. Tetramethylpyradizine prevents inducible NO’synthase expression and improves survival in rodent models of endotoxic shock[J].Naunyn Schmiedebergs Arch Pharrnacol,1999,360(4):435-44
95 WAN J M, SIT W H, LEE C L, et al. Protection of lethal toxicity of endotoxin by Salvia miltiorrhiza Bunge is via reduction in tumor necrosis factor alpha release and liver injury[J].Int Immunopharmacol ,2006,(5): 750-758.
96 WANG H, LI W, LI J, et al. The aqueous extract of a popular berbal nutrient supplement, Angelica sinensis, protects mice against lethal endotoxemia andsepsis [J].J Nutr,2006,136(2):360-365.
97 GENFA L, JLANG Z, HONG Z, et al. The screening and isolation of an effective anti-endotoxin monomer from Radix Paeoniae Rubra using affinity biosensor technology [J].Int Immunopharmaool, 2005,5(6):1007-1017.
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26 Suen JL,Chuang YH.Chiang BL.In vivo tolerance breakdown with dendritic cells pulsed with UI A protein in non—autoimmune mice:the induction of a high level of autoantibodies but not renal pathological changes.Immunology,2002,106(3):326-335.
27 Mehling A,Loser K,Varga G et a1.Overexpression of CD40 ligand in murine epidermis results in chronic skin inflammation and systemic autoimmunity.J Exp Med,2001,194:615-628.
28 Georgiev M,Agle LM,Chu JL et a1.Mature dendritic cells readily break tolerance in normal mice but do not lead to disease expression.Arthritis Rheum,2005,52(1):225-238.
29 Mudda PA,Teague BN,Farris AD.Regulatory T cells and systemic lupus erythematosus.Scand J Immunol,2006,64(3):2ll-218.
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36 Luft T, Pang KC, Thomas E, et al. Type I IFNs enhance the terminal differentiation of dendritic cells. J Immunol, 1998, 161(4):1947-1953.
37 Le Bon A, Etchart N, Rossmann C, et al. Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon. Nat Immunol, 2003, 4(10):1009- 1015.
38 Buelens C, Bartholome EJ, Amraoui Z, et al. Interleukin-3 and interferon beta cooperate to induce differentiation of monocytes into dendritic cells with potent helper T-cell stimulatory properties. Blood, 2002, 99(3):993-998.
39 Wu X, Hou W, Sun S, et al. Novel function of IFN-gamma: negative regulation of dendritic cell migration and T cell priming. J Immunol, 2006, 177(2):934-943.
40 Banyer JL, Halliday DC, Thomson SA, et al. Combinations of IFN-gamma and IL-4 induce distinct profiles of dendritic cell-associated immunoregulatory properties. Genes Immun, 2003, 4(6):427-440.
45. Tracy KJ, Cerami A. Tumor necrosis factor: a pleiotropic cytokine and therapeutic target. Annu Rev Med, 1994, 45:491-503.
46. Hanlon WA, Stolk J, Davies P, et al. rTNF alpha facilitates human polymer- phonuclear leukocyte adherence to fibrinogen matrices with mobilization of specific and tertiary but not azurophilic granule markers. J Leukoc Biol, 1991, 50:43-48.
47. Deguchi Y, Kishimoto S. Tumour necrosis factor/cachectin plays a key role in autoimmune pulmonary inflammation in lupus-prone mice. Clin Exp Immunol, 1991, 85: 392-395.
48. Tracey KJ; Cerami A. Tumor necrosis factor in the malnutrition (cachexia) of infection and cancer.. Am J Trop Med Hyg,1992, 47: 2-7
49. Schofield L, Vivas L, Hackett F. Neutralizing monoclonal antibodies to gly- cosylphosphatidylinositol, the dominant TNF-alpha-inducing toxin of plasmodium falciparum: prospects for the immunotherapy of severe malaria. Ann Trop Med Parasitol, 1993, 87: 617-626.
50. Tracey KJ, Cerami A. Tumor necrosis factor, other cytokines and disease.Annu Rev Cell Biol, 1993, 9:317-343.
51. Fiers W. Tumor necrosis: characterization at the molecular, celluar and in vivo level. FEBS Lett, 1991, 285:199-212.
52. Baker SJ, Reddy EP. Transducers of life and death: TNF receptor superfamily and associated proteins. Oncogene, 1996, 12:1-9.
53.蒋建新,姚咏明,郑江,主编.细菌内毒素基础与临床.第1版.北京:人民军医出版社, 2004. 363-371.
54. Erickson SL, de Savage FJ, Kikly K, et al. Decreased sensitivity to tumor-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice. Nature, 1994, 372:560-563.
55. Tartaglia LA, Pennica D, Goeddel DV. Ligand passing: The 75-kd tumor necrosis factor receptor recruit TNF for signaling by the 55-kd TNF receptor. J Biol Chem, 1993, 268:18542-18548.
56. Soares MP, Muniappan A, Kaczmarek, et al. Adenovirus mediated ezperssion of a dominant negative mutant of p65/Rela inhibit proinflammatory gene expression in endothelial cells. J Immunol, 1998, 161:4572-4582
57. Wang CY, Mayo MW, Korneluk RG, et al. NF-κB antiapoptosis: Induction of TRAF1 and TRAF2 and c-IPA1 and cIAP2 to suppress caspase-8 activation. Science 1998, 281:1680-1683.
58 Radvanyi LG, Banerjee A, Weir M, et al. Low levels of interferon-alpha induce CD86 (B7.2) expression and accelerates dendritic cell maturation from human peripheral blood mononuclear cells. Scand J Immunol, 1999, 50(5):499-509.
59 Luft T, Pang KC, Thomas E, et al. Type I IFNs enhance the terminal differentiation of dendritic cells. J Immunol, 1998, 161(4):1947-1953.
60 Le Bon A, Etchart N, Rossmann C, et al. Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon. Nat Immunol, 2003, 4(10):1009- 1015.
61 Buelens C, Bartholome EJ, Amraoui Z, et al. Interleukin-3 and interferon beta cooperate to induce differentiation of monocytes into dendritic cells with potent helper T-cell stimulatory properties. Blood, 2002, 99(3):993-998.
62 Wu X, Hou W, Sun S, et al. Novel function of IFN-gamma: negative regulation of dendritic cell migration and T cell priming. J Immunol, 2006, 177(2):934-943.
63 Banyer JL, Halliday DC, Thomson SA, et al. Combinations of IFN-gamma and IL-4 induce distinct profiles of dendritic cell-associated immunoregulatory properties. Genes Immun, 2003, 4(6):427-440.
64. Tracy KJ, Cerami A. Tumor necrosis factor: a pleiotropic cytokine and therapeutic target. Annu Rev Med, 1994, 45:491-503.
65. Hanlon WA, Stolk J, Davies P, et al. rTNF alpha facilitates human polymer- phonuclear leukocyte adherence to fibrinogen matrices with mobilization of specific and tertiary but not azurophilic granule markers. J Leukoc Biol, 1991, 50:43-48.
66. Deguchi Y, Kishimoto S. Tumour necrosis factor/cachectin plays a key role in autoimmune pulmonary inflammation in lupus-prone mice. Clin Exp Immunol, 1991, 85: 392-395.
67. Tracey KJ; Cerami A. Tumor necrosis factor in the malnutrition (cachexia) of infection and cancer.. Am J Trop Med Hyg,1992, 47: 2-7
68. Schofield L, Vivas L, Hackett F. Neutralizing monoclonal antibodies to gly- cosylphosphatidylinositol, the dominant TNF-alpha-inducing toxin of plasmodium falciparum: prospects for the immunotherapy of severe malaria. Ann Trop Med Parasitol, 1993, 87: 617-626.
69. Tracey KJ, Cerami A. Tumor necrosis factor, other cytokines and disease.Annu Rev Cell Biol, 1993, 9:317-343.
70. Fiers W. Tumor necrosis: characterization at the molecular, celluar and in vivo level. FEBS Lett, 1991, 285:199-212.
71. Baker SJ, Reddy EP. Transducers of life and death: TNF receptorsuperfamily and associated proteins. Oncogene, 1996, 12:1-9.
72.蒋建新,姚咏明,郑江,主编.细菌内毒素基础与临床.第1版.北京:人民军医出版社, 2004. 363-371.
73. Erickson SL, de Savage FJ, Kikly K, et al. Decreased sensitivity to tumor-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice. Nature, 1994, 372:560-563.
74. Tartaglia LA, Pennica D, Goeddel DV. Ligand passing: The 75-kd tumor necrosis factor receptor recruit TNF for signaling by the 55-kd TNF receptor. J Biol Chem, 1993, 268:18542-18548.
75. Soares MP, Muniappan A, Kaczmarek, et al. Adenovirus mediated ezperssion of a dominant negative mutant of p65/Rela inhibit proinflammatory gene expression in endothelial cells. J Immunol, 1998, 161:4572-4582
76. Wang CY, Mayo MW, Korneluk RG, et al. NF-κB antiapoptosis: Induction of TRAF1 and TRAF2 and c-IPA1 and cIAP2 to suppress caspase-8 activation. Science 1998, 281:1680-1683.
77. Matsuguchi T, Musikacharoen T, Ogawa T, et al. Gene expressions of Toll-like receptor 2, but not Toll-like receptor 4, is induced by LPS and inflammatory cytokines in mouse macrophages. J Immunol, 2000, 165: 5767-5772.
78. Semenzato G.Tumor necrosis factor:a cytokines with multiple biological activities [J].Br J Cancer,1990,61:354.
79. Hassuneh MR,Nagarkatti PS,Nagarkatti M.Evidence for the articipation of interleukin-2(IL-2) and IL-4 in the regulation of antonomous growth and tumorigenesis of trans-formed cells of lymphoid origin [J].Blood,1997,89:610.
80. Matesarz F,Fedetz M,Colladoromero M,et al.Allelic expression and interleukin-2 polymorphis in multiple sclerosis [J].J Neuroimmunol,2001,119:101-105.
81.Banyer JL, Halliday DC, Thomson SA, et al. Combinations of IFN-gamma and IL-4 induce distinct profiles of dendritic cell-associated immunoregulatory properties. Genes Immun, 2003, 4(6):427-440.
82 utz MB, Schnare M, Menges M, et al. Differential functions of IL-4 receptor types I and II for dendritic cell maturation and IL-12 production and their dependency on GM-CSF. J Immunol, 2002, 169(7):3574-3580
83 Roy KC, Bandyopadhyay G, Rakshit S, et al. IL-4 alone without the involvement of GM-CSF transforms human peripheral blood monocytes to a CD1a (dim), CD83(+) myeloid dendritic cell subset. J Cell Sci, 2004, 117(Pt 16):3435-3445.
84 Klimp AH, de Vries EG, Scherphof GL, et al. A potential role of macrophage activation in the treatment of cancer. Crit Rev Oncol Hematol, 2002, 44(2):143-161.
85 Syme R, Gluck S. Generation of dendritic cells: role of cytokines and potential clinical applications. Transfus Apher Sci, 2001, 24(2):117-124.
86 Hochrein H, O'Keeffe M, Luft T, et al. Interleukin (IL)-4 is a major regulatory cytokine governing bioactive IL-12 production by mouse and human dendritic cells. J Exp Med, 2000, 192(6):823-833.
87 Bertorelli G, Bocchino V, Zhou X, et al. Dendritic cell number is related to IL-4 expression in the airways of atopic asthmatic subjects. Allergy, 2000, 55(5):449-454.
88 Rogge L,Barberis-Maino L,Biffl M,et al.Selective expression of an interleukin-12 receptor component by human T help 1 cells[J]. J Expmed,1997,185:825-831.
89 Gabrielsson S, Soderlund A. Influence of atopic heredity on IL-4, IL-12 and IFN-gamma-producting cells in vitro activated cord blood mononuclear cells[J]. Clin Exp Immunol 2001,126(3):390-396.
90 Tyrrell-Price J, Lydyard PM. The effect of interleukin-10 and of interleukin-12 on the in vitro production of anti-double stranded DNA antibodies from patients with systemic lupus erythematosus[J]. Clin Exp Immunol 2001,124(1):118-125.
91. WEENING JJ, D'AGATI VD, SCHWARTZ MM, et a1.The classification of glo- merulonephritis in systemic lupus erythematosus revisited[J]. J Am Soc Nephrol, 2004,15(2):241-50.
92. WEENING JJ, D'AGATI VD, SCHWARTZ MM, et a1.The classification of glomerulonephritis in systemic lupus erythematosus revisited[J]. Kidney Int, 20 04 ,65(2):521-30.
93姚咏明,柴家科,林洪远,主编.现代脓毒症理论与实践.第1版.北京:科学出版社, 2005. 1112-1152.
94 U C C, LIAO M H, CHEN S J, et al. Tetramethylpyradizine prevents inducible NO’synthase expression and improves survival in rodent models of endotoxic shock[J].Naunyn Schmiedebergs Arch Pharrnacol,1999,360(4):435-44
95 WAN J M, SIT W H, LEE C L, et al. Protection of lethal toxicity of endotoxin by Salvia miltiorrhiza Bunge is via reduction in tumor necrosis factor alpha release and liver injury[J].Int Immunopharmacol ,2006,(5): 750-758.
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