人胎儿源间充质干细胞的分离鉴定及其在免疫性肝损伤中的免疫双效作用研究
|
摘要
目的:近年来,间充质干细胞(mesenchymal stem cell,MSC)以其能在自体、同种异体甚至异种异体体内,旺盛地增殖和多向地分化,有效修复甚至完全重建功能严重受损甚或几近缺如的组织器官而不被排斥,已经成为组织修复和再生重建领域内备受关注的研究热点。在人源MSC中,胎儿源MSC与成人源者相比,因其发育上更早、更少被病原体感染、安全性更高、获取和制备相对更为捷易等优点,更是成为人们多愿选择的来源。
现代免疫学研究已经揭示,自体和同基因个体(如同卵孪生和纯系内个体)间的组织器官移植之所以不被排斥,是因供体与受体的组织相容性抗原一致或几近一致所致。而同种异体间,尤其是异种异体间的组织器官移植一定会被排斥,是因供体和受体间组织相容性抗原不一致而致,且两者间的组织相容性抗原相差越远,则排斥反应的发生就越迅速、越强烈。由是,在人类为修复或重建功能已严重受损甚至已几近缺如的组织器官,除同卵孪生外,因实难觅组织相容性抗原一致或几近一致的供体,不得已而在移植后必须长期应用昂贵的免疫抑制剂维持,但随之又会带来易发严重感染甚至肿瘤的危险。由此,既不难理解为何人们会对人源尤其是胎儿源MSC寄予厚望而备受关注,同时也强烈提示,同种异体特别是异种异体MSC移植不被排斥,是否是其本身具有介导和启动有效免疫抑制作用机制所致;如是,则在其应用之后是否有抑制机体免疫功能特别是招致肿瘤发生的风险性,势必就成为该领域中必须予以高度重视和深入探索的重要课题。
迄今,已有许多研究小组对MSC在组织修复和免疫耐受重建等领域的实验研究和临床应用,进行了多方面的大胆探索和勇敢尝试。有关心肌修复、骨疾病及代谢性疾病的MSC细胞治疗的临床试验已在世界各地先后开展;而Le Blanc及其同事应用同种异体MSC于移植物抗宿主病(graft versus host disease, GVHD)的大胆尝试,更坚定了人们将其应用于免疫损伤性疾病治疗的信心。还有将自体或同种异体MSC以不同给药方式(局部、静脉和腹腔)治疗实验性自身免疫性脑脊髓炎(experimental autoimmune encephalomyelitis, EAE)及Ⅱ型胶原诱导的类风湿性关节炎(collagenⅡ-induced arthritis, CIA)模型的研究均获成功。更兼我们惊奇地发现经与未经预处理的人胎儿源MSC,对ConA诱导的免疫性肝损伤有双效作用,因这确是在世界上尚无报道,而极大地激发了我们对人胎儿源MSC免疫生物学特性及其与肿瘤免疫学关系的浓厚研究兴趣。
为此,本课题分离鉴定了胎儿骨髓源和羊水源MSC以优化来源,研究其免疫抑制功能特别是对ConA诱导免疫性肝损伤的双效作用,在分析其介导的免疫抑制分子的基础上,探索其之致瘤的风险性,为MSC的进一步研究和应用提供新的理论和实验依据。
方法:贴壁消化传代培养法,自人胎儿骨髓及羊水细胞获取,并经形态学、细胞表面标记和分化潜能鉴定,确系为人胎儿源MSC(以下简写为hMSC)。MTS法评价hMSC对ConA诱导小鼠脾细胞增殖的抑制作用。获取ConA刺激小鼠脾细胞增殖的培养上清,以其培养hMSC而获取经预处理的hMSC;观察其生长增殖、细胞表型、染色体核型等细胞生物学特性。参照Tiegs等的方法建立ConA诱导免疫性肝损伤动物模型,肝损伤指标包括小鼠存活率、血清谷丙转氨酶(glutamate-pyruvate transaminase,ALT)和谷草转氨酶(glutamic-oxalacetic transaminase,AST)含量以及肝组织病理损伤情况等。以模型动物肝损伤指标为对照,观察经或未经预处理的hMSC对模型动物肝损伤的影响,评价其对肝损伤的保护或促进作用。裸鼠皮下移植,排除hMSC成瘤可能;选择人肝癌细胞系MHCC/97H肿瘤细胞和小鼠肝癌细胞系H22肿瘤细胞为对象,观察hMSC对肿瘤细胞体内/外细胞周期、体外克隆形成能力、荷瘤小鼠生存期、皮下移植瘤体内生长增殖以及体内/外侵袭转移等的影响,评价其致瘤的风险性。
结果:
1人胎儿骨髓源及羊水源MSC的分离鉴定及其免疫抑制作用
贴壁消化传代培养法,自人胎儿骨髓及羊水细胞获取,连续传代培养3~5代后,其形态学、细胞表面标记和分化潜能鉴定,均具人MSC典型特征,确系获得了合格的hMSC。
ConA刺激小鼠脾细胞增殖实验显示,hMSC有显著的、剂量依赖式的免疫抑制作用(P<0.05)。
2未预处理的hMSC对ConA诱导小鼠免疫性肝损伤的作用
未预处理的hMSC可显著降低ConA诱导免疫性肝损伤模型小鼠存活率(P<0.05)、升高模型小鼠血清中肝功能指标ALT和AST含量(P<0.05)并促进肝组织的病理损伤(P<0.05)。显示未预处理的hMSC对ConA诱导免疫性肝损伤有显著的促进作用。
3未预处理的hMSC对模型小鼠肝损伤的促进作用与HLA分子表达及补体C3介导的关系
HLA-A,B,C(+)/HLA-DR(-)及HLA-A,B,C(-)/HLA-DR(-)的hMSC均可显著升高模型小鼠血清中肝损伤指标ALT的含量(P<0.05),显示未预处理的hMSC对模型小鼠肝损伤的促进作用,与其表面HLA分子表达无关;各组小鼠血清ALT和补体C3含量测定及回归分析,显示未预处理的hMSC促进模型小鼠肝损伤亦与补体C3介导无关。
4未预处理的hMSC对正常小鼠肝脏组织的影响
小鼠肝组织病理切片HE染色结果显示,未预处理的hMSC组与正常组小鼠相比,肝小叶周边、界板肝细胞及汇管区的点灶状溶解性坏死、凋亡小体及汇管区炎等病理指标差异明显(P<0.05);提示未预处理的hMSC腹腔注射可致正常小鼠肝组织轻微病理损伤。
5经预处理的hMSC对ConA诱导小鼠免疫性肝损伤的作用。
经预处理的hMSC可显著升高ConA诱导免疫性肝损伤模型小鼠存活率(P<0.05)、降低模型小鼠血清中肝功能指标ALT含量(P<0.05)并显著降低肝组织的病理损伤程度(P<0.05);显示经预处理的hMSC对ConA诱导免疫性肝损伤有显著的保护作用。
6经预处理的hMSC对模型小鼠肝组织FasL表达和脾Treg亚群细胞比例的影响。
经预处理的hMSC可显著减少模型组小鼠肝组织FasL表达(P<0.05)并增加早期时相(3h)脾细胞Treg亚群细胞比例(P<0.05)。提示使模型鼠肝组织FasL表达减少和脾Treg细胞比例增加,可能是经预处理的hMSC对模型小鼠免疫性肝损伤具有保护作用的分子机制。
7经与未经预处理的hMSC相关细胞因子分泌差异
经预处理的hMSC其IL-6、IL-8及RANTES等细胞因子分泌,较未预处理的hMSC增多。提示,经预处理的hMSC有可能藉增加这些细胞因子的分泌,参与对ConA诱导免疫性肝损伤的保护作用。
8经预处理的hMSC的自身成瘤性
以ConA刺激小鼠脾细胞增殖的培养上清对hMSC行预处理后, hMSC的细胞周期被阻于G0/G1期,增殖指数显著降低(P<0.05);细胞表型和染色体核型保持不变;接种于裸鼠皮下,亦无肿瘤形成。提示预处理未导致hMSC的自身成瘤性。
9经预处理的hMSC的促瘤性
经与未经预处理的hMSC,均可使人肝癌细胞系MHCC/97H肿瘤细胞及小鼠肝癌细胞系H22肿瘤细胞阻滞于G0/G1期,显著降低两种肿瘤细胞的增殖指数(P<0.05);均可使MHCC/97H肿瘤细胞体外克隆形成能力显著降低(P<0.05);预处理与否,不影响hMSC对这两种肿瘤细胞发挥上述这些抑制作用的强度(P>0.05)。经与未经预处理的hMSC,对MHCC/97H肿瘤细胞和H22肿瘤细胞体内移植瘤的生长增殖、体内/外侵袭转移及荷瘤小鼠生存期无影响(P>0.05)。提示预处理未导致hMSC的促瘤性。
结论:
1贴壁消化传代培养法可有效从骨髓和羊水,获取合格的人胎儿源MSC。
2人胎儿源MSC对ConA刺激的T细胞增殖有显著的免疫抑制作用。
3经或未经ConA刺激T细胞增殖的培养上清预处理,可显著改变人胎儿源MSC对ConA诱导免疫性肝损伤的影响模式,此结果与结论国内外未见报道。
4未预处理的人胎儿源MSC对ConA诱导免疫性肝损伤有显著的促进作用。
5经预处理的人胎儿源MSC对ConA诱导免疫性肝损伤有显著的保护作用。
6未预处理的人胎儿源MSC对ConA诱导免疫肝损伤的促进作用与其表面HLA分子表达及补体C3的介导作用无关。
7经预处理的人胎儿源MSC对ConA诱导免疫肝损伤的保护作用与其致肝组织FasL表达降低及脾细胞早期时相(3h)Treg亚群细胞比例增高有关。
8经预处理的人胎儿源MSC,其IL-6、IL-8及RANTES细胞因子表达增加。
9人胎儿源MSC在观察期内未见成瘤性和促瘤活性,初步判断其在所观察期内不具有致瘤风险性。
Obiectives: Have emerged as a promising therapeutic modality for tissue regeneration and repair, MSCs have low immunogenicity and the ability to migrate to sites of tissue injury and rapidly expand and differentiate along its own, allogeneil or xenogeneic lineages to repair the damaged tissue without rejection. Compare to the MSCs from adult, the human MSCs from fetus are present earlier during development, less likely to be infected with pathogen and can be more easily harvested. Therefore, MSCs from fetus are the main source for transplant.
It is known that transplant between individuals with different genetic background can induce the rejection, which has not been solved perfectly until now. It hinders the clinical application of transplant. MSC transplant have generated expectations since MSCs are capable of differentiating along multiple lineages and have low immunogenicity.Numerous studies have demonstrated that MSCs have powerful immunosuppressive function, and may be involved in the mechanism of the vanishing of graft rejection. Therefore, it is very important to show that the engraft of ectogenic MSCs do not induce tumorigenesis.
Up to now, MSCs are largely studied for their uses in tissue repair, immunotolerance reestablishment and other fields. The clinical trials of MSCs therapy in cardiac muscle repair, bone disease and metabolic disease have been carried out all over the world. Several studies indicated that adoption of autogeneic or allogenetic MSCs by different administration routes (region/i.v./i.p.) has therapeutic action on experimental autoimmune encephalomyelitis (EAE)and collagenⅡ-induced arthritis(CIA). Moreover, Le Blanc and his colleague have successfully harnessed MSCs to treat severe acute graft-versus-host disease(GVHD), and greatly reduced the incidence of GVHD. These results all suggest that MSCs could provide an ideal cell source in the treatment of immune-mediated diseases.
In this study we examined the effect of hMSCs on ConA-induced hepatitis, and verified the therapeutic value and mechanism of hMSC in autoimmune hepatitis (AIH). Additionally, we validated the potential oncogenicity and promotion to hepatoma growth of hMSCs.
Methods: hMSCs were isolated from aborted fetus’s bone marrow or amniotic fluid. In order to certifficate the cells cultured in vitro are hMSC, we observed the cell morphology under a phase microscope, detected the phenotype by flow cytometry (FCM) and identified the potential for differentiation by culture cells under conditions that favored adipogenic and osteogenic differentiation. To confirm the immunomodulatory effect of hMSCs isolated from aborted fetus’s bone marrow or amniotic fluid in vitro using MTS. Splenocytes stimulated by ConA were incubated in medium, the medium supernatant was harvested. hMSCs were incubated in the supernatant, and its features including proliferation, phenotype and chromosome caryotype were observed. ConA mice model were performed according to the protocol of Tiegs. The indexes of hepatic injury included the serum levels of alanine aminotransferase (ALT) , aspartate aminotransferase (AST) and C3, and the pathological lesion of liver. We used the indexes above to verify the effect of hMSCs with or without pretreated to the ConA mice model. To test if mice splenocytes cultivate supernatant pretreatment could induce the malignant growth of hMSCs, hMSCs with pretreated were subcutaneously inoculated in athymic mice. To test the influence of hMSCs to tumor, we used MHCC/97H (human hepatoma carcinoma cell) and H22(mouse hepatoma carcinoma cell) as the target cells of hMSC with or withou pretreated and detected the cell cycle, proliferation and the capability of invasion in vivo or in vitro.
Results:
1 The preparation and identification of hMSCs and its Immunosuppression.
hMSCs were isolated from aborted fetus’s bone marrow or amniotic fluid, and then was cultured as adherent cells. The cell of passage 3-5 displayed a morphology and phenotype typical of MSC, showing the potential for differentiation into adipogenic, chondrogenic and osteogenic cells.
Compared to the control group, the proliferation of splenocytes induced by ConA in the hMSC-treated group was significantly suppressed in a dose-dependent fashion(P<0.05).
2 hMSCs without pretreated can exacerbate the immunologic liver injury in ConA mice
hMSCs without pretreated could cut down the survival rate (P<0.05), heighten the serum content of ALT and AST (P<0.05) and intensify the ConA-induced liver injury (P<0.05).These findings indicated hMSCs without pretreated could exacerbate the immunologic liver injury in ConA mice.
3 The promotion to immunologic injury induced by ConA of hMSCs without pretreated were independent on the expression of HLA-A,B,C or the serum content of C3
HLA-A,B,C(-)/HLA-DR(-) and HLA-A,B,C(+)/HLA-DR(-) hMSCs without pretreated could both significantly increase the serum ALT levels(P<0.05). These results indicated the promotion to immunologic injury of hMSCs without pretreated were independent on the expression of HLA-A,B,C.
Multiple linear regression was used to analyze the relationship between C3 and ALT, excluding the influence of time and group, there was no relationship between ALT and C3 (P>0.05). The above result showed that the promotion to immunologic injury of hMSCs without pretreated was independent on the serum contents of C3.
4 hMSCs without pretreated can induce light damage of liver cells in normal mice
Compared with the NS/NS group,the focus lytic necrosis, apoptotic body and inflammation in the district of portal in the ambitus of acini hepatis and the district of portal in the NS/na?ve hMSC group were different(P<0.05), indicated that hMSCs without pretreated could induce light damage of liver cells in normal mice.
5 hMSCs with pretreated can extenuate the immunologic liver injury in ConA mice
hMSCs with pretreated could increase the survival rate (P<0.05), cut down the serum content of ALT and AST (P<0.05) and extenuate the ConA-induced liver injury (P<0.05). These findings indicated hMSCs with pretreated could protect the liver injury ConA mice .
6 The decrease of FasL expression on hepatic tissue and the increase in the Treg cell ratio in splenocytes may involve in the protective effect of hMSCs with pretreated.
hMSCs with pretreated can suppress the expression of FasL (P<0.05) and increase the ratio of Treg cell in splenocytes in the earlier period(3h) (P<0.05).
7 The expression of IL-6, IL-8 and RANTES were increased in hMSCs with pretreated.
By detecting the expression of inflammatory factor in the cultivate supernatant of hMSCs with or without pretreated by antibody array, we could find that the hMSC with pretreated expressed more IL-6, IL-8 and RANTES than hMSC without pretreated, and it may involve the protective effect of hMSCs with pretreated.
8 Pretreatment could not induce the malignant growth of hMSCs
The hMSCs with pretreated by mice splenocytes cultivate supernatant has the same phenotype(CD29+, CD44+, CD90+, CD105+;HLA-DR-, CD14-, CD19-, CD34-, CD45-, CD31-) and caryotype of chromosome (2n=46)with hMSCs with or without pretreated proliferate arrest by blocking cell cycle at G0/G1 stage(P<0.05). Subcutaneous inoculation of hMSCs with pretreated in athymic mice, and no tumor emerge. So pretreated hMSCs by mice splenocytes cultivate supernatant could not induce the malignant growth of hMSC.
9 The effect of hMSCs with or without pretreated on the growth of hepatica cells in vivo or vitro
hMSCs with or without pretreated can induce the MHCC/97H or H22 cells by blocking cell cycle at G0/G1 stage (P<0.05), and the inhibitory intensity between two type hMSC was not statistically significant (P>0.05). And hMSCs with or without pretreated had nothing to do with the capability of migration in vitro of MHCC/97H cell (P>0.05).
Subcutaneous inoculation of MHCC/97H and H22 in athymic and BABL/c mice respectively, then hMSCs with or without pretreated. hMSCs with or without pretreated had nothing to do with the life span, tumor growth and capability of migration of tumor cell in vivo(P>0.05).
Conclusions:
1 Use of adherence-digest-serial subcultivation can harvest functional hMSCs successfully.
2 hMSCs inhibit the proliferation of T cells stimulated by ConA.
3 As we know, this is the first report that hMSCs with or without pretreated has opposite function on the ConA mice.
4 hMSCs without pretreated can significantly exacerbate the immunologic liver injury in ConA mice.
5 hMSCs with pretreated can powerfully protect the ConA mice.
6 The promotion to immunologic injury of ConA mice by hMSCs without pretreated is independent on the expression of HLA-A,B,C and the serum content of C3.
7 The decrease of FasL expression on hepatic tissue and the increase in the Treg cell ratio in splenocytes are related to the protective effect of hMSCs with pretreated.
8 The expression of IL-6, IL-8 and RANTES is increased in hMSC with pretreated.
9 hMSCs isolated from aborted fetus’s bone marrow does not have the risk of tumorigenesis.
现代免疫学研究已经揭示,自体和同基因个体(如同卵孪生和纯系内个体)间的组织器官移植之所以不被排斥,是因供体与受体的组织相容性抗原一致或几近一致所致。而同种异体间,尤其是异种异体间的组织器官移植一定会被排斥,是因供体和受体间组织相容性抗原不一致而致,且两者间的组织相容性抗原相差越远,则排斥反应的发生就越迅速、越强烈。由是,在人类为修复或重建功能已严重受损甚至已几近缺如的组织器官,除同卵孪生外,因实难觅组织相容性抗原一致或几近一致的供体,不得已而在移植后必须长期应用昂贵的免疫抑制剂维持,但随之又会带来易发严重感染甚至肿瘤的危险。由此,既不难理解为何人们会对人源尤其是胎儿源MSC寄予厚望而备受关注,同时也强烈提示,同种异体特别是异种异体MSC移植不被排斥,是否是其本身具有介导和启动有效免疫抑制作用机制所致;如是,则在其应用之后是否有抑制机体免疫功能特别是招致肿瘤发生的风险性,势必就成为该领域中必须予以高度重视和深入探索的重要课题。
迄今,已有许多研究小组对MSC在组织修复和免疫耐受重建等领域的实验研究和临床应用,进行了多方面的大胆探索和勇敢尝试。有关心肌修复、骨疾病及代谢性疾病的MSC细胞治疗的临床试验已在世界各地先后开展;而Le Blanc及其同事应用同种异体MSC于移植物抗宿主病(graft versus host disease, GVHD)的大胆尝试,更坚定了人们将其应用于免疫损伤性疾病治疗的信心。还有将自体或同种异体MSC以不同给药方式(局部、静脉和腹腔)治疗实验性自身免疫性脑脊髓炎(experimental autoimmune encephalomyelitis, EAE)及Ⅱ型胶原诱导的类风湿性关节炎(collagenⅡ-induced arthritis, CIA)模型的研究均获成功。更兼我们惊奇地发现经与未经预处理的人胎儿源MSC,对ConA诱导的免疫性肝损伤有双效作用,因这确是在世界上尚无报道,而极大地激发了我们对人胎儿源MSC免疫生物学特性及其与肿瘤免疫学关系的浓厚研究兴趣。
为此,本课题分离鉴定了胎儿骨髓源和羊水源MSC以优化来源,研究其免疫抑制功能特别是对ConA诱导免疫性肝损伤的双效作用,在分析其介导的免疫抑制分子的基础上,探索其之致瘤的风险性,为MSC的进一步研究和应用提供新的理论和实验依据。
方法:贴壁消化传代培养法,自人胎儿骨髓及羊水细胞获取,并经形态学、细胞表面标记和分化潜能鉴定,确系为人胎儿源MSC(以下简写为hMSC)。MTS法评价hMSC对ConA诱导小鼠脾细胞增殖的抑制作用。获取ConA刺激小鼠脾细胞增殖的培养上清,以其培养hMSC而获取经预处理的hMSC;观察其生长增殖、细胞表型、染色体核型等细胞生物学特性。参照Tiegs等的方法建立ConA诱导免疫性肝损伤动物模型,肝损伤指标包括小鼠存活率、血清谷丙转氨酶(glutamate-pyruvate transaminase,ALT)和谷草转氨酶(glutamic-oxalacetic transaminase,AST)含量以及肝组织病理损伤情况等。以模型动物肝损伤指标为对照,观察经或未经预处理的hMSC对模型动物肝损伤的影响,评价其对肝损伤的保护或促进作用。裸鼠皮下移植,排除hMSC成瘤可能;选择人肝癌细胞系MHCC/97H肿瘤细胞和小鼠肝癌细胞系H22肿瘤细胞为对象,观察hMSC对肿瘤细胞体内/外细胞周期、体外克隆形成能力、荷瘤小鼠生存期、皮下移植瘤体内生长增殖以及体内/外侵袭转移等的影响,评价其致瘤的风险性。
结果:
1人胎儿骨髓源及羊水源MSC的分离鉴定及其免疫抑制作用
贴壁消化传代培养法,自人胎儿骨髓及羊水细胞获取,连续传代培养3~5代后,其形态学、细胞表面标记和分化潜能鉴定,均具人MSC典型特征,确系获得了合格的hMSC。
ConA刺激小鼠脾细胞增殖实验显示,hMSC有显著的、剂量依赖式的免疫抑制作用(P<0.05)。
2未预处理的hMSC对ConA诱导小鼠免疫性肝损伤的作用
未预处理的hMSC可显著降低ConA诱导免疫性肝损伤模型小鼠存活率(P<0.05)、升高模型小鼠血清中肝功能指标ALT和AST含量(P<0.05)并促进肝组织的病理损伤(P<0.05)。显示未预处理的hMSC对ConA诱导免疫性肝损伤有显著的促进作用。
3未预处理的hMSC对模型小鼠肝损伤的促进作用与HLA分子表达及补体C3介导的关系
HLA-A,B,C(+)/HLA-DR(-)及HLA-A,B,C(-)/HLA-DR(-)的hMSC均可显著升高模型小鼠血清中肝损伤指标ALT的含量(P<0.05),显示未预处理的hMSC对模型小鼠肝损伤的促进作用,与其表面HLA分子表达无关;各组小鼠血清ALT和补体C3含量测定及回归分析,显示未预处理的hMSC促进模型小鼠肝损伤亦与补体C3介导无关。
4未预处理的hMSC对正常小鼠肝脏组织的影响
小鼠肝组织病理切片HE染色结果显示,未预处理的hMSC组与正常组小鼠相比,肝小叶周边、界板肝细胞及汇管区的点灶状溶解性坏死、凋亡小体及汇管区炎等病理指标差异明显(P<0.05);提示未预处理的hMSC腹腔注射可致正常小鼠肝组织轻微病理损伤。
5经预处理的hMSC对ConA诱导小鼠免疫性肝损伤的作用。
经预处理的hMSC可显著升高ConA诱导免疫性肝损伤模型小鼠存活率(P<0.05)、降低模型小鼠血清中肝功能指标ALT含量(P<0.05)并显著降低肝组织的病理损伤程度(P<0.05);显示经预处理的hMSC对ConA诱导免疫性肝损伤有显著的保护作用。
6经预处理的hMSC对模型小鼠肝组织FasL表达和脾Treg亚群细胞比例的影响。
经预处理的hMSC可显著减少模型组小鼠肝组织FasL表达(P<0.05)并增加早期时相(3h)脾细胞Treg亚群细胞比例(P<0.05)。提示使模型鼠肝组织FasL表达减少和脾Treg细胞比例增加,可能是经预处理的hMSC对模型小鼠免疫性肝损伤具有保护作用的分子机制。
7经与未经预处理的hMSC相关细胞因子分泌差异
经预处理的hMSC其IL-6、IL-8及RANTES等细胞因子分泌,较未预处理的hMSC增多。提示,经预处理的hMSC有可能藉增加这些细胞因子的分泌,参与对ConA诱导免疫性肝损伤的保护作用。
8经预处理的hMSC的自身成瘤性
以ConA刺激小鼠脾细胞增殖的培养上清对hMSC行预处理后, hMSC的细胞周期被阻于G0/G1期,增殖指数显著降低(P<0.05);细胞表型和染色体核型保持不变;接种于裸鼠皮下,亦无肿瘤形成。提示预处理未导致hMSC的自身成瘤性。
9经预处理的hMSC的促瘤性
经与未经预处理的hMSC,均可使人肝癌细胞系MHCC/97H肿瘤细胞及小鼠肝癌细胞系H22肿瘤细胞阻滞于G0/G1期,显著降低两种肿瘤细胞的增殖指数(P<0.05);均可使MHCC/97H肿瘤细胞体外克隆形成能力显著降低(P<0.05);预处理与否,不影响hMSC对这两种肿瘤细胞发挥上述这些抑制作用的强度(P>0.05)。经与未经预处理的hMSC,对MHCC/97H肿瘤细胞和H22肿瘤细胞体内移植瘤的生长增殖、体内/外侵袭转移及荷瘤小鼠生存期无影响(P>0.05)。提示预处理未导致hMSC的促瘤性。
结论:
1贴壁消化传代培养法可有效从骨髓和羊水,获取合格的人胎儿源MSC。
2人胎儿源MSC对ConA刺激的T细胞增殖有显著的免疫抑制作用。
3经或未经ConA刺激T细胞增殖的培养上清预处理,可显著改变人胎儿源MSC对ConA诱导免疫性肝损伤的影响模式,此结果与结论国内外未见报道。
4未预处理的人胎儿源MSC对ConA诱导免疫性肝损伤有显著的促进作用。
5经预处理的人胎儿源MSC对ConA诱导免疫性肝损伤有显著的保护作用。
6未预处理的人胎儿源MSC对ConA诱导免疫肝损伤的促进作用与其表面HLA分子表达及补体C3的介导作用无关。
7经预处理的人胎儿源MSC对ConA诱导免疫肝损伤的保护作用与其致肝组织FasL表达降低及脾细胞早期时相(3h)Treg亚群细胞比例增高有关。
8经预处理的人胎儿源MSC,其IL-6、IL-8及RANTES细胞因子表达增加。
9人胎儿源MSC在观察期内未见成瘤性和促瘤活性,初步判断其在所观察期内不具有致瘤风险性。
Obiectives: Have emerged as a promising therapeutic modality for tissue regeneration and repair, MSCs have low immunogenicity and the ability to migrate to sites of tissue injury and rapidly expand and differentiate along its own, allogeneil or xenogeneic lineages to repair the damaged tissue without rejection. Compare to the MSCs from adult, the human MSCs from fetus are present earlier during development, less likely to be infected with pathogen and can be more easily harvested. Therefore, MSCs from fetus are the main source for transplant.
It is known that transplant between individuals with different genetic background can induce the rejection, which has not been solved perfectly until now. It hinders the clinical application of transplant. MSC transplant have generated expectations since MSCs are capable of differentiating along multiple lineages and have low immunogenicity.Numerous studies have demonstrated that MSCs have powerful immunosuppressive function, and may be involved in the mechanism of the vanishing of graft rejection. Therefore, it is very important to show that the engraft of ectogenic MSCs do not induce tumorigenesis.
Up to now, MSCs are largely studied for their uses in tissue repair, immunotolerance reestablishment and other fields. The clinical trials of MSCs therapy in cardiac muscle repair, bone disease and metabolic disease have been carried out all over the world. Several studies indicated that adoption of autogeneic or allogenetic MSCs by different administration routes (region/i.v./i.p.) has therapeutic action on experimental autoimmune encephalomyelitis (EAE)and collagenⅡ-induced arthritis(CIA). Moreover, Le Blanc and his colleague have successfully harnessed MSCs to treat severe acute graft-versus-host disease(GVHD), and greatly reduced the incidence of GVHD. These results all suggest that MSCs could provide an ideal cell source in the treatment of immune-mediated diseases.
In this study we examined the effect of hMSCs on ConA-induced hepatitis, and verified the therapeutic value and mechanism of hMSC in autoimmune hepatitis (AIH). Additionally, we validated the potential oncogenicity and promotion to hepatoma growth of hMSCs.
Methods: hMSCs were isolated from aborted fetus’s bone marrow or amniotic fluid. In order to certifficate the cells cultured in vitro are hMSC, we observed the cell morphology under a phase microscope, detected the phenotype by flow cytometry (FCM) and identified the potential for differentiation by culture cells under conditions that favored adipogenic and osteogenic differentiation. To confirm the immunomodulatory effect of hMSCs isolated from aborted fetus’s bone marrow or amniotic fluid in vitro using MTS. Splenocytes stimulated by ConA were incubated in medium, the medium supernatant was harvested. hMSCs were incubated in the supernatant, and its features including proliferation, phenotype and chromosome caryotype were observed. ConA mice model were performed according to the protocol of Tiegs. The indexes of hepatic injury included the serum levels of alanine aminotransferase (ALT) , aspartate aminotransferase (AST) and C3, and the pathological lesion of liver. We used the indexes above to verify the effect of hMSCs with or without pretreated to the ConA mice model. To test if mice splenocytes cultivate supernatant pretreatment could induce the malignant growth of hMSCs, hMSCs with pretreated were subcutaneously inoculated in athymic mice. To test the influence of hMSCs to tumor, we used MHCC/97H (human hepatoma carcinoma cell) and H22(mouse hepatoma carcinoma cell) as the target cells of hMSC with or withou pretreated and detected the cell cycle, proliferation and the capability of invasion in vivo or in vitro.
Results:
1 The preparation and identification of hMSCs and its Immunosuppression.
hMSCs were isolated from aborted fetus’s bone marrow or amniotic fluid, and then was cultured as adherent cells. The cell of passage 3-5 displayed a morphology and phenotype typical of MSC, showing the potential for differentiation into adipogenic, chondrogenic and osteogenic cells.
Compared to the control group, the proliferation of splenocytes induced by ConA in the hMSC-treated group was significantly suppressed in a dose-dependent fashion(P<0.05).
2 hMSCs without pretreated can exacerbate the immunologic liver injury in ConA mice
hMSCs without pretreated could cut down the survival rate (P<0.05), heighten the serum content of ALT and AST (P<0.05) and intensify the ConA-induced liver injury (P<0.05).These findings indicated hMSCs without pretreated could exacerbate the immunologic liver injury in ConA mice.
3 The promotion to immunologic injury induced by ConA of hMSCs without pretreated were independent on the expression of HLA-A,B,C or the serum content of C3
HLA-A,B,C(-)/HLA-DR(-) and HLA-A,B,C(+)/HLA-DR(-) hMSCs without pretreated could both significantly increase the serum ALT levels(P<0.05). These results indicated the promotion to immunologic injury of hMSCs without pretreated were independent on the expression of HLA-A,B,C.
Multiple linear regression was used to analyze the relationship between C3 and ALT, excluding the influence of time and group, there was no relationship between ALT and C3 (P>0.05). The above result showed that the promotion to immunologic injury of hMSCs without pretreated was independent on the serum contents of C3.
4 hMSCs without pretreated can induce light damage of liver cells in normal mice
Compared with the NS/NS group,the focus lytic necrosis, apoptotic body and inflammation in the district of portal in the ambitus of acini hepatis and the district of portal in the NS/na?ve hMSC group were different(P<0.05), indicated that hMSCs without pretreated could induce light damage of liver cells in normal mice.
5 hMSCs with pretreated can extenuate the immunologic liver injury in ConA mice
hMSCs with pretreated could increase the survival rate (P<0.05), cut down the serum content of ALT and AST (P<0.05) and extenuate the ConA-induced liver injury (P<0.05). These findings indicated hMSCs with pretreated could protect the liver injury ConA mice .
6 The decrease of FasL expression on hepatic tissue and the increase in the Treg cell ratio in splenocytes may involve in the protective effect of hMSCs with pretreated.
hMSCs with pretreated can suppress the expression of FasL (P<0.05) and increase the ratio of Treg cell in splenocytes in the earlier period(3h) (P<0.05).
7 The expression of IL-6, IL-8 and RANTES were increased in hMSCs with pretreated.
By detecting the expression of inflammatory factor in the cultivate supernatant of hMSCs with or without pretreated by antibody array, we could find that the hMSC with pretreated expressed more IL-6, IL-8 and RANTES than hMSC without pretreated, and it may involve the protective effect of hMSCs with pretreated.
8 Pretreatment could not induce the malignant growth of hMSCs
The hMSCs with pretreated by mice splenocytes cultivate supernatant has the same phenotype(CD29+, CD44+, CD90+, CD105+;HLA-DR-, CD14-, CD19-, CD34-, CD45-, CD31-) and caryotype of chromosome (2n=46)with hMSCs with or without pretreated proliferate arrest by blocking cell cycle at G0/G1 stage(P<0.05). Subcutaneous inoculation of hMSCs with pretreated in athymic mice, and no tumor emerge. So pretreated hMSCs by mice splenocytes cultivate supernatant could not induce the malignant growth of hMSC.
9 The effect of hMSCs with or without pretreated on the growth of hepatica cells in vivo or vitro
hMSCs with or without pretreated can induce the MHCC/97H or H22 cells by blocking cell cycle at G0/G1 stage (P<0.05), and the inhibitory intensity between two type hMSC was not statistically significant (P>0.05). And hMSCs with or without pretreated had nothing to do with the capability of migration in vitro of MHCC/97H cell (P>0.05).
Subcutaneous inoculation of MHCC/97H and H22 in athymic and BABL/c mice respectively, then hMSCs with or without pretreated. hMSCs with or without pretreated had nothing to do with the life span, tumor growth and capability of migration of tumor cell in vivo(P>0.05).
Conclusions:
1 Use of adherence-digest-serial subcultivation can harvest functional hMSCs successfully.
2 hMSCs inhibit the proliferation of T cells stimulated by ConA.
3 As we know, this is the first report that hMSCs with or without pretreated has opposite function on the ConA mice.
4 hMSCs without pretreated can significantly exacerbate the immunologic liver injury in ConA mice.
5 hMSCs with pretreated can powerfully protect the ConA mice.
6 The promotion to immunologic injury of ConA mice by hMSCs without pretreated is independent on the expression of HLA-A,B,C and the serum content of C3.
7 The decrease of FasL expression on hepatic tissue and the increase in the Treg cell ratio in splenocytes are related to the protective effect of hMSCs with pretreated.
8 The expression of IL-6, IL-8 and RANTES is increased in hMSC with pretreated.
9 hMSCs isolated from aborted fetus’s bone marrow does not have the risk of tumorigenesis.
引文
1 Sprinzl M , Dumortier J , Protzer U. Construction of recombinant adeno-viruses that produce infectious hepatitis B virus[J]. Method Mol Med, 2004, 96: 209-218
2 Hines IN,Wheeler MD. Recent advance in alcoholic liver diseaseⅢ. Role of the innate immune response in alcoholic hepatitis[J]. Am J Physiol Gastrointest Liver Phasiol, 2004, 287(2): G310-314
3 Li, Soloski M J, Diehl A M. Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease[J]. Hepatology, 2005, 42(4): 880-885
4 Teoh NC, Farrell GC. Hepatic ischemia reperfusion injury: Pathogenic mechanisms and basis for hepatoprotection[J]. J Gastroenterol Hepatol, 2003, 18(8): 891-902
5 Lapierre P, Djilali-Saiah I, Vitozzi S, et al. A murine model of type 2 autoimmune hepatitis:Xenoimmunization with human antigen[J]. Hepatology, 2004, 39(4): 1066-1074
6 Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells[J]. Lancet, 2004, 363(9419): 1439-1441
7 Ringdén O, Uzunel M, Rasmusson I, et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease[J]. Transplantation, 2006, 81(10): 1390-1397
8 Le Blanc K, Frassoni F, Ball L, et al. Developmental Committee of the European Group for Blood and Marrow Transplantation. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study[J]. Lancet, 2008, 371(9624): 1579-1586
9 Gerdoni E, Gallo B, Casazza S, et al. Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis[J]. Ann Neurol, 2007, 61(3): 219-227
10 Augello A, Tasso R, Negrini SM, et al. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis[J]. Arthritis Rheum, 2007, 56(4): 1175-1186
11 Sun LY, Zhang HY, Feng XB,et al. Abnormality of bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus [J]. Lupus, 2007, 16(2):121-128
12 Tiegs G, Hentschel J, Wendel A. A T cell-dependent experimental liver injury in mice inducible by concanavalin A[J]. J Clin Invest, 1992, 90(1):196-203
13 Kaneko Y, Harada M, Kawano T, et al. Augmentation of Va 14 NKT cell-mediated cytotoxicity by interleukin 4 in an autocrine mechanism resulting in the development of concanavalin A-induced hepatitis[J]. J Exp Med, 2000, 191(1): 105-114
14 Gantner F, Leist M, Lohse AW, et al. Concanavalin A-induced T cell-mediated hepatic injury in mice: the role of tumor necrosis factor[J]. Hepatology, 1995, 21(1): 190-198
15 Tiegs G. Cellular and cytokine-mediated mechanisms of inflammation and its modulation in immune-mediated liver injury[J]. Z Gastroenterol, 2007, 45(1): 63-70
16 Tse WT, Pendleton JD,Beyer WM, et al. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implication in transplantation[J]. 2003, 75(3): 389-397
17 Le Blanc K, Tammik C, Rosendahl K, et al. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells[J]. Exp. Hematol, 2003, 31(10): 890-896
18 Klyushnenkova E, Mosca JD, Zernetkina V, et al. T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression[J]. J. Biomed Sci, 2005, 12(1): 47-57
19 Glennie S, Soeiro I, Dyson PJ, et al. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells[J]. Blood, 2005, 105(7): 2821-2827
20 Maccario R, Podesta M, Moretta A, et al. Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype[J]. Haematologica, 2005, 90(4): 516-525
21 Beyth S, Borovsky Z, Mevorach D, et al. Human mesenchymal stem cells alter antigen- presenting cell maturation and induce T-cell unresponsiveness[J]. Blood, 2005, 105(5): 2214-2219
22 English K, Ryan JM, Tobin L, et al. Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25(High) forkhead box P3+ regulatory T cells[J]. Clin Exp Immunol, 2009, 156(1): 149-160
23 Ko E, Cho KA, Ju SY, et al. Mesenchymal stem cells inhibit the differentiation of CD4+ T cells into interleukin-17-secreting T cells[J]. Acta Haematol, 2008, 120(3): 165-167
24 Sheng H, Wang Y, Jin Y, et al. A critical role of IFNgamma in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1[J]. Cell Res, 2008, 18(8): 846-857
25 Ramasamy R, Tong CK, Seow HF, et al. The immunosuppressive effects of human bone marrow-derived mesenchymal stem cells target T cell proliferation but not its effector function[J]. Cell Immunol, 2008, 251(2): 131-136
26 Selmani Z, Naji A, Zidi I, et al. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+regulatory T cells[J]. Stem Cells, 2008, 26(1): 212-222
27 Tsai MS, Lee JL, Chang YJ, et al. Isolation of human multipotent mesenchymal stem cells from second-trimester amniotic fluid using a novel two-stage culture protocol[J]. Hum Reprod, 2004, 19(6): 1450-1456
28 Tsai MS, Hwang SM, Tsai YL, et al. Clonal amniotic fluid-derived stem cells express characteristics of both mesenchymal and neural stem cells[J]. Biol Reprod, 2006, 74(3): 545-551
29 Cananzi M, Atala A, De Coppi P. Stem cells derived from amniotic fluid: new potentials in regenerative medicine[J]. Reprod Biomed Online, 2009, 18 Suppl 1:17-27
30 Halme DG, Kessler DA. FDA regulation of stem-cell-based therapies[J]. N Engl J Med, 2006, 355(16): 1730-1735
1 Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acutegraft-versus-host disease with third party haploidentical mesenchymal stem cells[J]. Lancet, 2004, 363(9419): 1439–1441
2 Ringdén O, Uzunel M, Rasmusson I, et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease[J]. Transplantation, 2006, 81(10): 1390-1397
3 Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study[J]. Lancet, 2008, 371(9624): 1579–1586
4 Gerdoni E, Gallo B, Casazza S, et al. Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis[J]. Ann Neurol, 2007, 61(3): 219-227
5 Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease[J]. Nat Rev Immunol, 2008, 8(9): 726-36
6 González MA, Gonzalez-Rey E, Rico L, et al. Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells[J]. Arthritis Rheum, 2009, 60(4): 1006-1019
7 Tsai MS, Lee JL, Chang YJ, et al. Isolation of human multipotent mesenchymal stem cells from second-trimester amniotic fluid using a novel two-stage culture protocol[J]. Hum Reprod, 2004, 19(6): 1450-1456
8 Tsai MS, Hwang SM, Tsai YL, et al. Clonal amniotic fluid-derived stem cells express characteristics of both mesenchymal and neural stem cells[J]. Biol Reprod, 2006, 74(3): 545-551
9 Cananzi M, Atala A, De Coppi P. Stem cells derived from amniotic fluid: new potentials in regenerative medicine[J]. Reprod Biomed Online, 2009, 18 Suppl 1:17-27
10 Priest RE, Marimuthu KM, Priest JH. Origin of cells in human amniotic fluid cultures: ultrastructural features[J]. Lab Invest, 1978, 39(2): 106-109
11 Polgar K, Adany R, Abel G, et al. Characterization of rapidly adhering amniotic fluid cells by combined immunofluorescence and phagocytosis assays[J]. Am J Hum Genet, 1989, 45(5): 786-792
12 In’t Anker PS, Scherjon SA, Kleijburg-van, et al. Amniotic fluid as anovel source of mesenchymal stem cells for therapeutic transplantation[J]. Blood, 2003, 102(4):1548-1549
13 Coppi PD, Bartsch G, Siddiqui MM, et al. Isolation of amniotic stem cell lines with potential for therapy[J]. Nat Biotech, 2007, 25(1): 100-106
14 Kaviani A, Perry T, Dzakovic A, et al. The amniotic fluid as a source of cells for fetal tissue engineering[J]. J Ped Surgery, 2001, 36(11): 1662-1665
15 Bossolasco P,Montemurro T,Cova L, et al. Molecular and phenotypic characterization of human amniotic fluid cells and their differentiation potential[J]. Cell Res, 2006, 16(4): 329-336
16 Roubelakis MG, Pappa KI, Bitsika V, et al. Molecular and proteomic characterization of human mesenchymal stem cells derived from amniotic fluid: comparison to bone marrow mesenchymal stem cells[J]. Stem Cells Dev, 2007, 16(6): 931-952
1 Sprinzl M , Dumortier J , Protzer U. Construction of recombinant adeno-viruses that produce infectious hepatitis B virus[J]. Method Mol Med, 2004, 96: 209-218
2 Hines IN,Wheeler MD. Recent advance in alcoholic liver diseaseⅢ. Role of the innate immune response in alcoholic hepatitis[J]. Am J Physiol Gastrointest Liver Phasiol, 2004, 287(2): G310-314
3 Li, Soloski M J, Diehl A M. Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease[J]. Hepatology, 2005, 42(4): 880-885
4 Teoh NC, Farrell GC. Hepatic ischemia reperfusion injury: Pathogenic mechanisms and basis for hepatoprotection[J]. J Gastroenterol Hepatol, 2003, 18(8): 891-902
5 Lapierre P, Djilali-Saiah I, Vitozzi S, et al. A murine model of type 2 autoimmune hepatitis: Xenoimmunization with human antigen[J]. Hepatology, 2004, 39(4): 1066-1074
6 Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymalstem cells[J]. Lancet, 2004, 363(9419): 1439-1441
7 Ringdén O, Uzunel M, Rasmusson I, et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease[J]. Transplantation, 2006, 81(10): 1390-1397
8 Le Blanc K, Frassoni F, Ball L, et al. Developmental Committee of the European Group for Blood and Marrow Transplantation. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study[J]. Lancet, 2008, 371(9624): 1579-1586
9 Gerdoni E, Gallo B, Casazza S, et al. Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis[J]. Ann Neurol, 2007, 61(3): 219-227
10 Augello A, Tasso R, Negrini SM, et al. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis[J]. Arthritis Rheum, 2007, 56(4): 1175-1186
11 Tiegs G, Hentschel J, Wendel A. A T cell-dependent experimental liver injury in mice inducible by concanavalin A[J]. J Clin Invest, 1992, 90(1): 196-203
12 Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis[J]. J Hepatol, 1995, 22: 696-699
13 Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis[J]. HEPATOLOGY, 1981, 1: 431-435
14 González MA, Gonzalez-Rey E, Rico L, et al. Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells[J]. Arthritis Rheum, 2009, 60(4): 1006-1019
15 González MA, Gonzalez-Rey E, Rico L, et al. Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses[J]. Gastroenterology. 2009, 136(3): 978-989
16 Boumaza I, Srinivasan S, Witt WT, et al. Autologous bone marrow-derived rat mesenchymal stem cells promote PDX-1 and insulin expression in the islets, alter T cell cytokine pattern and preserve regulatory T cells in the periphery and induce sustained normoglycemia[J]. J Autoimmun, 2009, 32(1): 33-42
17 Zhou K, Zhang H, Jin O,et al. Transplantation of human bone marrow mesenchymal stem cell ameliorates the autoimmune pathogenesis in MRL/lpr mice[J]. Cell Mol Immunol, 2008, 5(6): 417-424
18 Kaneko Y, Harada M, Kawano T, et al. Augmentation of Va 14 NKT cell-mediated cytotoxicity by interleukin 4 in an autocrine mechanism resulting in the development of concanavalin A-induced hepatitis[J]. J Exp Med, 2000, 191(1): 105-114
19 Gantner F, Leist M, Lohse AW, et al. Concanavalin A-induced T cell-mediated hepatic injury in mice: the role of tumor necrosis factor [J]. Hepatology, 1995, 21(1): 190-198
20 Tiegs G. Cellular and cytokine-mediated mechanisms of inflammation and its modulation in immune-mediated liver injury[J]. Z Gastroenterol, 2007, 45(1): 63-70
21 Rasmusson I. Immune modulation by mesenchymal stem cells[J]. Exp Cell Res, 2006, 312(12): 2169-2179
22 Tse WT, Pendleton JD,Beyer WM, et al. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implication in transplantation[J]. 2003, 75(3): 389-397
23 Le Blanc K, Tammik C, Rosendahl K, et al. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells[J]. Exp. Hematol, 2003, 31(10): 890-896
24 Klyushnenkova E, Mosca JD, Zernetkina V, et al. T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression[J]. J. Biomed Sci, 2005, 12(1): 47-57
25 Glennie S, Soeiro I, Dyson PJ, et al. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells[J]. Blood, 2005,105(7): 2821-2827
26 Maccario R, Podesta M, Moretta A, et al. Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype[J]. Haematologica, 2005, 90(4): 516-525
27 Beyth S, Borovsky Z, Mevorach D, et al. Human mesenchymal stem cells alter antigen- presenting cell maturation and induce T-cell unresponsiveness[J]. Blood, 2005, 105(5): 2214-2219
28 English K, Ryan JM, Tobin L, et al. Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25(High) forkhead box P3+ regulatory T cells[J]. Clin Exp Immunol, 2009, 156(1): 149-160
29 Ko E, Cho KA, Ju SY, et al. Mesenchymal stem cells inhibit the differentiation of CD4+ T cells into interleukin-17-secreting T cells[J]. Acta Haematol., 2008, 120(3): 165-167
30 Sheng H, Wang Y, Jin Y, et al. A critical role of IFNgamma in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1[J]. Cell Res, 2008, 18(8): 846-857
31 Ramasamy R, Tong CK, Seow HF, et al. The immunosuppressive effects of human bone marrow-derived mesenchymal stem cells target T cell proliferation but not its effector function. Cell Immunol[J], 2008, 251(2): 131-136
32 Selmani Z, Naji A, Zidi I, et al. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells[J]. Stem Cells, 2008, 26(1): 212-222
33 Beyth S, Borovsky Z, Mevorach D, et al. Human mesenchymal stem cells alter antigen- presenting cell maturation and induce T-cell unresponsiveness[J]. Blood, 2005, 105(5): 2214-2219
34 Jiang XX, Zhang Y, Liu B, et al. Human mesenchymal stem cells inhibitifferentiation and function of monocyte-derived dendritic cells [J]. Blood, 2005, 105(5): 4120-4126
35 Nauta AJ, Kruisselbrink AB, Lurvink E. Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells[J]. J Immunol, 2006, 177(4): 2080-2087
36 English K, Barry FP, Mahon BP. Murine mesenchymal stem cells suppress dendritic cell migration, maturation and antigen presentation[J]. Immunol Lett, 2008, 115(1): 50-58
37 Li YP, Paczesny S, Lauret E, et al. Human mesenchymal stem cells license adult CD34+ hemopoietic progenitor cells to differentiate into regulatory dendritic cells through activation of the Notch pathway[J]. J Immunol, 2008, 180(3): 1598-1608
38 Zhang B, Liu R, Shi D, et al. Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2-dependent regulatory dendritic cell population[J]. Blood, 2009, 113(1): 46-57
39 Wang Q, Sun B, Wang D, et al. Murine bone marrow mesenchymal stem cells cause mature dendritic cells to promote T-cell tolerance[J]. Scand J Immunol, 2008, 68(6): 607-615
40 Augello A, Tasso R, Negrini SM, et al. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway[J]. Eur J Immunol, 2005, 35(5): 1482-1490
41 Krampera M, Cosmi L, Angeli R, et al. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells[J]. Stem Cells, 2006, 24(2): 386-398
42 Comoli P, Ginevri F, Maccario R, et al. Human mesenchymal stem cells inhibit antibody production induced in vitro by allostimulation[J]. Nephrol Dial Transplant, 2008, 23(4): 1196-1202
43 Tabera S, Pérez-Simón JA, et al. The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes. Haematologica, 2008, 93(9): 1301-1309
44 Le Blanc K, Tammik L, Sundberg B, et al. Mesenchymal stem cellsinhibit and stimulate mixed lymphocyte cultures and responses independently of the major histocompatibility complex. [J]. Scand J Immunol, 2003, 57(1): 11-20
45 Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. [J]. Blood, 2005, 105(4): 1815-1822
46 Kang HS, Habib M, Chan J, et al. A paradoxical role for IFN-gamma in the immune properties of mesenchymal stem cells during viral challenge. [J]. Exp. Hematol, 2005, 33(7): 796-803
47 Sotiropoulou PA, Perez SA, Gritzapis AD, et al. Interactions between human mesenchymal stem cells and natural killer cells. [J]. Stem Cells, 2006, 24(2): 74-85
48 Djouad F, Plence P, Bony C, et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood, 2003; 102(10): 3837-3844
49 Grinnemo KH, M?nsson A, Dellgren G, et al. Xenoreactivity and engraftment of human mesenchymal stem cells transplanted into infarcted rat myocardium. J. Thorac. Cardiovasc. Surg, 2004, 127(5): 1293-1300
50 Rossignol J, Boyer C, Thinard R, et al. Mesenchymal stem cells induce a weak immune response in the rat striatum after allo or xenotransplantation. J Cell Mol Med. 2009. [Epub ahead of print]
51 Nauta AJ, Westerhuis G, Kruisselbrink AB, et al. Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting. Blood, 2006, 108(6): 2114-2120
52 Inoue S, Popp FC, Koehl GE, et al. Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant model. Transplantation, 2006, 81(11): 1589-1595
53 Ren G, Zhang L, Zhao X, et al. Mesenchymal Stem Cell-Mediated Immunosuppression Occurs via Concerted Action of Chemokines and Nitric Oxide.Cell. Stem Cell, 2008, 2(2): 141-150
1 Ren G, Zhang L, Zhao X, et al. Mesenchymal Stem Cell-Mediated Immunosuppression Occurs via Concerted Action of Chemokines and Nitric Oxide[J]. Cell. Stem Cell, 2008, 2(2): 141-150
2 Beyth S, Borovsky Z, Mevorach D, et al. Human mesenchymal stem cells alter antigen- presenting cell maturation and induce T-cell unresponsiveness[J]. Blood, 2005, 105(5): 2214-2219
3 Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli[J]. Blood, 2002, 99(10): 3838-3843
4 Le Blanc K, Rasmusson I, Gotherstrom C, et al. Mesenchymal stem cells inhibit the expression of CD25 (interleukin-2 receptor) and CD38 on phytohaemagglutinin-activated lymphocytes[J]. Scand. J. Immunol, 2004, 60(3): 307-315
5 Tiegs G, Hentschel J, Wendel A. A T cell-dependent experimental liver injury in mice inducible by concanavalin A[J]. J Clin Invest, 1992, 90(1): 196-203
6 Kaneko Y, Harada M, Kawano T, et al. Augmentation of Va 14 NKT cell-mediated cytotoxicity by interleukin 4 in an autocrine mechanism resulting in the development of concanavalin A-induced hepatitis[J]. J Exp Med, 2000, 191(1): 105-114
7 Takeda K, Hayakawa Y, Van Kaer L, et al. Critical contribution of liver natural killer T cells to a murine model of hepatitis[J]. Proc Natl Acad SciU S A, 2000, 97(10): 5498-5503
8 Song E, Lee SK, Wang J, et al. RNA interference targeting Fas protects mice from fulminant hepatitis[J]. Nat Med, 2003, 9(3): 347-351
9 Descamps D, Vigant F, Esselin S, et al. Expression of non-signaling membrane-anchored death receptors protects murine livers in different models of hepatitis[J]. Hepatology, 2006, 44(2): 399-409
10 Maccario R, Podesta M, Moretta A, et al. Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype[J]. Haematologica, 2005, 90(4): 516-525
11 Le Blanc K, Tammik C, Rosendahl K, et al. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells[J]. Exp. Hematol, 2003, 31(10): 890-896
12 Ye Z, Wang Y, Xie HY, et al. Immunosuppressive effects of rat mesenchymal stem cells: involvement of CD4+CD25+ regulatory T cells[J]. Hepatobiliary Pancreat Dis Int, 2008, 7(6): 608-614
13 Di Ianni M, Del Papa B, De Ioanni M, et al. Mesenchymal cells recruit and regulate T regulatory cells[J]. Exp Hematol, 2008, 36(3): 309-318
14 Selmani Z, Naji A, Zidi I, et al. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells[J]. Stem Cells, 2008, 26(1): 212-222
15 English K, Ryan JM, Tobin L, et al. Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25(High) forkhead box P3+ regulatory T cells[J]. Clin Exp Immunol, 2009, 156(1): 149-160
16 Augello A, Tasso R, Negrini SM, et al. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis[J]. Arthritis Rheum, 2007, 56(4): 1175-1186
17 Parekkadan B, Tilles AW, Yarmush ML, et al. Bone marrow-derivedmesenchymal stem cells ameliorate autoimmune enteropathy independently of regulatory T cells[J]. Stem Cells, 2008, 26(7): 1913-1919
18 Casiraghi F, Azzollini N, Cassis P, et al. Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells[J]. J Immunol, 2008, 181(6): 3933-3946
19 Erhardt A, Biburger M, Papadopoulos T, et al. IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice[J]. Hepatology, 2007, 45(2): 475-485
20 Tse WT, Pendleton JD, Beyer WM, et al. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implication in transplantation[J]. Transplantation, 2003, 75(3): 389-397
21 Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses[J]. Blood, 2005, 105(4): 1815-1822
22 Rasmusson I, Ringden O, Sundberg B, et al. Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms[J]. Exp.Cell Res, 2005, 305(1): 33-41
23 Meisel R, Zibert A, Laryea M, et al. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation[J]. Blood, 2004, 103(12): 4619-4621
24 Fallarino F, Grohmann U, Vacca C, et al. T cell apoptosis by kynurenines[J]. Adv. Exp. Med. Biol, 2003, 527: 183-190
25 Chabannes D, Hill M, Merieau E, et al. A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells[J]. Blood, 2007, 110(10): 3691-3694
26 Gotherstrom C, West A, Liden J, et al. Difference in gene expression between human fetal liver and adult bone marrow mesenchymal stem cells[J]. Haematologica, 2005, 90(8): 1017-1026
27 Cressman DE, Greenbaum LE, DeAngelis RA, et al. Liver failure anddefective hepatocyte regeneration in interleukin-6-deficient mice[J]. Science, 1996, 274(5291): 1379-1383
28 Yang SH, Park MJ, Yoon IH, et al. Soluble Mediators from Mesenchymal Stem Cells Suppress T cell Proliferation by inducing IL-10[J]. Exp Mol Med, 2009. [Epub ahead of print]
29 Choi JJ, Yoo SA, Park SJ, et al. Mesenchymal stem cells overexpressing interleukin-10 attenuate collagen-induced arthritis in mice[J]. Clin Exp Immunol, 2008, 153(2): 269-276
30 Hong F, Jaruga B, Kim WH, et al. Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS[J]. J. Clin. Invest, 2002, 110(10): 1503-1513
31 Mizuhara H, Uno M, Seki N, et al. Critical involvement of Interferon-6 in the pathogenesis of T-cell activation-associated hepatitis and regulatory mechanisms of interleukin-6 for the manifestations of hepatitis[J]. Hepatology, 1996, 23(6): 1608-1615
32 Hong F, Kim WH, Tian Z, et al. Elevated interleukin-6 during ethanol consumption acts as a potential endogenous protective cytokine against ethanol-induced apoptosis in the liver: involvement of induction of Bcl-2 and Bcl-x(L) proteins[J]. Oncogene, 2002, 21(1): 32-43
33 Kovalovich K, Li W, DeAngelis R, et al. Interleukin-6 protects against Fas-mediated death by establishing a critical level of anti-apoptotic hepatic proteins FLIP, Bcl-2, and Bcl-xL[J]. J. Biol.Chem, 2001, 276(28): 26605-26613
34 Kovalovich K, DeAngelis RA, Li W, et al. Increased toxin-induced liver injury and fibrosis in interleukin-6-deficient mice[J]. Hepatology, 2000, 31(1): 149-159
35 Camargo CA Jr, Madden JF, Gao W, et al. Clavien. Interleukin-6 protects liver against warm ischemia/reperfusion injury and promotes hepatocyte proliferation in the rodent[J]. Hepatology, 1997, 26(6): 1513-1520
36 Masubuchi Y, Bourdi M, Reilly TP, et al. Role of interleukin-6 in hepatic heat shock protein expression and protection againstacetaminophen-induced liver disease. Biochem. Biophys[J]. Res. Commun, 2003, 304(1): 207-212
37 Meng ZH, Dyer K, Billiar TR, et al. Distinct effects of systemic infusion of G-CSF vs. IL-6 on lung and liver inflammation and injury in hemorrhagic shock[J]. Shock, 2000, 14(1): 41-48
38 Selzner N, Selzner M, Tian Y, et al. Cold ischemia decreases liver regeneration after partial liver transplantation in the rat: a TNF-α/IL-6- dependent mechanism[J]. Hepatology, 2002, 36: 812-818
39 Sun Z, Klein AS, Radaeva S, et al. In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats[J]. Gastroenterology, 2003, 125(1): 202-215
40 Li W, Liang X, Kellendonk C, et al. STAT3 contributes to the mitogenic response of hepatocytes during liver regeneration[J]. J. Biol. Chem, 2002, 277(32): 28411-28417
41 Wuestefeld T, Klein C, Streetz KL, et al. Interleukin-6/glycoprotein 130-dependent pathways are protective during liver regeneration[J]. J. Biol. Chem, 2003, 278(13): 11281-11288
42 Streetz KL, Tacke F, Leifeld L, et al. Interleukin 6/gp130-dependent pathways are protective during chronic liver diseases[J]. Hepatology, 2003, 38(1): 218-229
43 Streetz KL, Wustefeld T, Klein C, et al. Lack of gp130 expression in hepatocytes promotes liver injury[J]. Gastroenterology, 2003, 125(2): 532-543
44 Taub, R. Hepatoprotection via the IL-6/Stat3 pathway[J]. J. Clin. Invest, 2003, 112(7): 978-980
45 Haga S, Terui K, Zhang HQ, et al. Stat3 protects against Fas-induced liver injury by redox-dependent and -independent mechanisms[J]. J. Clin. Invest, 2003, 112(7): 989-998
46 Sun R, Tian Z, Kulkarni S, et al. IL-6 Prevents T Cell-mediated hepatitis via inhibition of NKT Cells in CD4+T cell- and STAT3-dependent manners[J]. J Immunol, 2004, 172(9): 5648-5655
47 Rasmusson I. Immune modulation by mesenchymal stem cells[J]. Exp Cell Res, 2006, 312(12): 2169-2179
48 Djouad F, Charbonnier LM, Bouffi C, et al. Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism[J]. Stem Cells, 2007, 25(8): 2025-2032
49 Hurst SM, Wilkinson TS, McLoughlin RM, et al. Control of leukocyte infiltration during inflammation: IL-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment[J]. Immunity, 2001, 14: 705-714
50 Karlmark KR, Wasmuth HE, Trautwein C, et al. Chemokine-directed immune cell infiltration in acute and chronic liver disease[J]. Expert Rev Gastroenterol Hepatol, 2008, 2(2): 233-242
1 Halme DG, Kessler DA. FDA regulation of stem-cell-based therapies[J]. N Engl J Med, 2006, 355(16): 1730-1735
2 Miura M, Miura Y, Padilla-Nash HM, et al. Accumulated chromosomal instability in murine bone marrow mesenchymal stem cells leads to malignant transformation[J]. Stem Cells, 2006, 24(4):1095-1103
3 Tolar J, Nauta AJ, Osborn MJ, et al. Sarcoma Derived from Cultured Mesenchymal Stem Cells[J]. Stem Cells, 2007, 25(2): 371-379
4 Ohlsson LB, Varas L, Kjellman C, et al. Mesenchymal progenitor cell-mediated inhibited of tumour growth in vivo and in vitro in gelation matrix[J]. Exp Mol Pathol, 2003, 75: 248-255
5 Diouad F, Plence P, Bony C, et al. Immunosuppressive effect of mesenchymal stem cell favors tumor growth in allogeneic animal[J]. Blood, 2003, 102: 3837-3844
6 Kuroda K, Nakashima J, Kanao K, et al. Interleukin 6 is associated with cachexia in patients with prostate cancer[J]. Urology, 2007, 69(1): 113-117
7 Kanazawa T, Nishino H, Hasegawa M, et al. Interleukin-6 directly influences proliferation and invasion potential of head and neck cancer cells[J]. Eur Arch Otorhinolaryngol, 2007, 264(7): 815-821
8 Duffy SA, Taylor JM, Terrell JE, et al. Interleukin-6 predicts recurrence and survival among head and neck cancer patients[J]. Cancer, 2008, 113(4): 750-757
9李万胜,胡洁,赵娟,等. IL-8基因真核表达载体构建及其在OVCAR-3卵巢癌细胞中的表达[J].军事医学科学院院刊, 2008, 32(2): 144-147
10胡洁,齐义新,姚智燕,等.乳腺癌患者白细胞介素8临床检测的意义[J].临床荟萃, 2006, 21 (10) : 726-728
11胡洁,王秀荣,齐义新,等.乳腺癌白细胞介素-8基因表达的临床检测意义[J].河北医科大学学报, 2006, 27(5): 367-369
12 Borczuk AC, Papanikolaou N, Toonkel RL, et al. Lung adenocarcinoma invasion in TGFbetaRII-deficient cells is mediated by CCL5/RANTES[J]. Oncogene, 2008, 27(4): 557-564
13 Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis[J]. Nature, 2007, 449(7162): 557-563
14 Rubio D, Garcia S, De la Cueva T, et al. Human mesenchymal stem cell transformation is associated with a mesenchymal-epithelial transition[J]. Exp Cell Res, 2008, 314(4): 691-698
15 Bernardo ME, Zaffaroni N, Novara F, Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms[J]. Cancer Res, 2007, 67(19): 9142-9149
16 Choumerianou DM, Dimitriou H, Perdikogianni C, et al. Study of oncogenic transformation in ex vivo expanded mesenchymal cells, from paediatric bone marrow[J]. Cell Prolif, 2008, (6): 909-922
17 Kim J, Kang JW, Park JH, et al. Biological characterization of long-term cultured human mesenchymal stem cells[J]. Arch Pharm Res, 2009, 32(1): 117-126
18 Santisteban M, Reiman JM, Asiedu MK, et al. Immune-induced epithelial to mesenchymal transition in vivo generates breast cancer stem cells[J]. Cancer Res, 2009, 69(7): 2887-2895
19 Haviv I, Polyak K, Qiu W, et al. Origin of carcinoma associated fibroblasts[J]. Cell Cycle., 2009, 8(4): 589-595
20 Mishra PJ, Mishra PJ, Humeniuk R, et al. Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells[J]. Cancer Res, 2008, (11): 4331-4439
21 Bagley RG, Weber W, Rouleau C, et al. Human mesenchymal stem cells from bone marrow express tumor endothelial and stromal markers[J]. Int J Oncol, 2009, 34(3): 619-627
22 Apparailly F, Jorgensen C, Lazennec G. Multipotent stromal cells: controversial impact on tumor development and metastasis[J]. Med Sci , 2008, 24(4):359-360
23 Zhang W. Mesenchymal stem cells in cancer: friends or foes[J]. Cancer Biol Ther, 2008, 7(2): 252-254
24 Dwyer RM, Potter-Beirne SM, Harrington KA, et al. Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells[J]. Clin Cancer Res, 2007, 13(17): 5020-5027
25 Gutova M, Najbauer J, Frank RT, et al. Urokinase plasminogen activator and urokinase plasminogen activator receptor mediate human stem cell tropism to malignant solid tumors[J]. Stem Cells, 2008, 26(6): 1406-1413
26 Spaeth E, Klopp A, Dembinski J, et al. Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells[J]. Gene Ther, 2008, 15(10): 730-738
27 Wang H, Chen X. Imaging mesenchymal stem cell migration and the implications for stem cell-based cancer therapies[J]. Future Oncol, 2008, 4(5): 623-628
28 Cheng P, Gao ZQ, Liu YH, et al. Platelet-derived growth factor BB promotes the migration of bone marrow-derived mesenchymal stem cells towards C6 glioma and up-regulates the expression of intracellular adhesion molecule-1[J]. Neurosci Lett, 2009, 451(1): 52-56
29 Hall B, Andreeff M, Marini F. The participation of mesenchymal stem cells in tumor stroma formation and their application as targeted-gene delivery vehicles[J]. Handb Exp Pharmacol, 2007, 180: 263-283
30 Cao H, Xu W, Qian H, et al. Bone marrow-derived cells and tumor growth: contribution of bone marrow-derived cells to tumor micro-environments with special focus on mesenchymal stem cells[J]. Crit Rev Oncol Hematol, 2009, 69(3): 187-198
31 Roorda BD, ter Elst A, Kamps WA, et al. Bone marrow-derived cells and tumor growth: contribution of bone marrow-derived cells to tumormicro-environments with special focus on mesenchymal stem cells[J]. Crit Rev Oncol Hematol, 2009, 69(3): 187-198
32 Alison MR, Lim S, Houghton JM. Bone marrow-derived cells and epithelial tumours: more than just an inflammatory relationship[J]. Curr Opin Oncol, 2009, 21(1): 77-82
33 Mishra PJ, Merlino G. A traitor in our midst: mesenchymal stem cells contribute to tumor progression and metastasis[J]. Future Oncol, 2008, 4(6): 745-749
34 Sun T, Sun BC, Ni CS, et al. Pilot study on the interaction between B16 melanoma cell-line and bone-marrow derived mesenchymal stem cells[J]. Cancer Lett, 2008, 263(1): 35-43
35 Yu JM, Jun ES, Bae YC, et al. Mesenchymal stem cells derived from human adipose tissues favor tumor cell growth in vivo[J]. Stem Cells Dev, 2008, 17(3): 463-473
36 Muehlberg FL, Song YH, Krohn A, et al. Tissue-resident stem cells promote breast cancer growth and metastasis[J]. Carcinogenesis, 2009, 30(4): 589-597
37 Xu WT, Bian ZY, Fan QM, et al. Human mesenchymal stem cells (hMSCs) target osteosarcoma and promote its growth and pulmonary metastasis[J]. Cancer Lett, 2009. [Epub ahead of print]
38 Tasso R, Augello A, Carida' M, et al. Development of sarcomas in mice implanted with mesenchymal stem cells seeded onto bioscaffolds[J]. Carcinogenesis, 2009, 30(1): 150-157
39 Lu YR, Yuan Y, Wang XJ, et al. The growth inhibitory effect of mesenchymal stem cells on tumor cells in vitro and in vivo[J]. Cancer Biol Ther, 2008, 7(2): 245-251
40 Qiao L, Xu Z, Zhao T, et al. Suppression of tumorigenesis by human mesenchymal stem cells in a hepatoma model[J]. Cell Res, 2008, 18(4): 500-507
41 Jiang H, Ren J. Inoculation of murine bone marrow mesenchymal stem cells induces tumor necrosis in mouse with orthotopic hepatocellularcarcinoma[J]. Beijing Da Xue Xue Bao, 2008, 40(5): 453-458
42 Sarmadi VH, Heng FS, Ramasamy R. The effect of human mesenchymal stem cells on tumour cell proliferation[J]. Med J Malaysia, 2008, Suppl A: 63-64
43 Zhu Y, Sun Z, Han Q, et al. Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1[J]. Leukemia, 2009. [Epub ahead of print]
1 Friedenstein AJ, Gorskaja JF, Kulagina NN. Fibroblast precursors in normal and irradiated mouse hematopoietic organs[J]. Exp Hematol, 1976, 4(5): 267-274
2 Caplan AI. Mesenchymal stem cells [J]. J Orthop Res, 1991, 9(5): 641-650
3 Horwitz EM, Le Blanc K, Dominici M, et al. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement[J]. Cytotherapy, 2005, 7(5): 393-395
4 Anjos-Afonso F, Bonnet D. Non-hematopoietic/endothelial SSEA-1pos cells defines the most primitive progenitors in the adult murine bone marrow mesenchymal compartment[J]. Blood, 2007, 109(3): 1298-1306
5 Kuo C K, Tuan R S. Tissue engineering with mesenchymal stem cells[J]. IEEE Eng Med Biol Mag, 2003, 22(5): 51-56
6 Tse WT, Pendleton JD,Beyer WM, et al. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implication in transplantation[J]. Transplantation, 2003, 75(3): 389-397
7 Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survivalin vivo[J]. Exp. Hematol, 2002, 30(1): 42-48
8 Potian J A, Aviv H, Ponzio N M, et al. Veto-like activity of mesenchymal stem cells: functional discrimination between cellular responses to alloantigens and recall antigens[J]. J. Immunol, 2003, 171(7): 3426-3434
9 Maitra B, Szekely E, Gjini K, et al. Human mesenchymal stem cells support unrelated donor hematopoietic stem cells and suppress T-cell activation[J]. Bone Marrow Transplant, 2004, 33(6): 597-604
10 Le Blanc K, Tammik C, Rosendahl K, et al. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells[J]. Exp. Hematol, 2003, 31(10): 890-896
11 Arinzeh TL, Peter SJ, Archambault MP, et al. Allogeneic mesenchymal stem cells regenerate bone in a critical-sized canine segmental defect[J]. J Bone Joint Surg Am, 2003, 85-A(10): 1927-1935
12 Toma C, Pittenger MF, Cahill KS, et al. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart[J]. Circulation, 2002, 105(1): 93-98
13 Saito T, Kuang J Q, Bittira B, et al. Xenotransplant cardiac chimera: immune tolerance of adult stem cells[J]. Ann Thorac Surg, 2002, 74(1): 19-24
14 Moadsiri A, Polchert D, Genrich K. Mesenchymal stem cells enhance xenochimerism in NK-depleted hosts[J]. Surgery, 2006, 140(2): 315-321
15 Le Blanc K, Tammik L, Sundberg B, et al. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and responses independently of the major histocompatibility complex[J]. Scand J Immunol, 2003, 57(1): 11-20
16 Ren G, Zhang L, Zhao X, et al. Mesenchymal Stem Cell-Mediated Immunosuppression Occurs via Concerted Action of Chemokines and Nitric Oxide[J]. Cell. Stem Cell, 2008, 2(2): 141-150
17 Klyushnenkova E, Mosca JD, Zernetkina V, et al. T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance,and suppression[J]. J. Biomed Sci, 2005, 12(1): 47-57
18 Glennie S, Soeiro I, Dyson PJ, et al. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells[J]. Blood, 2005, 105(7): 2821-2827
19 Ko E, Cho KA, Ju SY, et al. Mesenchymal stem cells inhibit the differentiation of CD4+ T cells into interleukin-17-secreting T cells[J]. Acta Haematol, 2008, 120(3): 165-167
20 Ramasamy R, Tong CK, Seow HF, et al. The immunosuppressive effects of human bone marrow-derived mesenchymal stem cells target T cell proliferation but not its effector function[J]. Cell Immunol, 2008, 251(2): 131-136
21 Maccario R, Podesta M, Moretta A, et al. Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype[J]. Haematologica, 2005, 90(4): 516-525
22 Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses[J]. Blood, 2005, 105(4): 1815-1822
23 Beyth S, Borovsky Z, Mevorach D, et al. Human mesenchymal stem cells alter antigen- presenting cell maturation and induce T-cell unresponsiveness. [J]. Blood, 2005, 105(5): 2214-2219
24 Ye Z, Wang Y, Xie HY, et al. Immunosuppressive effects of rat mesenchymal stem cells: involvement of CD4+CD25+ regulatory T cells[J]. Hepatobiliary Pancreat Dis Int, 2008, 7(6): 608-614
25 Selmani Z, Naji A, Zidi I, et al. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells[J]. Stem Cells, 2008, 26(1): 212-222
26 English K, Ryan JM, Tobin L, et al. Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25(High) forkhead box P3+regulatory T cells[J]. Clin Exp Immunol, 2009, 156(1): 149-160
27 Jiang XX, Zhang Y, Liu B, et al. Human mesenchymal stem cells inhibit ifferentiation and function of monocyte-derived dendritic cells[J]. Blood, 2005, 105(5): 4120-4126
28 Nauta AJ, Kruisselbrink AB, Lurvink E. Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells[J]. J Immunol, 2006, 177(4): 2080-2087
29 English K, Barry FP, Mahon BP, et al. Murine mesenchymal stem cells suppress dendritic cell migration, maturation and antigen presentation[J]. Immunol Lett, 2008, 115(1): 50-58
30 Li YP, Paczesny S, Lauret E, et al. Human mesenchymal stem cells license adult CD34+ hemopoietic progenitor cells to differentiate into regulatory dendritic cells through activation of the Notch pathway[J]. J Immunol, 2008, 180(3): 1598-1608
31 Zhang B, Liu R, Shi D, et al. Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2-dependent regulatory dendritic cell population[J]. Blood, 2009, 113(1): 46-57
32 Augello A, Tasso R, Negrini SM, et al. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway[J]. Eur J Immunol, 2005, 35(5): 1482-1490
33 Tabera S, Pérez-Simón JA, Díez-Campelo M, et al. The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes[J]. Haematologica, 2008, 93(9): 1301-1309
34 Bochev I, Elmadjian G, Kyurkchiev D, et al. Mesenchymal stem cells from human bone marrow or adipose tissue differently modulate mitogen-stimulated B-cell immunoglobulin production in vitro[J]. Cell Biol Int, 2008, 32(4): 384-393
35 Comoli P, Ginevri F, Maccario R, et al. Human mesenchymal stem cells inhibit antibody production induced in vitro by allostimulation. Nephrol Dial Transplant, 2008, 23(4): 1196-1202
36 Krampera M, Cosmi L, Angeli R, et al. Role for interferon-gamma in theimmunomodulatory activity of human bone marrow mesenchymal stem cells. [J]. Stem Cells, 2006, 24(2): 386-398
37 Kang HS, Habib M, Chan J, et al. A paradoxical role for IFN-gamma in the immune properties of mesenchymal stem cells during viral challenge[J]. Exp. Hematol, 2005, 33(7): 796-803
38 Sotiropoulou PA, Perez SA, Gritzapis AD, et al. Interactions between human mesenchymal stem cells and natural killer cells[J]. Stem Cells, 2006, 24(2): 74-85
39 Spaggiari GM, Capobianco A, Becchetti S, et al. Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation[J]. Blood, 2006, 107(4): 1484-1490
40 Rasmusson I. Immune modulation by mesenchymal stem cells[J]. Exp Cell Res, 2006, 312(12): 2169-2179
41 Nauta AJ, Westerhuis G, Kruisselbrink AB, et al. Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting[J]. Blood, 2006, 108(6): 2114-2120
42 Yanez R, Lamana ML, Garcia-Castro J, et al. Adipose tissue-derived mesenchymal stem cells (AD-MSC) have in vivo immunosuppressive properties applicable for the control of graft-versus-host disease (GVHD)[J]. Stem Cells, 2006, 24(11): 2582-2591
43 Lazarus HM, Koc ON, Devine SM, et al. Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients[J]. Blood Marrow Transplant, 2005, 11(5): 389-398
44 Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells[J]. Lancet, 2004, 363(9419): 1439-1441
45 Ringden O, Uzunel M, Rasmusson I, et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease[J].Transplantation, 2006, 81(10): 1390-1397
46 Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study[J]. Lancet, 2008, 371(9624): 1579-1586
47 von Bonin M, St?lzel F, Goedecke A, et al. Treatment of refractory acute GVHD with third-party MSC expanded in platelet lysate-containing medium[J]. Bone Marrow Transplant, 2009, 43(3): 245-251
48 Li H, Guo Z, Jiang X, et al. Mesenchymal stem cells alter migratory property of T and dendritic cells to delay the development of murine lethal acute graft-versus-host disease[J]. Stem Cells, 2008, 26(10): 2531-2541
49 Gerdoni E, Gallo B, Casazza S, et al. Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis[J]. Ann Neurol, 2007, 61(3): 219-227
50 Augello A, Tasso R, Negrini SM, et al. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis[J]. Arthritis Rheum, 2007, 56(4): 1175-1186
51 González MA, Gonzalez-Rey E, Rico L, et al. Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells[J]. Arthritis Rheum, 2009, 60(4): 1006-1019
52 González MA, Gonzalez-Rey E, Rico L, et al. Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses[J]. Gastroenterology. 2009, 136(3): 978-989
53 Boumaza I, Srinivasan S, Witt WT, et al. Autologous bone marrow-derived rat mesenchymal stem cells promote PDX-1 and insulin expression in the islets, alter T cell cytokine pattern and preserve regulatory T cells in the periphery and induce sustained normoglycemia[J]. J Autoimmun, 2009, 32(1): 33-42
54 Zhou K, Zhang H, Jin O,et al. Transplantation of human bone marrow mesenchymal stem cell ameliorates the autoimmune pathogenesis inMRL/lpr mice[J]. Cell Mol Immunol, 2008, 5(6): 417-424
55 Itakura S, Asari S, Rawson J, et al. Mesenchymal stem cells facilitate the induction of mixed hematopoietic chimerism and islet allograft tolerance without GVHD in the rat[J]. Am J Transplant, 2007, 7(2): 336-346
56 Sbano P, Cuccia A, Mazzanti B, et al. Use of donor bone marrow mesenchymal stem cells for treatment of skin allograft rejection in a preclinical rat model[J]. Arch Dermatol Res, 2008, 300(3): 115-124
57 Casiraghi F, Azzollini N, Cassis P, et al. Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells[J]. J Immunol, 2008, 181(6): 3933-3946
58 Hoogduijn MJ, Crop MJ, Peeters AM, et al. Donor-derived mesenchymal stem cells remain present and functional in the transplanted human heart[J]. Am J Transplant, 2009, 9(1): 222-230
59 Crop MJ, Baan CC, Korevaar SS, et al. Donor-derived mesenchymal stem cells suppress alloreactivity of kidney transplant patients[J]. Transplantation. 2009, 87(6): 896-906
60 Hong ZF, Huang XJ, Yin ZY, et al. Immunosuppressive function of bone marrow mesenchymal stem cells on acute rejection of liver allografts in rats[J]. Transplant Proc, 2009, 41(1): 403-409
61 Solari MG, Srinivasan S, Boumaza I, et al. Marginal mass islet transplantation with autologous mesenchymal stem cells promotes long-term islet allograft survival and sustained normoglycemia[J]. J Autoimmun, 2009, 32(2): 116-124
62 Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli[J]. Blood, 2002, 99(10): 3838-3843
63 Zhao ZG, Li WM, Chen ZC, et al. Immunosuppressive properties of mesenchymal stem cells derived from bone marrow of patients with chronic myeloid leukemia[J]. Immunol Invest, 2008, 37(7): 726-739
64 Zhi-Gang Z, Wei-Ming L, Zhi-Chao C, et al. Immunosuppressiveproperties of mesenchymal stem cells derived from bone marrow of patient with hematological malignant diseases[J]. Leuk Lymphoma, 2008, 49(11): 2187-2195
65 Ye Z, Wang Y, Xie HY, et al. Immunosuppressive effects of rat mesenchymal stem cells: involvement of CD4+CD25+ regulatory T cells[J]. Hepatobiliary Pancreat Dis Int, 2008, 7(6): 608-614
66 Gao K, Chen Y, Wei L, et al. Inhibitory effect of mesenchymal stem cells on lymphocyte proliferation[J]. Cell Biochem Funct, 2008, 26(8): 900-907
67 Le Blanc K, Rasmusson I, Gotherstrom C, et al. Mesenchymal stem cells inhibit the expression of CD25 (interleukin-2 receptor) and CD38 on phytohaemagglutinin-activated lymphocytes[J]. Scand. J. Immunol, 2004, 60(3): 307-315
68 Gotherstrom C, West A, Liden J, et al. Difference in gene expression between human fetal liver and adult bone marrow mesenchymal stem cells[J]. Haematologica, 2005, 90(8): 1017-1026
69 Djouad F, Charbonnier LM, Bouffi C, et al. Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism[J]. Stem Cells, 2007, 25(8): 2025-2032
70 Rasmusson I, Ringden O, Sundberg B, et al. Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms[J]. Exp.Cell Res, 2005, 305(1): 33-41
71 Choi JJ, Yoo SA, Park SJ, et al. Mesenchymal stem cells overexpressing interleukin-10 attenuate collagen-induced arthritis in mice[J]. Clin Exp Immunol, 2008, 153(2): 269-276
72 Meisel R, Zibert A, Laryea M, et al. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation[J]. Blood, 2004, 103(12): 4619-4621
73 Fallarino F, Grohmann U, Vacca C, et al. T cell apoptosis by kynurenines.[J]. Adv. Exp. Med. Biol, 2003, 527: 183-190
74 Zappia E, Casazza S, Pedemonte E, et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T cell anergy[J]. Blood, 2005, 106(5): 1755-1761
75 Chabannes D, Hill M, Merieau E, et al. A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells[J]. Blood, 2007, 110(10): 3691-3694
76 Halme DG, Kessler DA. FDA regulation of stem-cell-based therapies[J]. N Engl J Med, 2006, 355(16): 1730-1735
77 Chan JL, Tang KC, Patel AP, et al. Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-gamma[J]. Blood, 2006, 107(12): 4817-4824
78 Stagg J, Pommey S, Eliopoulos N, et al. Interferon-gamma-stimulated marrow stromal cells: a new type of nonhematopoietic antigen-presenting cell [J]. Blood, 2006, 107(6): 2570-2577
79 Djouad F, Plence P, Bony C, et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals[J]. Blood, 2003, 102(10): 3837-3844
80 Grinnemo KH, Mansson A, Dellgren G, et al. Xenoreactivity and engraftment of human mesenchymal stem cells transplanted into infarcted rat myocardium[J]. J. Thorac. Cardiovasc. Surg, 2004, 127(5): 1293-1300
81 Tyndall A, Walker UA, Cope A, et al. Immunomodulatory properties of mesenchymal stem cells: a review based on an interdisciplinary meeting held at the Kennedy Institute of Rheumatology Division, London, UK, 31 October 2005[J]. Arthritis Res Ther, 2007, 9(1): 301
82 Sun LY, Zhang HY, Feng XB, et al. Abnormality of bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus[J]. Lupus, 2007, 16(2): 121-128
83 Inoue S, Popp FC, Koehl GE, et al. Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant model[J]. Transplantation, 2006, 81(11): 1589-1595
84 Horwitz EM, Gordon PL, Koo WK et al. Isolated allogeneic bone marrowderived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone[J]. Proc Natl Acad Sci U S A, 2002, 99(13): 8932-8937
85 Breitbach M, Bostani T, Roell W et al. Potential risks of bone marrow cell transplantation into infarcted hearts[J]. Blood, 2007, 110(4): 1362-1369
86 Miura M, Miura Y, Padilla-Nash HM, et al. Accumulated chromosomal instability in murine bone marrow mesenchymal stem cells leads to malignant transformation[J]. Stem Cells, 2006, 24(4): 1095-1103
87 Tolar J, Nauta AJ, Osborn MJ, et al. Sarcoma Derived from Cultured Mesenchymal Stem Cells[J]. Stem Cells, 2007,25(2):371-379
1 Sprinzl M , Dumortier J , Protzer U. Construction of recombinant adeno-viruses that produce infectious hepatitis B virus [J]. Method Mol Med, 2004, 96: 209-218
2 Hines IN,Wheeler MD. Recent advance in alcoholic liver diseaseⅢ. Role of the innate immune response in alcoholic hepatitis [J]. Am J Physiol Gastrointest Liver Phasiol, 2004, 287(2): G310-314
3 Li, Soloski M J, Diehl A M. Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease[J]. Hepatology, 2005, 42(4): 880-885
4 Teoh NC, Farrell GC. Hepatic ischemia reperfusion injury: Pathogenic mechanisms and basis for hepatoprotection[J]. J Gastroenterol Hepatol, 2003, 18(8): 891-902
5 Lapierre P, Djilali-Saiah I, Vitozzi S, et al. A murine model of type 2 autoimmune hepatitis:Xenoimmunization with human antigen[J]. Hepatology, 2004, 39(4): 1066-1074
6 Tiegs G, Hentschel J, Wendel A. A T cell-dependent experimental liver injury in mice inducible by concanavalin A[J]. J Clin Invest, 1992, 90(1): 196-203
7 Sahai A, Malladi P, Melin-Aldana H, et al. Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model[J]. Am J Physiol Gastrointest Liver Physiol, 2004, 287(1): G264-273
8 Erhardt A, Biburger M, Papadopoulos T, et al. IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice [J]. Hepatology, 2007, 45(2): 475-485
9 Kaneko Y, Harada M, Kawano T, et al. Augmentation of Va 14 NKT cell-mediated cytotoxicity by interleukin 4 in an autocrine mechanism resulting in the development of concanavalin A-induced hepatitis[J]. J Exp Med, 2000, 191(1): 105-114
10 Gantner F, Leist M, Lohse AW, et al. Concanavalin A-induced T cell-mediated hepatic injury in mice: the role of tumor necrosis factor[J]. Hepatology, 1995, 21(1): 190-198
11 Sass G, Heinlein S, Agli A, et al. Cytokine expression in three mouse models of experimental hepatitisJ]. Cytokine, 2002, 19(3): 115-120
12 Bowen DG, Warren A, Davis T, et al. Cytokine-dependent bystander hepatitis due to intrahepatic murine CD8+T-cell activation by bone marrow-derived cells[J]. Gastroenterology, 2002, 123(4): 1252-1264
13 Mizuhara H, O’Neill E, Seki N, et al. Cytokine-dependent bystander hepatitis injury: mediation by tumor necrosis factors and protection by interleukin 6[J]. J Exp Med, 1994, 179(5): 1529-1537
14 Wolf D, Hallmann R, Sass G, et al. TNF-alpha-induced expression of adhesion molecules in the liver is under the control of TNFR1--relevance for concanavalin A-induced hepatitis[J]. J Immunol, 2001, 166(2):1300-1307
15 Cao Q, Batey R, Pang G, et al. IL-6, IFN-γand TNF-αproduction by liver-associated T cells and acute liver injury in rats administered concanavalin A[J]. Immunol Cell Biol, 1998, 76(6): 542-549
16 Streetz K, Fregien B, Plümpe J, et al. Dissection of the intracellular pathways in hepatocytes suggests a role for Jun kinase and IFN regulatory factor-1 in Con A-induced liver failure[J]. J Immunol, 2001, 167(1): 514-523
17 Schümann J, Wolf D, Pahl A, et al. Importance of Kupffer cells for T-cell-dependent liver injury in mice[J]. Am J Pathol, 2000, 157(5): 1671-1683
18 Klugewitz K, Adams DH, Emoto M,et al. The composition of intrahepatic lymphocytes: shaped by selective recruitment[J]. Trends Immunol, 2004, 25(11): 590-594
19 Ajuebor MN, Hogaboam CM, Le T, et al. CCL3/MIP-1alpha is pro-inflammatory in murine T cell-mediated hepatitis by recruiting CCR1-expressing CD4(+) T cells to the liver[J]. Eur J Immunol, 2004, 34(10): 2907-2918
20 Tiegs G. Cellular and cytokine-mediated mechanisms of inflammation and its modulation in immune-mediated liver injury[J]. Z Gastroenterol, 2007, 45(1): 63-70
21 Chen D, McKallip RJ, Zeytun A, et al. CD44-deficient mice exhibit enhanced hepatitis after concanavalin A injection: evidence for involvement of CD44 in activation-induced cell death[J]. Immunol, 2001, 166(10): 5889-5897
22 Fontenot JD, Rudensky AY. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3[J]. Nat Immunol, 2005, 6(4): 331-337
23 Takeda K, Hayakawa Y, Van Kaer L, et al. Critical contribution of liver natural killer T cells to a murine model of hepatitis[J]. Proc Natl Acad Sci U S A, 2000, 97(10): 5498-5503
24 Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses[J]. Annu Rev Immunol, 2004, 22: 531-562
25 Maeda S, Chang L, Li ZW, et al. IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFalpha[J]. Immunity, 2003, 19(5): 725-737
26 Schumann J, Muhlen K, Kiemer AK, et al. Parenchymal, but not leukocyte, TNF receptor 2 mediates T cell-dependent hepatitis in mice[J]. J Immunol, 2003, 170(4): 2129-2137
27 Song E, Lee SK, Wang J, et al. RNA interference targeting Fas protects mice from fulminant hepatitis[J]. Nat Med, 2003, 9(3): 347-351
28 Descamps D, Vigant F, Esselin S, et al. Expression of non-signaling membrane-anchored death receptors protects murine livers in different models of hepatitis[J]. Hepatology, 2006, 44(2): 399-409
29 Zheng SJ, Wang P, Tsabary G, et al. Critical roles of TRAIL in hepatic cell death and hepatic inflammation[J]. J Clin Invest, 2004, 113(1): 58-64
30 Anand S, Wang P, Yoshimura K, et al. Essential role of TNF family molecule LIGHT as a cytokine in the pathogenesis of hepatitis[J]. J Clin Invest, 2006, 116(4): 1045-1051
31 Hong F, Jaruga B, Kim WH, et al. Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS[J]. J Clin Invest, 2002, 110(10): 1503-1513
32 Siebler J, Wirtz S, Klein S, et al. A key pathogenic role for the STAT1/T-bet signaling pathway in T-cell-mediated liver inflammation[J]. Hepatology, 2003, 38(6): 1573-1580
33 Senaldi G, Shaklee CL, Guo J, et al. Protection against the mortality associated with disease models mediated by TNF and IFN-gamma in mice lacking IFN regulatory factor-1[J]. J Immunol, 1999, 163(12): 6820-6826
34 Jaruga B, Hong F, Sun R, et al. Crucial role of IL-4/STAT6 in T cell-mediated hepatitis: up-regulating eotaxins and IL-5 and recruiting leukocytes[J]. J Immunol, 2003, 171(6): 3233-3244
35 Louis H, Le Moine A, Flamand V, et al. Critical role of interleukin 5 and eosinophils in concanavalin A-induced hepatitis in mice[J]. Gastroenterology, 2002, 122(7): 2001-2010
36 Gao B. Cytokines, STATs and liver disease[J]. Cell Mol Immunol, 2005, 2(2): 92-100
37 Sun R, Tian Z, Kulkarni S, et al. IL-6 prevents T cell-mediated hepatitis via inhibition of NKT cells in CD4+ T cell- and STAT3-dependent manners[J]. J Immunol, 2004, 172(9): 5648-5655
38 Trayhurn P, Wood IS. Signalling role of adipose tissue: adipokines and inflammation in obesity[J]. Biochem Soc Trans, 2005, 33: 1078-1081
39 Siegmund B, Lear-Kaul KC, Faggioni R, et al. Leptin deficiency, not obesity, protects mice from Con A-induced hepatitis[J]. Eur J Immunol, 2002, 32(2): 552-560
40 Wolf AM, Wolf D, Avila MA, et al. Up-regulation of the anti-inflammatory adipokine adiponectin in acute liver failure in mice[J]. J Hepatol, 2006, 44(3): 537-543
41 Isayama F, Hines IN, Kremer M, et al. Favored T helper 1 response in a mouse model of hepatosteatosis is associated with enhanced T cell-mediated hepatitis[J]. Hepatology, 2006, 44(1): 216-227
42 Van Kaer L. alpha-Galactosylceramide therapy for autoimmune diseases: prospects and obstacles[J]. Nat Rev Immunol, 2005, 5(1): 31-42
2 Hines IN,Wheeler MD. Recent advance in alcoholic liver diseaseⅢ. Role of the innate immune response in alcoholic hepatitis[J]. Am J Physiol Gastrointest Liver Phasiol, 2004, 287(2): G310-314
3 Li, Soloski M J, Diehl A M. Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease[J]. Hepatology, 2005, 42(4): 880-885
4 Teoh NC, Farrell GC. Hepatic ischemia reperfusion injury: Pathogenic mechanisms and basis for hepatoprotection[J]. J Gastroenterol Hepatol, 2003, 18(8): 891-902
5 Lapierre P, Djilali-Saiah I, Vitozzi S, et al. A murine model of type 2 autoimmune hepatitis:Xenoimmunization with human antigen[J]. Hepatology, 2004, 39(4): 1066-1074
6 Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells[J]. Lancet, 2004, 363(9419): 1439-1441
7 Ringdén O, Uzunel M, Rasmusson I, et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease[J]. Transplantation, 2006, 81(10): 1390-1397
8 Le Blanc K, Frassoni F, Ball L, et al. Developmental Committee of the European Group for Blood and Marrow Transplantation. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study[J]. Lancet, 2008, 371(9624): 1579-1586
9 Gerdoni E, Gallo B, Casazza S, et al. Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis[J]. Ann Neurol, 2007, 61(3): 219-227
10 Augello A, Tasso R, Negrini SM, et al. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis[J]. Arthritis Rheum, 2007, 56(4): 1175-1186
11 Sun LY, Zhang HY, Feng XB,et al. Abnormality of bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus [J]. Lupus, 2007, 16(2):121-128
12 Tiegs G, Hentschel J, Wendel A. A T cell-dependent experimental liver injury in mice inducible by concanavalin A[J]. J Clin Invest, 1992, 90(1):196-203
13 Kaneko Y, Harada M, Kawano T, et al. Augmentation of Va 14 NKT cell-mediated cytotoxicity by interleukin 4 in an autocrine mechanism resulting in the development of concanavalin A-induced hepatitis[J]. J Exp Med, 2000, 191(1): 105-114
14 Gantner F, Leist M, Lohse AW, et al. Concanavalin A-induced T cell-mediated hepatic injury in mice: the role of tumor necrosis factor[J]. Hepatology, 1995, 21(1): 190-198
15 Tiegs G. Cellular and cytokine-mediated mechanisms of inflammation and its modulation in immune-mediated liver injury[J]. Z Gastroenterol, 2007, 45(1): 63-70
16 Tse WT, Pendleton JD,Beyer WM, et al. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implication in transplantation[J]. 2003, 75(3): 389-397
17 Le Blanc K, Tammik C, Rosendahl K, et al. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells[J]. Exp. Hematol, 2003, 31(10): 890-896
18 Klyushnenkova E, Mosca JD, Zernetkina V, et al. T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression[J]. J. Biomed Sci, 2005, 12(1): 47-57
19 Glennie S, Soeiro I, Dyson PJ, et al. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells[J]. Blood, 2005, 105(7): 2821-2827
20 Maccario R, Podesta M, Moretta A, et al. Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype[J]. Haematologica, 2005, 90(4): 516-525
21 Beyth S, Borovsky Z, Mevorach D, et al. Human mesenchymal stem cells alter antigen- presenting cell maturation and induce T-cell unresponsiveness[J]. Blood, 2005, 105(5): 2214-2219
22 English K, Ryan JM, Tobin L, et al. Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25(High) forkhead box P3+ regulatory T cells[J]. Clin Exp Immunol, 2009, 156(1): 149-160
23 Ko E, Cho KA, Ju SY, et al. Mesenchymal stem cells inhibit the differentiation of CD4+ T cells into interleukin-17-secreting T cells[J]. Acta Haematol, 2008, 120(3): 165-167
24 Sheng H, Wang Y, Jin Y, et al. A critical role of IFNgamma in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1[J]. Cell Res, 2008, 18(8): 846-857
25 Ramasamy R, Tong CK, Seow HF, et al. The immunosuppressive effects of human bone marrow-derived mesenchymal stem cells target T cell proliferation but not its effector function[J]. Cell Immunol, 2008, 251(2): 131-136
26 Selmani Z, Naji A, Zidi I, et al. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+regulatory T cells[J]. Stem Cells, 2008, 26(1): 212-222
27 Tsai MS, Lee JL, Chang YJ, et al. Isolation of human multipotent mesenchymal stem cells from second-trimester amniotic fluid using a novel two-stage culture protocol[J]. Hum Reprod, 2004, 19(6): 1450-1456
28 Tsai MS, Hwang SM, Tsai YL, et al. Clonal amniotic fluid-derived stem cells express characteristics of both mesenchymal and neural stem cells[J]. Biol Reprod, 2006, 74(3): 545-551
29 Cananzi M, Atala A, De Coppi P. Stem cells derived from amniotic fluid: new potentials in regenerative medicine[J]. Reprod Biomed Online, 2009, 18 Suppl 1:17-27
30 Halme DG, Kessler DA. FDA regulation of stem-cell-based therapies[J]. N Engl J Med, 2006, 355(16): 1730-1735
1 Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acutegraft-versus-host disease with third party haploidentical mesenchymal stem cells[J]. Lancet, 2004, 363(9419): 1439–1441
2 Ringdén O, Uzunel M, Rasmusson I, et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease[J]. Transplantation, 2006, 81(10): 1390-1397
3 Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study[J]. Lancet, 2008, 371(9624): 1579–1586
4 Gerdoni E, Gallo B, Casazza S, et al. Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis[J]. Ann Neurol, 2007, 61(3): 219-227
5 Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease[J]. Nat Rev Immunol, 2008, 8(9): 726-36
6 González MA, Gonzalez-Rey E, Rico L, et al. Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells[J]. Arthritis Rheum, 2009, 60(4): 1006-1019
7 Tsai MS, Lee JL, Chang YJ, et al. Isolation of human multipotent mesenchymal stem cells from second-trimester amniotic fluid using a novel two-stage culture protocol[J]. Hum Reprod, 2004, 19(6): 1450-1456
8 Tsai MS, Hwang SM, Tsai YL, et al. Clonal amniotic fluid-derived stem cells express characteristics of both mesenchymal and neural stem cells[J]. Biol Reprod, 2006, 74(3): 545-551
9 Cananzi M, Atala A, De Coppi P. Stem cells derived from amniotic fluid: new potentials in regenerative medicine[J]. Reprod Biomed Online, 2009, 18 Suppl 1:17-27
10 Priest RE, Marimuthu KM, Priest JH. Origin of cells in human amniotic fluid cultures: ultrastructural features[J]. Lab Invest, 1978, 39(2): 106-109
11 Polgar K, Adany R, Abel G, et al. Characterization of rapidly adhering amniotic fluid cells by combined immunofluorescence and phagocytosis assays[J]. Am J Hum Genet, 1989, 45(5): 786-792
12 In’t Anker PS, Scherjon SA, Kleijburg-van, et al. Amniotic fluid as anovel source of mesenchymal stem cells for therapeutic transplantation[J]. Blood, 2003, 102(4):1548-1549
13 Coppi PD, Bartsch G, Siddiqui MM, et al. Isolation of amniotic stem cell lines with potential for therapy[J]. Nat Biotech, 2007, 25(1): 100-106
14 Kaviani A, Perry T, Dzakovic A, et al. The amniotic fluid as a source of cells for fetal tissue engineering[J]. J Ped Surgery, 2001, 36(11): 1662-1665
15 Bossolasco P,Montemurro T,Cova L, et al. Molecular and phenotypic characterization of human amniotic fluid cells and their differentiation potential[J]. Cell Res, 2006, 16(4): 329-336
16 Roubelakis MG, Pappa KI, Bitsika V, et al. Molecular and proteomic characterization of human mesenchymal stem cells derived from amniotic fluid: comparison to bone marrow mesenchymal stem cells[J]. Stem Cells Dev, 2007, 16(6): 931-952
1 Sprinzl M , Dumortier J , Protzer U. Construction of recombinant adeno-viruses that produce infectious hepatitis B virus[J]. Method Mol Med, 2004, 96: 209-218
2 Hines IN,Wheeler MD. Recent advance in alcoholic liver diseaseⅢ. Role of the innate immune response in alcoholic hepatitis[J]. Am J Physiol Gastrointest Liver Phasiol, 2004, 287(2): G310-314
3 Li, Soloski M J, Diehl A M. Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease[J]. Hepatology, 2005, 42(4): 880-885
4 Teoh NC, Farrell GC. Hepatic ischemia reperfusion injury: Pathogenic mechanisms and basis for hepatoprotection[J]. J Gastroenterol Hepatol, 2003, 18(8): 891-902
5 Lapierre P, Djilali-Saiah I, Vitozzi S, et al. A murine model of type 2 autoimmune hepatitis: Xenoimmunization with human antigen[J]. Hepatology, 2004, 39(4): 1066-1074
6 Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymalstem cells[J]. Lancet, 2004, 363(9419): 1439-1441
7 Ringdén O, Uzunel M, Rasmusson I, et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease[J]. Transplantation, 2006, 81(10): 1390-1397
8 Le Blanc K, Frassoni F, Ball L, et al. Developmental Committee of the European Group for Blood and Marrow Transplantation. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study[J]. Lancet, 2008, 371(9624): 1579-1586
9 Gerdoni E, Gallo B, Casazza S, et al. Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis[J]. Ann Neurol, 2007, 61(3): 219-227
10 Augello A, Tasso R, Negrini SM, et al. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis[J]. Arthritis Rheum, 2007, 56(4): 1175-1186
11 Tiegs G, Hentschel J, Wendel A. A T cell-dependent experimental liver injury in mice inducible by concanavalin A[J]. J Clin Invest, 1992, 90(1): 196-203
12 Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis[J]. J Hepatol, 1995, 22: 696-699
13 Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis[J]. HEPATOLOGY, 1981, 1: 431-435
14 González MA, Gonzalez-Rey E, Rico L, et al. Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells[J]. Arthritis Rheum, 2009, 60(4): 1006-1019
15 González MA, Gonzalez-Rey E, Rico L, et al. Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses[J]. Gastroenterology. 2009, 136(3): 978-989
16 Boumaza I, Srinivasan S, Witt WT, et al. Autologous bone marrow-derived rat mesenchymal stem cells promote PDX-1 and insulin expression in the islets, alter T cell cytokine pattern and preserve regulatory T cells in the periphery and induce sustained normoglycemia[J]. J Autoimmun, 2009, 32(1): 33-42
17 Zhou K, Zhang H, Jin O,et al. Transplantation of human bone marrow mesenchymal stem cell ameliorates the autoimmune pathogenesis in MRL/lpr mice[J]. Cell Mol Immunol, 2008, 5(6): 417-424
18 Kaneko Y, Harada M, Kawano T, et al. Augmentation of Va 14 NKT cell-mediated cytotoxicity by interleukin 4 in an autocrine mechanism resulting in the development of concanavalin A-induced hepatitis[J]. J Exp Med, 2000, 191(1): 105-114
19 Gantner F, Leist M, Lohse AW, et al. Concanavalin A-induced T cell-mediated hepatic injury in mice: the role of tumor necrosis factor [J]. Hepatology, 1995, 21(1): 190-198
20 Tiegs G. Cellular and cytokine-mediated mechanisms of inflammation and its modulation in immune-mediated liver injury[J]. Z Gastroenterol, 2007, 45(1): 63-70
21 Rasmusson I. Immune modulation by mesenchymal stem cells[J]. Exp Cell Res, 2006, 312(12): 2169-2179
22 Tse WT, Pendleton JD,Beyer WM, et al. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implication in transplantation[J]. 2003, 75(3): 389-397
23 Le Blanc K, Tammik C, Rosendahl K, et al. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells[J]. Exp. Hematol, 2003, 31(10): 890-896
24 Klyushnenkova E, Mosca JD, Zernetkina V, et al. T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression[J]. J. Biomed Sci, 2005, 12(1): 47-57
25 Glennie S, Soeiro I, Dyson PJ, et al. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells[J]. Blood, 2005,105(7): 2821-2827
26 Maccario R, Podesta M, Moretta A, et al. Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype[J]. Haematologica, 2005, 90(4): 516-525
27 Beyth S, Borovsky Z, Mevorach D, et al. Human mesenchymal stem cells alter antigen- presenting cell maturation and induce T-cell unresponsiveness[J]. Blood, 2005, 105(5): 2214-2219
28 English K, Ryan JM, Tobin L, et al. Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25(High) forkhead box P3+ regulatory T cells[J]. Clin Exp Immunol, 2009, 156(1): 149-160
29 Ko E, Cho KA, Ju SY, et al. Mesenchymal stem cells inhibit the differentiation of CD4+ T cells into interleukin-17-secreting T cells[J]. Acta Haematol., 2008, 120(3): 165-167
30 Sheng H, Wang Y, Jin Y, et al. A critical role of IFNgamma in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1[J]. Cell Res, 2008, 18(8): 846-857
31 Ramasamy R, Tong CK, Seow HF, et al. The immunosuppressive effects of human bone marrow-derived mesenchymal stem cells target T cell proliferation but not its effector function. Cell Immunol[J], 2008, 251(2): 131-136
32 Selmani Z, Naji A, Zidi I, et al. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells[J]. Stem Cells, 2008, 26(1): 212-222
33 Beyth S, Borovsky Z, Mevorach D, et al. Human mesenchymal stem cells alter antigen- presenting cell maturation and induce T-cell unresponsiveness[J]. Blood, 2005, 105(5): 2214-2219
34 Jiang XX, Zhang Y, Liu B, et al. Human mesenchymal stem cells inhibitifferentiation and function of monocyte-derived dendritic cells [J]. Blood, 2005, 105(5): 4120-4126
35 Nauta AJ, Kruisselbrink AB, Lurvink E. Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells[J]. J Immunol, 2006, 177(4): 2080-2087
36 English K, Barry FP, Mahon BP. Murine mesenchymal stem cells suppress dendritic cell migration, maturation and antigen presentation[J]. Immunol Lett, 2008, 115(1): 50-58
37 Li YP, Paczesny S, Lauret E, et al. Human mesenchymal stem cells license adult CD34+ hemopoietic progenitor cells to differentiate into regulatory dendritic cells through activation of the Notch pathway[J]. J Immunol, 2008, 180(3): 1598-1608
38 Zhang B, Liu R, Shi D, et al. Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2-dependent regulatory dendritic cell population[J]. Blood, 2009, 113(1): 46-57
39 Wang Q, Sun B, Wang D, et al. Murine bone marrow mesenchymal stem cells cause mature dendritic cells to promote T-cell tolerance[J]. Scand J Immunol, 2008, 68(6): 607-615
40 Augello A, Tasso R, Negrini SM, et al. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway[J]. Eur J Immunol, 2005, 35(5): 1482-1490
41 Krampera M, Cosmi L, Angeli R, et al. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells[J]. Stem Cells, 2006, 24(2): 386-398
42 Comoli P, Ginevri F, Maccario R, et al. Human mesenchymal stem cells inhibit antibody production induced in vitro by allostimulation[J]. Nephrol Dial Transplant, 2008, 23(4): 1196-1202
43 Tabera S, Pérez-Simón JA, et al. The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes. Haematologica, 2008, 93(9): 1301-1309
44 Le Blanc K, Tammik L, Sundberg B, et al. Mesenchymal stem cellsinhibit and stimulate mixed lymphocyte cultures and responses independently of the major histocompatibility complex. [J]. Scand J Immunol, 2003, 57(1): 11-20
45 Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. [J]. Blood, 2005, 105(4): 1815-1822
46 Kang HS, Habib M, Chan J, et al. A paradoxical role for IFN-gamma in the immune properties of mesenchymal stem cells during viral challenge. [J]. Exp. Hematol, 2005, 33(7): 796-803
47 Sotiropoulou PA, Perez SA, Gritzapis AD, et al. Interactions between human mesenchymal stem cells and natural killer cells. [J]. Stem Cells, 2006, 24(2): 74-85
48 Djouad F, Plence P, Bony C, et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood, 2003; 102(10): 3837-3844
49 Grinnemo KH, M?nsson A, Dellgren G, et al. Xenoreactivity and engraftment of human mesenchymal stem cells transplanted into infarcted rat myocardium. J. Thorac. Cardiovasc. Surg, 2004, 127(5): 1293-1300
50 Rossignol J, Boyer C, Thinard R, et al. Mesenchymal stem cells induce a weak immune response in the rat striatum after allo or xenotransplantation. J Cell Mol Med. 2009. [Epub ahead of print]
51 Nauta AJ, Westerhuis G, Kruisselbrink AB, et al. Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting. Blood, 2006, 108(6): 2114-2120
52 Inoue S, Popp FC, Koehl GE, et al. Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant model. Transplantation, 2006, 81(11): 1589-1595
53 Ren G, Zhang L, Zhao X, et al. Mesenchymal Stem Cell-Mediated Immunosuppression Occurs via Concerted Action of Chemokines and Nitric Oxide.Cell. Stem Cell, 2008, 2(2): 141-150
1 Ren G, Zhang L, Zhao X, et al. Mesenchymal Stem Cell-Mediated Immunosuppression Occurs via Concerted Action of Chemokines and Nitric Oxide[J]. Cell. Stem Cell, 2008, 2(2): 141-150
2 Beyth S, Borovsky Z, Mevorach D, et al. Human mesenchymal stem cells alter antigen- presenting cell maturation and induce T-cell unresponsiveness[J]. Blood, 2005, 105(5): 2214-2219
3 Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli[J]. Blood, 2002, 99(10): 3838-3843
4 Le Blanc K, Rasmusson I, Gotherstrom C, et al. Mesenchymal stem cells inhibit the expression of CD25 (interleukin-2 receptor) and CD38 on phytohaemagglutinin-activated lymphocytes[J]. Scand. J. Immunol, 2004, 60(3): 307-315
5 Tiegs G, Hentschel J, Wendel A. A T cell-dependent experimental liver injury in mice inducible by concanavalin A[J]. J Clin Invest, 1992, 90(1): 196-203
6 Kaneko Y, Harada M, Kawano T, et al. Augmentation of Va 14 NKT cell-mediated cytotoxicity by interleukin 4 in an autocrine mechanism resulting in the development of concanavalin A-induced hepatitis[J]. J Exp Med, 2000, 191(1): 105-114
7 Takeda K, Hayakawa Y, Van Kaer L, et al. Critical contribution of liver natural killer T cells to a murine model of hepatitis[J]. Proc Natl Acad SciU S A, 2000, 97(10): 5498-5503
8 Song E, Lee SK, Wang J, et al. RNA interference targeting Fas protects mice from fulminant hepatitis[J]. Nat Med, 2003, 9(3): 347-351
9 Descamps D, Vigant F, Esselin S, et al. Expression of non-signaling membrane-anchored death receptors protects murine livers in different models of hepatitis[J]. Hepatology, 2006, 44(2): 399-409
10 Maccario R, Podesta M, Moretta A, et al. Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype[J]. Haematologica, 2005, 90(4): 516-525
11 Le Blanc K, Tammik C, Rosendahl K, et al. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells[J]. Exp. Hematol, 2003, 31(10): 890-896
12 Ye Z, Wang Y, Xie HY, et al. Immunosuppressive effects of rat mesenchymal stem cells: involvement of CD4+CD25+ regulatory T cells[J]. Hepatobiliary Pancreat Dis Int, 2008, 7(6): 608-614
13 Di Ianni M, Del Papa B, De Ioanni M, et al. Mesenchymal cells recruit and regulate T regulatory cells[J]. Exp Hematol, 2008, 36(3): 309-318
14 Selmani Z, Naji A, Zidi I, et al. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells[J]. Stem Cells, 2008, 26(1): 212-222
15 English K, Ryan JM, Tobin L, et al. Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25(High) forkhead box P3+ regulatory T cells[J]. Clin Exp Immunol, 2009, 156(1): 149-160
16 Augello A, Tasso R, Negrini SM, et al. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis[J]. Arthritis Rheum, 2007, 56(4): 1175-1186
17 Parekkadan B, Tilles AW, Yarmush ML, et al. Bone marrow-derivedmesenchymal stem cells ameliorate autoimmune enteropathy independently of regulatory T cells[J]. Stem Cells, 2008, 26(7): 1913-1919
18 Casiraghi F, Azzollini N, Cassis P, et al. Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells[J]. J Immunol, 2008, 181(6): 3933-3946
19 Erhardt A, Biburger M, Papadopoulos T, et al. IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice[J]. Hepatology, 2007, 45(2): 475-485
20 Tse WT, Pendleton JD, Beyer WM, et al. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implication in transplantation[J]. Transplantation, 2003, 75(3): 389-397
21 Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses[J]. Blood, 2005, 105(4): 1815-1822
22 Rasmusson I, Ringden O, Sundberg B, et al. Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms[J]. Exp.Cell Res, 2005, 305(1): 33-41
23 Meisel R, Zibert A, Laryea M, et al. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation[J]. Blood, 2004, 103(12): 4619-4621
24 Fallarino F, Grohmann U, Vacca C, et al. T cell apoptosis by kynurenines[J]. Adv. Exp. Med. Biol, 2003, 527: 183-190
25 Chabannes D, Hill M, Merieau E, et al. A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells[J]. Blood, 2007, 110(10): 3691-3694
26 Gotherstrom C, West A, Liden J, et al. Difference in gene expression between human fetal liver and adult bone marrow mesenchymal stem cells[J]. Haematologica, 2005, 90(8): 1017-1026
27 Cressman DE, Greenbaum LE, DeAngelis RA, et al. Liver failure anddefective hepatocyte regeneration in interleukin-6-deficient mice[J]. Science, 1996, 274(5291): 1379-1383
28 Yang SH, Park MJ, Yoon IH, et al. Soluble Mediators from Mesenchymal Stem Cells Suppress T cell Proliferation by inducing IL-10[J]. Exp Mol Med, 2009. [Epub ahead of print]
29 Choi JJ, Yoo SA, Park SJ, et al. Mesenchymal stem cells overexpressing interleukin-10 attenuate collagen-induced arthritis in mice[J]. Clin Exp Immunol, 2008, 153(2): 269-276
30 Hong F, Jaruga B, Kim WH, et al. Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS[J]. J. Clin. Invest, 2002, 110(10): 1503-1513
31 Mizuhara H, Uno M, Seki N, et al. Critical involvement of Interferon-6 in the pathogenesis of T-cell activation-associated hepatitis and regulatory mechanisms of interleukin-6 for the manifestations of hepatitis[J]. Hepatology, 1996, 23(6): 1608-1615
32 Hong F, Kim WH, Tian Z, et al. Elevated interleukin-6 during ethanol consumption acts as a potential endogenous protective cytokine against ethanol-induced apoptosis in the liver: involvement of induction of Bcl-2 and Bcl-x(L) proteins[J]. Oncogene, 2002, 21(1): 32-43
33 Kovalovich K, Li W, DeAngelis R, et al. Interleukin-6 protects against Fas-mediated death by establishing a critical level of anti-apoptotic hepatic proteins FLIP, Bcl-2, and Bcl-xL[J]. J. Biol.Chem, 2001, 276(28): 26605-26613
34 Kovalovich K, DeAngelis RA, Li W, et al. Increased toxin-induced liver injury and fibrosis in interleukin-6-deficient mice[J]. Hepatology, 2000, 31(1): 149-159
35 Camargo CA Jr, Madden JF, Gao W, et al. Clavien. Interleukin-6 protects liver against warm ischemia/reperfusion injury and promotes hepatocyte proliferation in the rodent[J]. Hepatology, 1997, 26(6): 1513-1520
36 Masubuchi Y, Bourdi M, Reilly TP, et al. Role of interleukin-6 in hepatic heat shock protein expression and protection againstacetaminophen-induced liver disease. Biochem. Biophys[J]. Res. Commun, 2003, 304(1): 207-212
37 Meng ZH, Dyer K, Billiar TR, et al. Distinct effects of systemic infusion of G-CSF vs. IL-6 on lung and liver inflammation and injury in hemorrhagic shock[J]. Shock, 2000, 14(1): 41-48
38 Selzner N, Selzner M, Tian Y, et al. Cold ischemia decreases liver regeneration after partial liver transplantation in the rat: a TNF-α/IL-6- dependent mechanism[J]. Hepatology, 2002, 36: 812-818
39 Sun Z, Klein AS, Radaeva S, et al. In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats[J]. Gastroenterology, 2003, 125(1): 202-215
40 Li W, Liang X, Kellendonk C, et al. STAT3 contributes to the mitogenic response of hepatocytes during liver regeneration[J]. J. Biol. Chem, 2002, 277(32): 28411-28417
41 Wuestefeld T, Klein C, Streetz KL, et al. Interleukin-6/glycoprotein 130-dependent pathways are protective during liver regeneration[J]. J. Biol. Chem, 2003, 278(13): 11281-11288
42 Streetz KL, Tacke F, Leifeld L, et al. Interleukin 6/gp130-dependent pathways are protective during chronic liver diseases[J]. Hepatology, 2003, 38(1): 218-229
43 Streetz KL, Wustefeld T, Klein C, et al. Lack of gp130 expression in hepatocytes promotes liver injury[J]. Gastroenterology, 2003, 125(2): 532-543
44 Taub, R. Hepatoprotection via the IL-6/Stat3 pathway[J]. J. Clin. Invest, 2003, 112(7): 978-980
45 Haga S, Terui K, Zhang HQ, et al. Stat3 protects against Fas-induced liver injury by redox-dependent and -independent mechanisms[J]. J. Clin. Invest, 2003, 112(7): 989-998
46 Sun R, Tian Z, Kulkarni S, et al. IL-6 Prevents T Cell-mediated hepatitis via inhibition of NKT Cells in CD4+T cell- and STAT3-dependent manners[J]. J Immunol, 2004, 172(9): 5648-5655
47 Rasmusson I. Immune modulation by mesenchymal stem cells[J]. Exp Cell Res, 2006, 312(12): 2169-2179
48 Djouad F, Charbonnier LM, Bouffi C, et al. Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism[J]. Stem Cells, 2007, 25(8): 2025-2032
49 Hurst SM, Wilkinson TS, McLoughlin RM, et al. Control of leukocyte infiltration during inflammation: IL-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment[J]. Immunity, 2001, 14: 705-714
50 Karlmark KR, Wasmuth HE, Trautwein C, et al. Chemokine-directed immune cell infiltration in acute and chronic liver disease[J]. Expert Rev Gastroenterol Hepatol, 2008, 2(2): 233-242
1 Halme DG, Kessler DA. FDA regulation of stem-cell-based therapies[J]. N Engl J Med, 2006, 355(16): 1730-1735
2 Miura M, Miura Y, Padilla-Nash HM, et al. Accumulated chromosomal instability in murine bone marrow mesenchymal stem cells leads to malignant transformation[J]. Stem Cells, 2006, 24(4):1095-1103
3 Tolar J, Nauta AJ, Osborn MJ, et al. Sarcoma Derived from Cultured Mesenchymal Stem Cells[J]. Stem Cells, 2007, 25(2): 371-379
4 Ohlsson LB, Varas L, Kjellman C, et al. Mesenchymal progenitor cell-mediated inhibited of tumour growth in vivo and in vitro in gelation matrix[J]. Exp Mol Pathol, 2003, 75: 248-255
5 Diouad F, Plence P, Bony C, et al. Immunosuppressive effect of mesenchymal stem cell favors tumor growth in allogeneic animal[J]. Blood, 2003, 102: 3837-3844
6 Kuroda K, Nakashima J, Kanao K, et al. Interleukin 6 is associated with cachexia in patients with prostate cancer[J]. Urology, 2007, 69(1): 113-117
7 Kanazawa T, Nishino H, Hasegawa M, et al. Interleukin-6 directly influences proliferation and invasion potential of head and neck cancer cells[J]. Eur Arch Otorhinolaryngol, 2007, 264(7): 815-821
8 Duffy SA, Taylor JM, Terrell JE, et al. Interleukin-6 predicts recurrence and survival among head and neck cancer patients[J]. Cancer, 2008, 113(4): 750-757
9李万胜,胡洁,赵娟,等. IL-8基因真核表达载体构建及其在OVCAR-3卵巢癌细胞中的表达[J].军事医学科学院院刊, 2008, 32(2): 144-147
10胡洁,齐义新,姚智燕,等.乳腺癌患者白细胞介素8临床检测的意义[J].临床荟萃, 2006, 21 (10) : 726-728
11胡洁,王秀荣,齐义新,等.乳腺癌白细胞介素-8基因表达的临床检测意义[J].河北医科大学学报, 2006, 27(5): 367-369
12 Borczuk AC, Papanikolaou N, Toonkel RL, et al. Lung adenocarcinoma invasion in TGFbetaRII-deficient cells is mediated by CCL5/RANTES[J]. Oncogene, 2008, 27(4): 557-564
13 Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis[J]. Nature, 2007, 449(7162): 557-563
14 Rubio D, Garcia S, De la Cueva T, et al. Human mesenchymal stem cell transformation is associated with a mesenchymal-epithelial transition[J]. Exp Cell Res, 2008, 314(4): 691-698
15 Bernardo ME, Zaffaroni N, Novara F, Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms[J]. Cancer Res, 2007, 67(19): 9142-9149
16 Choumerianou DM, Dimitriou H, Perdikogianni C, et al. Study of oncogenic transformation in ex vivo expanded mesenchymal cells, from paediatric bone marrow[J]. Cell Prolif, 2008, (6): 909-922
17 Kim J, Kang JW, Park JH, et al. Biological characterization of long-term cultured human mesenchymal stem cells[J]. Arch Pharm Res, 2009, 32(1): 117-126
18 Santisteban M, Reiman JM, Asiedu MK, et al. Immune-induced epithelial to mesenchymal transition in vivo generates breast cancer stem cells[J]. Cancer Res, 2009, 69(7): 2887-2895
19 Haviv I, Polyak K, Qiu W, et al. Origin of carcinoma associated fibroblasts[J]. Cell Cycle., 2009, 8(4): 589-595
20 Mishra PJ, Mishra PJ, Humeniuk R, et al. Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells[J]. Cancer Res, 2008, (11): 4331-4439
21 Bagley RG, Weber W, Rouleau C, et al. Human mesenchymal stem cells from bone marrow express tumor endothelial and stromal markers[J]. Int J Oncol, 2009, 34(3): 619-627
22 Apparailly F, Jorgensen C, Lazennec G. Multipotent stromal cells: controversial impact on tumor development and metastasis[J]. Med Sci , 2008, 24(4):359-360
23 Zhang W. Mesenchymal stem cells in cancer: friends or foes[J]. Cancer Biol Ther, 2008, 7(2): 252-254
24 Dwyer RM, Potter-Beirne SM, Harrington KA, et al. Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells[J]. Clin Cancer Res, 2007, 13(17): 5020-5027
25 Gutova M, Najbauer J, Frank RT, et al. Urokinase plasminogen activator and urokinase plasminogen activator receptor mediate human stem cell tropism to malignant solid tumors[J]. Stem Cells, 2008, 26(6): 1406-1413
26 Spaeth E, Klopp A, Dembinski J, et al. Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells[J]. Gene Ther, 2008, 15(10): 730-738
27 Wang H, Chen X. Imaging mesenchymal stem cell migration and the implications for stem cell-based cancer therapies[J]. Future Oncol, 2008, 4(5): 623-628
28 Cheng P, Gao ZQ, Liu YH, et al. Platelet-derived growth factor BB promotes the migration of bone marrow-derived mesenchymal stem cells towards C6 glioma and up-regulates the expression of intracellular adhesion molecule-1[J]. Neurosci Lett, 2009, 451(1): 52-56
29 Hall B, Andreeff M, Marini F. The participation of mesenchymal stem cells in tumor stroma formation and their application as targeted-gene delivery vehicles[J]. Handb Exp Pharmacol, 2007, 180: 263-283
30 Cao H, Xu W, Qian H, et al. Bone marrow-derived cells and tumor growth: contribution of bone marrow-derived cells to tumor micro-environments with special focus on mesenchymal stem cells[J]. Crit Rev Oncol Hematol, 2009, 69(3): 187-198
31 Roorda BD, ter Elst A, Kamps WA, et al. Bone marrow-derived cells and tumor growth: contribution of bone marrow-derived cells to tumormicro-environments with special focus on mesenchymal stem cells[J]. Crit Rev Oncol Hematol, 2009, 69(3): 187-198
32 Alison MR, Lim S, Houghton JM. Bone marrow-derived cells and epithelial tumours: more than just an inflammatory relationship[J]. Curr Opin Oncol, 2009, 21(1): 77-82
33 Mishra PJ, Merlino G. A traitor in our midst: mesenchymal stem cells contribute to tumor progression and metastasis[J]. Future Oncol, 2008, 4(6): 745-749
34 Sun T, Sun BC, Ni CS, et al. Pilot study on the interaction between B16 melanoma cell-line and bone-marrow derived mesenchymal stem cells[J]. Cancer Lett, 2008, 263(1): 35-43
35 Yu JM, Jun ES, Bae YC, et al. Mesenchymal stem cells derived from human adipose tissues favor tumor cell growth in vivo[J]. Stem Cells Dev, 2008, 17(3): 463-473
36 Muehlberg FL, Song YH, Krohn A, et al. Tissue-resident stem cells promote breast cancer growth and metastasis[J]. Carcinogenesis, 2009, 30(4): 589-597
37 Xu WT, Bian ZY, Fan QM, et al. Human mesenchymal stem cells (hMSCs) target osteosarcoma and promote its growth and pulmonary metastasis[J]. Cancer Lett, 2009. [Epub ahead of print]
38 Tasso R, Augello A, Carida' M, et al. Development of sarcomas in mice implanted with mesenchymal stem cells seeded onto bioscaffolds[J]. Carcinogenesis, 2009, 30(1): 150-157
39 Lu YR, Yuan Y, Wang XJ, et al. The growth inhibitory effect of mesenchymal stem cells on tumor cells in vitro and in vivo[J]. Cancer Biol Ther, 2008, 7(2): 245-251
40 Qiao L, Xu Z, Zhao T, et al. Suppression of tumorigenesis by human mesenchymal stem cells in a hepatoma model[J]. Cell Res, 2008, 18(4): 500-507
41 Jiang H, Ren J. Inoculation of murine bone marrow mesenchymal stem cells induces tumor necrosis in mouse with orthotopic hepatocellularcarcinoma[J]. Beijing Da Xue Xue Bao, 2008, 40(5): 453-458
42 Sarmadi VH, Heng FS, Ramasamy R. The effect of human mesenchymal stem cells on tumour cell proliferation[J]. Med J Malaysia, 2008, Suppl A: 63-64
43 Zhu Y, Sun Z, Han Q, et al. Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1[J]. Leukemia, 2009. [Epub ahead of print]
1 Friedenstein AJ, Gorskaja JF, Kulagina NN. Fibroblast precursors in normal and irradiated mouse hematopoietic organs[J]. Exp Hematol, 1976, 4(5): 267-274
2 Caplan AI. Mesenchymal stem cells [J]. J Orthop Res, 1991, 9(5): 641-650
3 Horwitz EM, Le Blanc K, Dominici M, et al. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement[J]. Cytotherapy, 2005, 7(5): 393-395
4 Anjos-Afonso F, Bonnet D. Non-hematopoietic/endothelial SSEA-1pos cells defines the most primitive progenitors in the adult murine bone marrow mesenchymal compartment[J]. Blood, 2007, 109(3): 1298-1306
5 Kuo C K, Tuan R S. Tissue engineering with mesenchymal stem cells[J]. IEEE Eng Med Biol Mag, 2003, 22(5): 51-56
6 Tse WT, Pendleton JD,Beyer WM, et al. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implication in transplantation[J]. Transplantation, 2003, 75(3): 389-397
7 Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survivalin vivo[J]. Exp. Hematol, 2002, 30(1): 42-48
8 Potian J A, Aviv H, Ponzio N M, et al. Veto-like activity of mesenchymal stem cells: functional discrimination between cellular responses to alloantigens and recall antigens[J]. J. Immunol, 2003, 171(7): 3426-3434
9 Maitra B, Szekely E, Gjini K, et al. Human mesenchymal stem cells support unrelated donor hematopoietic stem cells and suppress T-cell activation[J]. Bone Marrow Transplant, 2004, 33(6): 597-604
10 Le Blanc K, Tammik C, Rosendahl K, et al. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells[J]. Exp. Hematol, 2003, 31(10): 890-896
11 Arinzeh TL, Peter SJ, Archambault MP, et al. Allogeneic mesenchymal stem cells regenerate bone in a critical-sized canine segmental defect[J]. J Bone Joint Surg Am, 2003, 85-A(10): 1927-1935
12 Toma C, Pittenger MF, Cahill KS, et al. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart[J]. Circulation, 2002, 105(1): 93-98
13 Saito T, Kuang J Q, Bittira B, et al. Xenotransplant cardiac chimera: immune tolerance of adult stem cells[J]. Ann Thorac Surg, 2002, 74(1): 19-24
14 Moadsiri A, Polchert D, Genrich K. Mesenchymal stem cells enhance xenochimerism in NK-depleted hosts[J]. Surgery, 2006, 140(2): 315-321
15 Le Blanc K, Tammik L, Sundberg B, et al. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and responses independently of the major histocompatibility complex[J]. Scand J Immunol, 2003, 57(1): 11-20
16 Ren G, Zhang L, Zhao X, et al. Mesenchymal Stem Cell-Mediated Immunosuppression Occurs via Concerted Action of Chemokines and Nitric Oxide[J]. Cell. Stem Cell, 2008, 2(2): 141-150
17 Klyushnenkova E, Mosca JD, Zernetkina V, et al. T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance,and suppression[J]. J. Biomed Sci, 2005, 12(1): 47-57
18 Glennie S, Soeiro I, Dyson PJ, et al. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells[J]. Blood, 2005, 105(7): 2821-2827
19 Ko E, Cho KA, Ju SY, et al. Mesenchymal stem cells inhibit the differentiation of CD4+ T cells into interleukin-17-secreting T cells[J]. Acta Haematol, 2008, 120(3): 165-167
20 Ramasamy R, Tong CK, Seow HF, et al. The immunosuppressive effects of human bone marrow-derived mesenchymal stem cells target T cell proliferation but not its effector function[J]. Cell Immunol, 2008, 251(2): 131-136
21 Maccario R, Podesta M, Moretta A, et al. Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype[J]. Haematologica, 2005, 90(4): 516-525
22 Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses[J]. Blood, 2005, 105(4): 1815-1822
23 Beyth S, Borovsky Z, Mevorach D, et al. Human mesenchymal stem cells alter antigen- presenting cell maturation and induce T-cell unresponsiveness. [J]. Blood, 2005, 105(5): 2214-2219
24 Ye Z, Wang Y, Xie HY, et al. Immunosuppressive effects of rat mesenchymal stem cells: involvement of CD4+CD25+ regulatory T cells[J]. Hepatobiliary Pancreat Dis Int, 2008, 7(6): 608-614
25 Selmani Z, Naji A, Zidi I, et al. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells[J]. Stem Cells, 2008, 26(1): 212-222
26 English K, Ryan JM, Tobin L, et al. Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25(High) forkhead box P3+regulatory T cells[J]. Clin Exp Immunol, 2009, 156(1): 149-160
27 Jiang XX, Zhang Y, Liu B, et al. Human mesenchymal stem cells inhibit ifferentiation and function of monocyte-derived dendritic cells[J]. Blood, 2005, 105(5): 4120-4126
28 Nauta AJ, Kruisselbrink AB, Lurvink E. Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells[J]. J Immunol, 2006, 177(4): 2080-2087
29 English K, Barry FP, Mahon BP, et al. Murine mesenchymal stem cells suppress dendritic cell migration, maturation and antigen presentation[J]. Immunol Lett, 2008, 115(1): 50-58
30 Li YP, Paczesny S, Lauret E, et al. Human mesenchymal stem cells license adult CD34+ hemopoietic progenitor cells to differentiate into regulatory dendritic cells through activation of the Notch pathway[J]. J Immunol, 2008, 180(3): 1598-1608
31 Zhang B, Liu R, Shi D, et al. Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2-dependent regulatory dendritic cell population[J]. Blood, 2009, 113(1): 46-57
32 Augello A, Tasso R, Negrini SM, et al. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway[J]. Eur J Immunol, 2005, 35(5): 1482-1490
33 Tabera S, Pérez-Simón JA, Díez-Campelo M, et al. The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes[J]. Haematologica, 2008, 93(9): 1301-1309
34 Bochev I, Elmadjian G, Kyurkchiev D, et al. Mesenchymal stem cells from human bone marrow or adipose tissue differently modulate mitogen-stimulated B-cell immunoglobulin production in vitro[J]. Cell Biol Int, 2008, 32(4): 384-393
35 Comoli P, Ginevri F, Maccario R, et al. Human mesenchymal stem cells inhibit antibody production induced in vitro by allostimulation. Nephrol Dial Transplant, 2008, 23(4): 1196-1202
36 Krampera M, Cosmi L, Angeli R, et al. Role for interferon-gamma in theimmunomodulatory activity of human bone marrow mesenchymal stem cells. [J]. Stem Cells, 2006, 24(2): 386-398
37 Kang HS, Habib M, Chan J, et al. A paradoxical role for IFN-gamma in the immune properties of mesenchymal stem cells during viral challenge[J]. Exp. Hematol, 2005, 33(7): 796-803
38 Sotiropoulou PA, Perez SA, Gritzapis AD, et al. Interactions between human mesenchymal stem cells and natural killer cells[J]. Stem Cells, 2006, 24(2): 74-85
39 Spaggiari GM, Capobianco A, Becchetti S, et al. Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation[J]. Blood, 2006, 107(4): 1484-1490
40 Rasmusson I. Immune modulation by mesenchymal stem cells[J]. Exp Cell Res, 2006, 312(12): 2169-2179
41 Nauta AJ, Westerhuis G, Kruisselbrink AB, et al. Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting[J]. Blood, 2006, 108(6): 2114-2120
42 Yanez R, Lamana ML, Garcia-Castro J, et al. Adipose tissue-derived mesenchymal stem cells (AD-MSC) have in vivo immunosuppressive properties applicable for the control of graft-versus-host disease (GVHD)[J]. Stem Cells, 2006, 24(11): 2582-2591
43 Lazarus HM, Koc ON, Devine SM, et al. Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients[J]. Blood Marrow Transplant, 2005, 11(5): 389-398
44 Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells[J]. Lancet, 2004, 363(9419): 1439-1441
45 Ringden O, Uzunel M, Rasmusson I, et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease[J].Transplantation, 2006, 81(10): 1390-1397
46 Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study[J]. Lancet, 2008, 371(9624): 1579-1586
47 von Bonin M, St?lzel F, Goedecke A, et al. Treatment of refractory acute GVHD with third-party MSC expanded in platelet lysate-containing medium[J]. Bone Marrow Transplant, 2009, 43(3): 245-251
48 Li H, Guo Z, Jiang X, et al. Mesenchymal stem cells alter migratory property of T and dendritic cells to delay the development of murine lethal acute graft-versus-host disease[J]. Stem Cells, 2008, 26(10): 2531-2541
49 Gerdoni E, Gallo B, Casazza S, et al. Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis[J]. Ann Neurol, 2007, 61(3): 219-227
50 Augello A, Tasso R, Negrini SM, et al. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis[J]. Arthritis Rheum, 2007, 56(4): 1175-1186
51 González MA, Gonzalez-Rey E, Rico L, et al. Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells[J]. Arthritis Rheum, 2009, 60(4): 1006-1019
52 González MA, Gonzalez-Rey E, Rico L, et al. Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses[J]. Gastroenterology. 2009, 136(3): 978-989
53 Boumaza I, Srinivasan S, Witt WT, et al. Autologous bone marrow-derived rat mesenchymal stem cells promote PDX-1 and insulin expression in the islets, alter T cell cytokine pattern and preserve regulatory T cells in the periphery and induce sustained normoglycemia[J]. J Autoimmun, 2009, 32(1): 33-42
54 Zhou K, Zhang H, Jin O,et al. Transplantation of human bone marrow mesenchymal stem cell ameliorates the autoimmune pathogenesis inMRL/lpr mice[J]. Cell Mol Immunol, 2008, 5(6): 417-424
55 Itakura S, Asari S, Rawson J, et al. Mesenchymal stem cells facilitate the induction of mixed hematopoietic chimerism and islet allograft tolerance without GVHD in the rat[J]. Am J Transplant, 2007, 7(2): 336-346
56 Sbano P, Cuccia A, Mazzanti B, et al. Use of donor bone marrow mesenchymal stem cells for treatment of skin allograft rejection in a preclinical rat model[J]. Arch Dermatol Res, 2008, 300(3): 115-124
57 Casiraghi F, Azzollini N, Cassis P, et al. Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells[J]. J Immunol, 2008, 181(6): 3933-3946
58 Hoogduijn MJ, Crop MJ, Peeters AM, et al. Donor-derived mesenchymal stem cells remain present and functional in the transplanted human heart[J]. Am J Transplant, 2009, 9(1): 222-230
59 Crop MJ, Baan CC, Korevaar SS, et al. Donor-derived mesenchymal stem cells suppress alloreactivity of kidney transplant patients[J]. Transplantation. 2009, 87(6): 896-906
60 Hong ZF, Huang XJ, Yin ZY, et al. Immunosuppressive function of bone marrow mesenchymal stem cells on acute rejection of liver allografts in rats[J]. Transplant Proc, 2009, 41(1): 403-409
61 Solari MG, Srinivasan S, Boumaza I, et al. Marginal mass islet transplantation with autologous mesenchymal stem cells promotes long-term islet allograft survival and sustained normoglycemia[J]. J Autoimmun, 2009, 32(2): 116-124
62 Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli[J]. Blood, 2002, 99(10): 3838-3843
63 Zhao ZG, Li WM, Chen ZC, et al. Immunosuppressive properties of mesenchymal stem cells derived from bone marrow of patients with chronic myeloid leukemia[J]. Immunol Invest, 2008, 37(7): 726-739
64 Zhi-Gang Z, Wei-Ming L, Zhi-Chao C, et al. Immunosuppressiveproperties of mesenchymal stem cells derived from bone marrow of patient with hematological malignant diseases[J]. Leuk Lymphoma, 2008, 49(11): 2187-2195
65 Ye Z, Wang Y, Xie HY, et al. Immunosuppressive effects of rat mesenchymal stem cells: involvement of CD4+CD25+ regulatory T cells[J]. Hepatobiliary Pancreat Dis Int, 2008, 7(6): 608-614
66 Gao K, Chen Y, Wei L, et al. Inhibitory effect of mesenchymal stem cells on lymphocyte proliferation[J]. Cell Biochem Funct, 2008, 26(8): 900-907
67 Le Blanc K, Rasmusson I, Gotherstrom C, et al. Mesenchymal stem cells inhibit the expression of CD25 (interleukin-2 receptor) and CD38 on phytohaemagglutinin-activated lymphocytes[J]. Scand. J. Immunol, 2004, 60(3): 307-315
68 Gotherstrom C, West A, Liden J, et al. Difference in gene expression between human fetal liver and adult bone marrow mesenchymal stem cells[J]. Haematologica, 2005, 90(8): 1017-1026
69 Djouad F, Charbonnier LM, Bouffi C, et al. Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism[J]. Stem Cells, 2007, 25(8): 2025-2032
70 Rasmusson I, Ringden O, Sundberg B, et al. Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms[J]. Exp.Cell Res, 2005, 305(1): 33-41
71 Choi JJ, Yoo SA, Park SJ, et al. Mesenchymal stem cells overexpressing interleukin-10 attenuate collagen-induced arthritis in mice[J]. Clin Exp Immunol, 2008, 153(2): 269-276
72 Meisel R, Zibert A, Laryea M, et al. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation[J]. Blood, 2004, 103(12): 4619-4621
73 Fallarino F, Grohmann U, Vacca C, et al. T cell apoptosis by kynurenines.[J]. Adv. Exp. Med. Biol, 2003, 527: 183-190
74 Zappia E, Casazza S, Pedemonte E, et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T cell anergy[J]. Blood, 2005, 106(5): 1755-1761
75 Chabannes D, Hill M, Merieau E, et al. A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells[J]. Blood, 2007, 110(10): 3691-3694
76 Halme DG, Kessler DA. FDA regulation of stem-cell-based therapies[J]. N Engl J Med, 2006, 355(16): 1730-1735
77 Chan JL, Tang KC, Patel AP, et al. Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-gamma[J]. Blood, 2006, 107(12): 4817-4824
78 Stagg J, Pommey S, Eliopoulos N, et al. Interferon-gamma-stimulated marrow stromal cells: a new type of nonhematopoietic antigen-presenting cell [J]. Blood, 2006, 107(6): 2570-2577
79 Djouad F, Plence P, Bony C, et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals[J]. Blood, 2003, 102(10): 3837-3844
80 Grinnemo KH, Mansson A, Dellgren G, et al. Xenoreactivity and engraftment of human mesenchymal stem cells transplanted into infarcted rat myocardium[J]. J. Thorac. Cardiovasc. Surg, 2004, 127(5): 1293-1300
81 Tyndall A, Walker UA, Cope A, et al. Immunomodulatory properties of mesenchymal stem cells: a review based on an interdisciplinary meeting held at the Kennedy Institute of Rheumatology Division, London, UK, 31 October 2005[J]. Arthritis Res Ther, 2007, 9(1): 301
82 Sun LY, Zhang HY, Feng XB, et al. Abnormality of bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus[J]. Lupus, 2007, 16(2): 121-128
83 Inoue S, Popp FC, Koehl GE, et al. Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant model[J]. Transplantation, 2006, 81(11): 1589-1595
84 Horwitz EM, Gordon PL, Koo WK et al. Isolated allogeneic bone marrowderived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone[J]. Proc Natl Acad Sci U S A, 2002, 99(13): 8932-8937
85 Breitbach M, Bostani T, Roell W et al. Potential risks of bone marrow cell transplantation into infarcted hearts[J]. Blood, 2007, 110(4): 1362-1369
86 Miura M, Miura Y, Padilla-Nash HM, et al. Accumulated chromosomal instability in murine bone marrow mesenchymal stem cells leads to malignant transformation[J]. Stem Cells, 2006, 24(4): 1095-1103
87 Tolar J, Nauta AJ, Osborn MJ, et al. Sarcoma Derived from Cultured Mesenchymal Stem Cells[J]. Stem Cells, 2007,25(2):371-379
1 Sprinzl M , Dumortier J , Protzer U. Construction of recombinant adeno-viruses that produce infectious hepatitis B virus [J]. Method Mol Med, 2004, 96: 209-218
2 Hines IN,Wheeler MD. Recent advance in alcoholic liver diseaseⅢ. Role of the innate immune response in alcoholic hepatitis [J]. Am J Physiol Gastrointest Liver Phasiol, 2004, 287(2): G310-314
3 Li, Soloski M J, Diehl A M. Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease[J]. Hepatology, 2005, 42(4): 880-885
4 Teoh NC, Farrell GC. Hepatic ischemia reperfusion injury: Pathogenic mechanisms and basis for hepatoprotection[J]. J Gastroenterol Hepatol, 2003, 18(8): 891-902
5 Lapierre P, Djilali-Saiah I, Vitozzi S, et al. A murine model of type 2 autoimmune hepatitis:Xenoimmunization with human antigen[J]. Hepatology, 2004, 39(4): 1066-1074
6 Tiegs G, Hentschel J, Wendel A. A T cell-dependent experimental liver injury in mice inducible by concanavalin A[J]. J Clin Invest, 1992, 90(1): 196-203
7 Sahai A, Malladi P, Melin-Aldana H, et al. Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model[J]. Am J Physiol Gastrointest Liver Physiol, 2004, 287(1): G264-273
8 Erhardt A, Biburger M, Papadopoulos T, et al. IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice [J]. Hepatology, 2007, 45(2): 475-485
9 Kaneko Y, Harada M, Kawano T, et al. Augmentation of Va 14 NKT cell-mediated cytotoxicity by interleukin 4 in an autocrine mechanism resulting in the development of concanavalin A-induced hepatitis[J]. J Exp Med, 2000, 191(1): 105-114
10 Gantner F, Leist M, Lohse AW, et al. Concanavalin A-induced T cell-mediated hepatic injury in mice: the role of tumor necrosis factor[J]. Hepatology, 1995, 21(1): 190-198
11 Sass G, Heinlein S, Agli A, et al. Cytokine expression in three mouse models of experimental hepatitisJ]. Cytokine, 2002, 19(3): 115-120
12 Bowen DG, Warren A, Davis T, et al. Cytokine-dependent bystander hepatitis due to intrahepatic murine CD8+T-cell activation by bone marrow-derived cells[J]. Gastroenterology, 2002, 123(4): 1252-1264
13 Mizuhara H, O’Neill E, Seki N, et al. Cytokine-dependent bystander hepatitis injury: mediation by tumor necrosis factors and protection by interleukin 6[J]. J Exp Med, 1994, 179(5): 1529-1537
14 Wolf D, Hallmann R, Sass G, et al. TNF-alpha-induced expression of adhesion molecules in the liver is under the control of TNFR1--relevance for concanavalin A-induced hepatitis[J]. J Immunol, 2001, 166(2):1300-1307
15 Cao Q, Batey R, Pang G, et al. IL-6, IFN-γand TNF-αproduction by liver-associated T cells and acute liver injury in rats administered concanavalin A[J]. Immunol Cell Biol, 1998, 76(6): 542-549
16 Streetz K, Fregien B, Plümpe J, et al. Dissection of the intracellular pathways in hepatocytes suggests a role for Jun kinase and IFN regulatory factor-1 in Con A-induced liver failure[J]. J Immunol, 2001, 167(1): 514-523
17 Schümann J, Wolf D, Pahl A, et al. Importance of Kupffer cells for T-cell-dependent liver injury in mice[J]. Am J Pathol, 2000, 157(5): 1671-1683
18 Klugewitz K, Adams DH, Emoto M,et al. The composition of intrahepatic lymphocytes: shaped by selective recruitment[J]. Trends Immunol, 2004, 25(11): 590-594
19 Ajuebor MN, Hogaboam CM, Le T, et al. CCL3/MIP-1alpha is pro-inflammatory in murine T cell-mediated hepatitis by recruiting CCR1-expressing CD4(+) T cells to the liver[J]. Eur J Immunol, 2004, 34(10): 2907-2918
20 Tiegs G. Cellular and cytokine-mediated mechanisms of inflammation and its modulation in immune-mediated liver injury[J]. Z Gastroenterol, 2007, 45(1): 63-70
21 Chen D, McKallip RJ, Zeytun A, et al. CD44-deficient mice exhibit enhanced hepatitis after concanavalin A injection: evidence for involvement of CD44 in activation-induced cell death[J]. Immunol, 2001, 166(10): 5889-5897
22 Fontenot JD, Rudensky AY. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3[J]. Nat Immunol, 2005, 6(4): 331-337
23 Takeda K, Hayakawa Y, Van Kaer L, et al. Critical contribution of liver natural killer T cells to a murine model of hepatitis[J]. Proc Natl Acad Sci U S A, 2000, 97(10): 5498-5503
24 Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses[J]. Annu Rev Immunol, 2004, 22: 531-562
25 Maeda S, Chang L, Li ZW, et al. IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFalpha[J]. Immunity, 2003, 19(5): 725-737
26 Schumann J, Muhlen K, Kiemer AK, et al. Parenchymal, but not leukocyte, TNF receptor 2 mediates T cell-dependent hepatitis in mice[J]. J Immunol, 2003, 170(4): 2129-2137
27 Song E, Lee SK, Wang J, et al. RNA interference targeting Fas protects mice from fulminant hepatitis[J]. Nat Med, 2003, 9(3): 347-351
28 Descamps D, Vigant F, Esselin S, et al. Expression of non-signaling membrane-anchored death receptors protects murine livers in different models of hepatitis[J]. Hepatology, 2006, 44(2): 399-409
29 Zheng SJ, Wang P, Tsabary G, et al. Critical roles of TRAIL in hepatic cell death and hepatic inflammation[J]. J Clin Invest, 2004, 113(1): 58-64
30 Anand S, Wang P, Yoshimura K, et al. Essential role of TNF family molecule LIGHT as a cytokine in the pathogenesis of hepatitis[J]. J Clin Invest, 2006, 116(4): 1045-1051
31 Hong F, Jaruga B, Kim WH, et al. Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS[J]. J Clin Invest, 2002, 110(10): 1503-1513
32 Siebler J, Wirtz S, Klein S, et al. A key pathogenic role for the STAT1/T-bet signaling pathway in T-cell-mediated liver inflammation[J]. Hepatology, 2003, 38(6): 1573-1580
33 Senaldi G, Shaklee CL, Guo J, et al. Protection against the mortality associated with disease models mediated by TNF and IFN-gamma in mice lacking IFN regulatory factor-1[J]. J Immunol, 1999, 163(12): 6820-6826
34 Jaruga B, Hong F, Sun R, et al. Crucial role of IL-4/STAT6 in T cell-mediated hepatitis: up-regulating eotaxins and IL-5 and recruiting leukocytes[J]. J Immunol, 2003, 171(6): 3233-3244
35 Louis H, Le Moine A, Flamand V, et al. Critical role of interleukin 5 and eosinophils in concanavalin A-induced hepatitis in mice[J]. Gastroenterology, 2002, 122(7): 2001-2010
36 Gao B. Cytokines, STATs and liver disease[J]. Cell Mol Immunol, 2005, 2(2): 92-100
37 Sun R, Tian Z, Kulkarni S, et al. IL-6 prevents T cell-mediated hepatitis via inhibition of NKT cells in CD4+ T cell- and STAT3-dependent manners[J]. J Immunol, 2004, 172(9): 5648-5655
38 Trayhurn P, Wood IS. Signalling role of adipose tissue: adipokines and inflammation in obesity[J]. Biochem Soc Trans, 2005, 33: 1078-1081
39 Siegmund B, Lear-Kaul KC, Faggioni R, et al. Leptin deficiency, not obesity, protects mice from Con A-induced hepatitis[J]. Eur J Immunol, 2002, 32(2): 552-560
40 Wolf AM, Wolf D, Avila MA, et al. Up-regulation of the anti-inflammatory adipokine adiponectin in acute liver failure in mice[J]. J Hepatol, 2006, 44(3): 537-543
41 Isayama F, Hines IN, Kremer M, et al. Favored T helper 1 response in a mouse model of hepatosteatosis is associated with enhanced T cell-mediated hepatitis[J]. Hepatology, 2006, 44(1): 216-227
42 Van Kaer L. alpha-Galactosylceramide therapy for autoimmune diseases: prospects and obstacles[J]. Nat Rev Immunol, 2005, 5(1): 31-42