抗体诱导的移植免疫耐受依赖于B细胞来源的TGF-β的调节  

Effect of B cell-derived TGF-β on regulating antibody-induced immune tolerance after transplantation

作　　者：赵高平[1,2] 杨卯竹[2] 李姝蓉[2] 魏玲玲[2] 邓绍平[2] 

机构地区：[1]四川省医学科学院,四川省人民医院,电子科技大学附属医院胃肠外科,成都610072 [2]器官移植转化医学四川省重点实验室,成都610072

出　　处：《器官移植》2016年第3期171-176,共6页Organ Transplantation

基　　金：国家自然科学基金(81172832;81571565);四川省杰出青年基金(2013JQ0020);四川省青年科技创新团队专项计划(2014TD0010);国家人力资源和社会保障部留学回国人员科技活动项目;四川省卫生和计划生育委员会课题(110190)

摘　　要：目的研究抗CD45RB抗体或联合抗Tim-1抗体诱导的移植免疫耐受中转化生长因子(TGF)-β的调节作用。方法建立小鼠同种异体心脏移植以及胰岛移植模型,前者用抗CD45RB抗体和(或)抗TGF-β抗体治疗,后者用抗CD45RB抗体联合抗Tim-1抗体治疗并加用或不用抗TGF-β抗体,观察移植物长期存活时间。分离胰岛移植物长期耐受的受体B细胞,过继输注至胰岛细胞移植模型小鼠体内,经抗TGF-β抗体治疗后观察移植胰岛的存活情况。在体外将经双抗体治疗14 d的移植有胰岛细胞的受体B细胞与脂多糖(LPS)混合刺激培养过夜,采用流式细胞仪检测CD19+LAP+细胞的比例。结果抗CD45RB抗体治疗后有6/9的同种异体小鼠心脏长期存活,但若加用抗TGF-β抗体治疗则所有移植心脏均被排斥。在小鼠胰岛细胞移植模型中,抗CD45RB抗体联合抗Tim-1抗体治疗后有90%移植物长期耐受,但加用抗TGF-β抗体后则无1例移植物长期存活。B细胞输注治疗后,8/9的胰岛移植物不被排斥,而加用抗TGF-β抗体后则移植物很快被排斥。B细胞体外刺激培养,流式细胞术检测显示CD19+LAP+细胞在B细胞中的比例显著增高(P<0.0001)。结论抗CD45RB抗体或联合抗Tim-1抗体诱导的移植免疫耐受需要TGF-β,其可能受调节性B细胞的调节。Objective To investigate the regulatory function of transforming growth factor（ TGF）-β in transplantation immune tolerance induced by anti-CD45 RB antibody or in combination with anti-Tim-1 antibody. Methods Mouse models with allogeneic cardiac and pancreatic islet transplantation were established. The animals with allogeneic cardiac transplantation were treated with anti-CD45 RB antibody and（ or） anti- TGF-β antibody and those with pancreatic islet transplantation were handled with anti-CD45 RB antibody in combination with anti-Tim-1 antibody supplemented with /without anti-TGF-β antibody. The long-term survival of transplant graft was observed. B cells from recipients which tolerated by pancreas islet transplantation for long time,were isolated and subsequently infused into the mouse models with islet cell transplantation. The survival of pancreas islet transplant graft was observed after anti-TGF-β antibody therapy. After doubleantibody treatment in vitro for 14 d,B cell from recipients were mingled with lipopolysaccharide（ LPS） and cultured overnight. The percentage of CD19^＋LAP^＋ cell was quantitatively measured by flow cytometer analysis. Results Six among9 mice with allogeneic cardiac transplantation survived for a long term after anti-CD45 RB antibody therapy. All cardiac grafts developed transplant rejection if use of anti-TGF-β antibody was supplemented. In mouse models with islet cell transplantation,combined use of anti-CD45 RB and anti-Tim-1 antibodies induced long-term immune tolerance in 90% of transplant grafts. No transplant graft survived for a long period after anti-TGF-β antibody was delivered. Following B cell infusion,8 of 9 pancreas islet grafts induced no transplant rejection,whereas yielded transplant rejection immediately after supplementing anti-TGF-β antibody. B cells were stimulated and cultured in vitro. Flow cytometry analysis revealed the proportion of CD196^＋LAP^＋cells in B cells was significantly elevated（ P〈0. 0001）. Conclusions Immune tolerance

关 键 词：免疫耐受 调节性B细胞 转化生长因子-Β 心脏移植 胰岛移植 

分 类 号：R617[医药卫生—外科学] R392.3[医药卫生—临床医学]