Oral Tolerance Induction by Type V Collagen in Lung Transplantation

目的：同种异体肺移植排斥反应涉及对V型胶原的免疫反应。Col1(V)诱导的口服耐受消除了对供体抗原的迟发性超敏反应(DTH)，并防止了急性和慢性肺移植排斥反应。这些数据表明，COL(V)诱导的耐受可能刺激了抑制排斥反应的调节性T细胞。本研究的目的是确定Col(V)口服耐受是否诱导调节性T细胞，并利用F344同种异体肺移植到WKY(RT1^1)大鼠体内，以确定这些细胞诱导免疫抑制的机制。材料和方法：我们利用我们最近建立的Col(V)诱导的同种异体肺移植耐受模型，在移植前给WKY大鼠喂饲Col(V)诱导对F344肺移植的耐受。从包括耐受大鼠在内的不同组WKY大鼠的脾中提纯CD4+和CD8+T细胞，并用于过继转移研究。结果：从耐受大鼠向未治疗的同种异体移植受者过继转移CD4+T细胞，而不是CD8+T细胞，可消除对供体抗原的DTH反应，并预防急性和慢性肺移植排斥反应。结果表明，耐受大鼠外周血中的CD_4~+T细胞可结构性地产生转化生长因子-β，并对同种异体抗原产生反应。结论：COL(V)诱导的口服耐受导致调节性β+T细胞的活性，而调节性的CD4+T细胞通过产生转化生长因子-β抑制同种异体反应。

Objective : Lung allograft rejection involves an immune response to type V collagen [col(V)]. Oral tolerance induced by col(V) abrogates delayed type hypersensitivity (DTH) responses to donor antigens, and prevented acute and chronic lung allograft rejection. These data suggest that col(V)-induced tolerance might have stimulated regulatory T cells that suppress rejection responses. The purpose of the current study was to determine if col(V) oral tolerance induced regulatory T cells, and to determine the mechanism of immune suppression induced by these cells utilizing F344 lung allografts (RT1^<lv1> for orthotopic transplantation into WKY (RT1^1) rat recipients.Materials and Methods : We utilized our recently described model of col(V)-induced oral tolerance to lung allografts in which feeding col(V) to WKY rats prior to transplantation induced tolerance to F344 lung allografts. CD4+ and CD8+ T cells were purified from spleens of different groups of WKY rats including tolerant rats and used for adoptive transfer studies. DTH responses and rejection pathology were assessed in different groups of adoptively transferred animals.Results : Data showed that adoptive transfer of CD4+, but not CD8+, T cells from tolerant rats to untreated allograft recipients abrogated DTH responses to donor antigens, and prevented acute and chronic lung allograft rejection. MLR's revealed that CD4+ T cells from tolerant rats produced TGF-β constitutively and in response to alloantigen. Finally, anti- TGF-β antibodies recovered DTH responses suppressed by adoptive transfer of "tolerant" CD4+ T cells.Conclusion : We conclude that col(V)-induced oral tolerance results in activity of regulatory CD4+ T cells that suppress alloreactivity by production of TGF-β.