Oral Tolerance Induction by Type V Collagen in Lung Transplantation

目的：肺同种异体移植排斥反应涉及对V型胶原的免疫反应[col(V)]。col(V)诱导的口服耐受消除了对供体抗原的延迟型超敏反应（DTH），并防止急性和慢性肺同种异体移植排斥反应。这些数据表明，col(V)诱导的耐受性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，并确定这些细胞诱导的免疫抑制机制，利用F344肺同种异体移植物（RT1^<lv1>）原位移植到WKY （RT1^1）大鼠受体中。材料和方法：我们利用我们最近描述的col(V)诱导的肺同种异体移植耐受模型，在移植前给WKY大鼠喂食col(V)诱导对F344肺同种异体移植的耐受。从包括耐受大鼠在内的不同组WKY大鼠脾脏中纯化CD4+和CD8+ T细胞，用于过继性转移研究。对不同组动物的DTH反应和排斥病理进行了评估。结果：数据显示，耐受大鼠的CD4+（而非CD8+） T细胞过继转移到未治疗的同种异体移植受体，消除了对供体抗原的DTH反应，并预防了急性和慢性同种异体肺移植排斥反应。MLR结果显示，耐受大鼠的CD4+ T细胞组成性地对同种异体抗原产生TGF-β。最后，抗TGF-β抗体恢复了被“耐受”CD4+ T细胞过继转移抑制的DTH反应。结论：col(V)诱导的口服耐受性导致调节性CD4+ T细胞活性，通过TGF-β的产生抑制同种异体反应性。

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.