MODULATION OF REGULATORY TOLERANCE TO TRANSPLANTS

描述(由申请人提供)：开发“天然”免疫抑制策略以消除T细胞对移植组织的同种反应性是非特异性、药物介导的T细胞免疫抑制的一种非常可取的替代方案。通过临床前小型猪肾移植模型的基因转移，我们已经证明，单个MHC II类(CI2)分子的部分供体/受体匹配促进了T细胞对随后的转基因匹配移植物的耐受性的传播，并下调了宿主T细胞对所有移植物相关的主要和次要抗原的激活。鉴于1)部分CI2相合也促进了对人类移植的调节性耐受，2)小型猪是唯一可以可靠地研究CI2在T细胞耐受中作用的动物模型，本项目的目的是利用CI2基因转移猪模型阐明MHC CI2介导的调节性T淋巴细胞耐受的机制。这一知识是开发治疗方案的必要前提，该方案可以激活对人类抗移植物反应的自然抑制。最近使用这种方法的数据表明，CI2转基因介导的耐受与调节性T(T-reg)细胞下调T细胞对移植物的反应性有关。此外，转基因CI2衍生的多肽似乎参与了T-reg细胞的激活，这些细胞迁移到移植物上。这些发现表明，TG CI2多肽是宿主T-reg细胞库的一部分，随后可能被移植配型的CI2激活，以形成对移植的调节耐受性。本研究旨在评估调节性耐受在导致同种异体移植接受的其他耐受机制中的重要性。为此，我们将1)检测细胞内肽和表面CI2转基因表达对耐受诱导的影响；2)评估CI2转基因表达模式对TG相合肾移植宿主免疫的影响；3)表征T-reg介导的抑制的特异性和作用方式。希望这些研究能为临床应用于移植生物学的新型治疗分子的设计提供动力。

DESCRIPTION (provided by applicant): The development of "natural" immunosuppressive strategies to obviate T cell alloreactivity towards grafted tissues is a highly desirable alternative to non-specific, drug-mediated, T cell immunosuppression. We have shown, by gene transfer in a preclinical miniature swine kidney transplant model, that a partial donor/recipient match for a single MHC class II (CI2) molecule promotes spreading T cell tolerance to subsequent transgene-matched grafts and the down-regulation of host T cell activation to all graft-associated major and minor antigens. Given that 1) Partial CI2 matching also fosters regulatory tolerance to human transplants and 2) The miniature swine is the only animal model in which the role of CI2 in T cell tolerance can be reliably studied, the goal of this project is to elucidate, using the CI2 gene transfer pig model, the mechanism of regulatory T lymphocyte tolerance mediated by MHC CI2. This knowledge is a necessary prerequisite to the development of therapeutic protocols that activate the natural suppression of anti-graft responses in humans. Recent data using this approach indicate that CI2 transgenesis-mediated tolerance is associated with the down-regulation of T cell reactivity to the graft by regulatory T (T-reg) cells. In addition, transgenic CI2-derived peptides seem to be involved in the activation of T-reg cells which migrate to the graft. These findings suggest that Tg CI2 peptides fashion part of the host T-reg cell repertoire that may, subsequently, be activated by graft-matched CI2 to develop regulatory tolerance to the transplant. The present study intends to evaluate the importance of regulatory tolerance among other tolerogenic mechanisms leading to allograft acceptance. To this end, we will 1) Examine the effects of intracellular (peptides) and surface CI2 transgene expression on tolerance induction; 2) Assess the effects of CI2 transgene expression patterns on host immunity to Tg-matched kidney grafts and 3) Characterize the specificity and mode of action of T-reg-mediated suppression. It is hoped that these studies will provide the impetus for the design of new therapeutic molecules with clinical application in transplantation biology.