MODULATION OF REGULATORY TOLERANCE TO TRANSPLANTS

描述（由申请人提供）：开发“天然”免疫抑制策略以抑制T细胞对移植组织的同种异体反应性是非特异性药物介导的T细胞免疫抑制的非常理想的替代方案。我们已经表明，通过临床前小型猪肾移植模型中的基因转移，单个MHC II类（CI 2）分子的部分供体/受体匹配促进了T细胞耐受性对随后的转基因匹配移植物的扩散，以及宿主T细胞活化对所有移植物相关的主要和次要抗原的下调。鉴于1）部分CI 2匹配也促进对人移植的调节性耐受和2）小型猪是唯一可以可靠地研究CI 2在T细胞耐受中的作用的动物模型，本项目的目标是使用CI 2基因转移猪模型阐明由MHC CI 2介导的调节性T淋巴细胞耐受的机制。这些知识是开发激活人体抗移植物反应自然抑制的治疗方案的必要先决条件。使用这种方法的最新数据表明，CI 2转基因介导的耐受性与调节性T（T-reg）细胞对移植物的T细胞反应性的下调有关。此外，转基因C12衍生肽似乎参与了迁移到移植物的T-reg细胞的活化。这些发现表明Tg CI 2肽形成宿主T-reg细胞库的一部分，其随后可被移植物匹配的CI 2激活以发展对移植物的调节耐受性。本研究旨在评价调节性耐受在导致同种异体移植物接受的其他致耐受机制中的重要性。为此，我们将1）检查细胞内（肽）和表面C12转基因表达对耐受诱导的影响; 2）评估C12转基因表达模式对宿主对Tg匹配的肾移植物的免疫的影响;和3）表征T-reg介导的抑制的特异性和作用模式。希望这些研究将为设计具有移植生物学临床应用的新治疗分子提供动力。

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.