Tolerance to heart transplants in Miniature Swine

小型猪的心脏/肾脏共移植提供了大型动物非消融性心脏同种异体移植耐受的唯一一致和可重复的模型。它还模拟了人类心脏和肾脏共同移植的有益效果。同种异体肾移植诱导的耐受状态保护心脏免受急性和慢性排斥反应的机制尚不清楚。在我们以前的资助中，我们描述了供体肾脏和宿主胸腺在耐受性心脏/肾脏受体中的作用，并开始研究肾脏来源的细胞群。基于这些研究，我们现在假设，宿主胸腺衍生的调节性T细胞，由来自供体肾脏的细胞或抗原产生，负责诱导心脏/肾脏受体对心脏同种异体移植物的耐受。其必然结果是，调节性T细胞存在于长期心脏移植的耐受受体中， 在长期接受心脏移植的慢性免疫抑制受体中不存在。我们将通过1）确定来自耐受性心脏/肾受体的调节性T细胞的体外特征，2）确定调节性T细胞在心脏/肾受体中的耐受性诱导和维持阶段中的作用，3）确定耐受状态如何改变心脏/肾受体中移植物内细胞因子过量的作用，和4）比较通过耐受诱导与慢性免疫抑制延长的同种异体心脏移植动物中移植免疫的体外参数。 了解T细胞调节的机制可能会导致人类移植中新的耐受策略。

Heart/kidney co-transplantation in miniature swine provides the only consistent and reproducible model of nonablative cardiac allograft tolerance in large animals. It also mimics the beneficial effects of co-transplanting hearts and kidneys in humans. The mechanism by which a heart is protected from both acute and chronic rejection by the tolerant state induced by a kidney allograft is unknown. In our previous grant we characterized the role of the donor kidney and host thymus in tolerant heart/kidney recipients and began to investigate kidney-derived cell populations. Based on those studies, we now hypothesize that host thymus-derived regulatory T cells, generated by cells or antigens derived from the donor kidney, are responsible for the induction of tolerance to cardiac allografts in heart/kidney recipients. The corollary is that regulatory T cells are present in tolerant recipients bearing long-term cardiac allografts but are not present in chronically immunosuppressed recipients bearing long-term cardiac allografts. We will test this hypothesis by 1) determining the in vitro characteristics of regulatory T cells from tolerant heart/kidney recipients, 2) determining the role of regulatory T cells in the induction and maintenance phase of tolerance in heart/kidney recipients, 3) determining how a state of tolerance modifies the effects of intragraft cytokine excess in heart/kidney recipients, and 4) comparing the in vitro parameters of transplant immunity in animals bearing allogeneic heart transplants prolonged by tolerance induction vs. chronic immunosuppression. Understanding the mechanisms of T cell regulation may lead to novel tolerance strategies in human transplantation.