T Cell Memory in Organ Transplantation

描述(来自申请人摘要的逐字)长寿命记忆T细胞 承认供体同种异体抗原可能危及救命生物的生存 器官移植。我们在这里提出同种异体记忆性T细胞是一种 重要的障碍是实现同种异体移植的接受性，因为它们的独特性 在受者体内持续存在并对供者抗原做出反应的能力 与原始T细胞相比，条件要宽松得多。为了测试 这一假说，我们计划探索支配 脑内同种异体记忆T细胞的长期维持和回忆反应 并调查是否以这些机制中的一个或多个为目标 促进同种异体移植的接受性。具体目标是：(1)调查 同种异体记忆T的维持和回忆的解剖学要求 细胞。具体而言，我们将研究次级淋巴器官的作用；(2) 调查维护和召回的功能要求 同种异体记忆T细胞。具体地说，我们将研究IL-15和 T细胞共刺激；以及(3)研究抑制同种异体T细胞 靶向IL-15或常见细胞因子受体γ链的细胞记忆 促进同种异体移植物的接受和耐受诱导。变种人， 基因敲除和T细胞受体转基因小鼠品系将用于 追踪记忆T细胞并研究它们的生物学。血管化异位 同种异体心脏移植模型将用于研究T细胞记忆在心脏移植中的作用 器官移植。了解管理 异体反应记忆T细胞的维护和召回可以提供洞察力 制定临床策略以实现永久接受同种异体移植物 和移植耐受性。

DESCRIPTION (Verbatim from the applicant's abstract) Long-lived memory T cells that recognize donor alloantigens may jeopardize the survival of life-saving organ transplants. We propose here that allospecific memory T cells are an important impediment to achieving allograft acceptance because of their unique abilities to persist in the recipient and to respond to donor antigens under much less stringent conditions than those required for naive T cells. To test this hypothesis, we plan to explore the fundamental mechanisms that govern the long-term maintenance and the recall response of allospecific memory T cells in the mouse and to investigate whether targeting one or more of these mechanisms promotes allograft acceptance. The specific aims are: (1) To investigate the anatomic requirements for the maintenance and recall of allospecific memory T cells. Specifically, we will study the role of secondary lymphoid organs; (2) To investigate the functional requirements for the maintenance and recall of allospecific memory T cells. Specifically, we will study the roles of IL-15 and T cell costimulation; and (3) To investigate whether suppressing allospecific T cell memory by targeting IL-15 or the common cytokine receptor gamma-chain facilitates allograft acceptance and tolerance induction. Mutant, gene-knockout, and T cell receptor transgenic mouse strains will be used to track memory T cells and study their biology. The vascularized heterotopic heart allograft model will be used to investigate the role of T cell memory in organ transplantation. Understanding the fundamental mechanisms that govern the maintenance and recall of alloreactive memory T cells could provide insights into devising clinical strategies for achieving permanent allograft acceptance and transplantation tolerance.