The Role of TIM-1: TIM-4 Pathway in Allograft Rejection and Tolerance

描述（由申请人提供）：新型受体-配体对的T细胞免疫球蛋白粘蛋白（TIM）家族在T细胞活化、分化和效应子功能中以及在自身免疫和过敏/哮喘的免疫应答调节中发挥重要作用，但其在同种免疫应答中的功能定义不清。我们的中心假设，支持广泛的初步数据，是TIM-1：TIM-4途径，通过影响T辅助细胞的分化，在同种免疫反应和耐受体内发挥重要作用。此外，来自我们小组和其他人的数据表明TIM家族分子在调节性T细胞功能中的可能作用。该提案的主要目标是定义TIM-1：TIM-4途径在体内调节同种免疫应答中的作用并理解其作用机制，作为在小鼠移植模型中实现持久和可再现耐受性的手段。独特的工具，包括抗TIM激动性和阻断性抗体和融合蛋白，以及基因敲除和TCR转基因动物将用于使用急性和慢性排斥的血管化移植模型和皮肤移植的严格模型来剖析同种免疫中TIM-1：TIM-4通路的功能。更具体地说，该项目的目标是：1。目的探讨TIM-1：TIM-4通路在同种异体免疫应答中的作用。2.目的探讨TIM-1：TIM-4通路在慢性排斥反应中的作用。3.通过确定同种异体反应性T细胞在体内的命运，研究靶向TIM-1：TIM-4通路在同种异体反应性和耐受中的作用机制。4.研究TIM-1：TIM-4通路在体内Foxp 3调节性T细胞的产生/功能中的作用。总的来说，我们的具体目标描述了互补的方法，这些方法应该导致创新策略的发展，以允许实体器官移植物的接受，而不会产生慢性排斥反应，从而转化为灵长类动物和人类。

DESCRIPTION (provided by applicant): The T cell immunoglobulin mucin (TIM) family of novel receptor-ligand pairs plays important roles in T cell activation, differentiation and effector function, and in regulation of immune responses in autoimmunity and allergy/asthma, but its functions in alloimmune responses are poorly defined. Our central hypothesis, supported by extensive preliminary data, is that the TIM-1 :TIM-4 pathway, by affecting T helper cell differentiation, play important roles in alloimmune responses and tolerance in vivo. In addition, data from our group and others suggest a possible role of the TIM family of molecules in the function of regulatory T cells. The main goal of this proposal is to define the role and understand the mechanisms of action of the TIM-1:TIM-4 pathway in regulating alloimmune responses in vivo as a means of achieving durable and reproducible tolerance in murine transplant models. Unique tools, including anti-TIM agonistic and blocking antibodies and fusion proteins, and gene knockout and TCR transgenic animals will be used to dissect the functions of the TIM-1 :TIM-4 pathway in alloimmunity using vascularized transplant models of acute and chronic rejection, and stringent models of skin transplantation. More specifically, the aims of the project are: 1. To investigate the functions of the TIM-1 :TIM-4 pathway in alloimmune responses in vivo. 2. To investigate the functions of the TIM-1 :TIM-4 pathway in chronic rejection. 3. To investigate the mechanisms of action of targeting the TIM-1 :TIM-4 pathway in alloreactivity and tolerance via defining the fate of alloreactive T cells in vivo. 4. To study the role of the TIM-1 :TIM-4 pathway in generation/function of Foxp3 regulatory T cells in vivo. Overall, our specific aims describe complimentary approaches that should lead to the development of innovative strategies to permit solid organ graft acceptance without chronic rejection to translate to primates and humans.