Negative Costimulatory Pathways in Rejection & Tolerance

描述(申请人提供)：我的建议的目的是研究新的抑制性共刺激分子PD-PDL和B7-H3在同种异体移植排斥反应中的体内功能和作用机制，目的是利用它们的功能来实现同种异体移植耐受。本课题对于一般的移植具有重要的临床意义，因为阻断常规的阳性T细胞共刺激通路如B7-CD28在严格的小鼠移植模型中以及在较大的动物如灵长类动物中不能有效地重复性地诱导耐受。我的建议的一个重要主题是，除了积极的T细胞共刺激阻断外，利用新的负T细胞共刺激通路调节的生理学机制对于实现人类的耐受至关重要。我已经生成了大量关于负共刺激通路CTLA4-B7和PD-1/PDL在体内CD4和CDS介导的同种免疫反应中的作用的数据。我也有关于最近描述的CD28家族成员B7-H3在血管心脏模型中的作用的有希望的初步数据。我计划使用一些独特的工具来扩展这些研究，这些工具将使我能够剖析负向和正向共刺激通路在调节体内同种免疫反应中的功能、机制和相互作用。这些包括成熟的动物模型，针对特定共刺激分子的新型基因敲除动物，针对新的共刺激途径的药物，以及允许跟踪体内同种异体反应T细胞反应的CD8和CD4TCR转基因小鼠的优雅模型。导师临床科学家发展奖将为我提供一个关键的机会，进一步扩大我在免疫学方面的知识，这是实现独立所必需的。我的导师和合作导师的实验室为实现我的项目目标提供了一个理想的环境，因为他们在移植免疫学方面有很强的背景，他们的合作势头以及他们模范的说教和伦理课程。

DESCRIPTION (provided by applicant): The aim of my proposal is to examine the in vivo functions and the mechanisms of action of novel inhibitory costimulatory molecules PD-PDL and B7-H3 in allograft rejection with the goal of harnessing their function to achieve allograft tolerance. This topic has great clinical relevance for transplantation in general as blockade of conventional positive T cell costimulatory pathway such as B7-CD28 has not been effective in reproducibly inducing tolerance in stringent murine transplant models as well as in larger animals such as primates. An important theme of my proposal is that harnessing physiologic mechanisms of regulation by novel negative T cell costimulatory pathways in addition to positive T cell costimulatory blockade are critical to achieve tolerance in humans. I have generated extensive data about the role of negative costimulatory pathways CTLA4-B7 and PD-1/PDL in CD4 and CDS mediated alloimmune responses in vivo. I also have promising preliminary data about the role of the recently described member of CD28 family, B7-H3 in a vascularized cardiac model. I plan to extend these studies using a number of unique tools that will enable me to dissect the functions, mechanisms and interactions of negative and positive costimulatory pathways in regulating alloimmune responses in vivo. These include well established animal models, novel gene knockout animals targeting specific costimulatory molecules, agents to target novel costimulatory pathways and finally elegant models of CD8+ and CD4+ TCR transgenic mice that allow tracking of alloreactive T cell responses in vivo. The Mentored Clinical Scientist Development Award will provide me with the critical opportunity to further expand my knowledge in immunology necessary for achieving independence. My mentor's and co-mentor's laboratories provide an ideal environment to accomplish the aims of my project because of their strong background in transplantation immonology, their collaborative momentum and their exemplary didactic and ethical curricula.