Role of New Costimulatory Pathways in Graft Rejection

为移植设计新的免疫调节疗法的最终目标是诱导和维持供体特异性免疫耐受状态。该项目的主要目标是研究新的T细胞共刺激通路在体内调节同种异体免疫反应中的作用。针对CD28-B7和/或CD154-CD40通路的T细胞共刺激阻断，虽然在某些啮齿动物模型中有效，但在小鼠移植模型和灵长类动物中可能不能重复性地诱导耐受。我们推测这可能是由于包括其他T细胞共刺激通路的功能在内的几种机制，和/或这可能是由于包括其他T细胞共刺激通路的功能和/或B7/CD154共刺激阻断抵抗CD8同种异体反应性T细胞或记忆性T细胞的几种机制所致。在本项目中，我们将重点研究ICOS/B7h、CD134-CD134L(OX40-OX40L)和CD27-CD70 T细胞共刺激通路的功能，因为它们在免疫应答中具有独特的功能。我们有许多独特而重要的工具，使我们能够剖析这些新的共刺激途径在调节体内同种免疫反应中的功能、机制和相互作用。我们已经获得了基因敲除动物(ICOS和CD134L)，这是一种在T细胞上结构性表达ICOS的转基因动物(ICOS/c)，以及分别对I类和II类MHC抗原具有同种反应的CD8和CD4转基因小鼠。我们也有针对新发现的T细胞共刺激分子(ICOSL/B7h，CD134L，CD70)的单抗和融合蛋白。本研究拟从CD28/CDTLA-4-B7-1/B7-2和CD154-CD450三个途径研究NOEL T细胞共刺激通路的功能及其相互作用，以期在小鼠带血管心脏和皮肤(作为严格模型)移植模型中实现和明确移植耐受的机制。了解新的T细胞共刺激通路在同种异体免疫反应中的功能，是诱导移植耐受转化到灵长类动物并最终转移到人类的新策略的重要发展。

The ultimate goal of designing new immunomodulatory therapies for transplantation is the induction and maintenance of a state of donor- specific immunologic tolerance. The main goal of the project is to study the role of novel T cell costimulatory pathways in regulating alloimmune responses in vivo. T cell costimulatory blockade directed at the CD28-B7 and/or CD154-CD40 pathways, while effective in some rodent models, may not be effective in reproducibly inducing tolerance in murine transplant models, and in primates. We hypothesize that this may be due to several mechanisms including the functions of other T cell costimulatory pathways, and/or this may be due to several mechanisms including the functions of other T cell costimulatory pathways, and/or B7/CD154 costimulation blockade resistant CD8+ alloreactive T cells or memory T cells. In this project, we will focus on studying the functions of the ICOS/B7h, CD134-CD134L (OX40-OX40L) and CD27-CD70 T cell costimulatory pathways because of their established unique functions in immune responses. We have a number of unique and important tools that will enable us to dissect the functions, mechanisms, and interactions of these novel costimulatory pathways in regulating alloimmune responses in vivo. We have made available gene knockout animals (ICOS and CD134L), a transgenic animal that constitutively expresses ICOS on T cells (ICOS/c), and CD8+ and CD4+ transgenic mice that are alloreactive to specific class I and class II MHC antigens, respectively. We also have monoclonal antibodies and fusion proteins directed at the newly identified T cell co-stimulatory molecules (ICOSL/B7h, CD134L, CD70). We plan to study th functions of the three noel T cell costimulatory pathways and dissect their interactions 3ityh the CD28/CDTLA-4-B7-1/B7-2 and CD154-CD450 pathways, with the goal of achieving and defining the mechanisms of transplantation tolerance in murine vascularized cardiac and skin (as a stringent model) transplantation models. Understanding the functions of th new T cell costimulatory pathways in alloimmune responses is important development of novel strategies to induce transplantation tolerance to translate to primates and ultimately humans.