Role of New Costimulatory Pathways in Graft Rejection

设计用于移植的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的状态。该项目的主要目标是研究新型T细胞共刺激通路在体内调节同种免疫应答中的作用。针对CD 28-B7和/或CD 154-CD 40通路的T细胞共刺激阻断虽然在一些啮齿动物模型中有效，但在鼠移植模型和灵长类动物中可能不能有效地可再现地诱导耐受。我们假设这可能是由于几种机制，包括其他T细胞共刺激途径的功能，和/或这可能是由于几种机制，包括其他T细胞共刺激途径的功能，和/或B7/CD 154共刺激阻断抗性CD 8+同种异体反应性T细胞或记忆T细胞。由于ICOS/B7 h、CD 134-CD 134 L（OX 40-OX 40 L）和CD 27-CD 70三条T细胞共刺激通路在免疫应答中具有独特的功能，本课题将重点研究这三条通路的功能。我们有一些独特的和重要的工具，将使我们能够剖析这些新的共刺激途径在调节同种异体免疫反应在体内的功能，机制和相互作用。我们已经获得了基因敲除动物（ICOS和CD 134 L），一种在T细胞上组成型表达ICOS的转基因动物（ICOS/c），以及分别对特定I类和II类MHC抗原具有同种异体反应性的CD 8+和CD 4+转基因小鼠。我们也有针对新鉴定的T细胞共刺激分子（ICOSL/B7 h，CD 134 L，CD 70）的单克隆抗体和融合蛋白。本研究拟通过对这三条诺埃尔共刺激通路的功能研究，探讨它们与CD 28/CDTLA-4-B7-1/B7-2和CD 154-CD 450通路之间的相互作用，以期在小鼠血管化心脏和皮肤（作为严格模型）移植模型中获得并阐明移植耐受的机制。了解新的T细胞共刺激通路在同种免疫应答中的功能是诱导移植耐受转化到灵长类动物并最终转化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.