T CELL Costimulation in Intestinal Allograft Rejection

描述：(逐字摘自申请者的摘要)幻觉是 对多种器官衰竭的明确治疗。然而，结果是 肠移植不如其他移植器官，因为 独特的肠道排斥反应严重程度。为了了解导致这种异常严重的排斥反应的因素，肠道和心脏的结果 并与小鼠移植进行比较。CD8 T细胞，但不足以 同种异体心脏移植的排斥反应足以排斥肠道 异体移植。这一观察结果突显了CD8 T细胞可以 在同种异体移植排斥反应中发挥作用，并表明不同的免疫原性 心脏和肠道的异体移植物至少部分是由于不同的 排斥机制。这些数据说明有必要确定 抑制CD8 T细胞的免疫抑制剂。肠道杂音 移植模型是一个很好的工具，既可以达到这一目的，也可以研究 CD8T细胞在体内的免疫生物学阻断T细胞共刺激信号 已经在几个实验模型中被证明可以防止排斥反应。然而， 虽然阻断了CD28/B7或CD154/CD4O共刺激通路，但使用 CTLA4Ig或MR1抑制同种异体心脏移植排斥反应 同种异体肠移植排斥反应。重要的是，这两种药物都抑制了 同种异体小肠移植排斥反应由CD_4，T细胞引起，而不是由CD_8，T细胞引起。这些数据提供了 CD4、ANC、CD8 T细胞共刺激需求不同的直接证据 体内的细胞。新数据显示CD8 T细胞介导的排斥反应被抑制 在LTbRIg的短期实验中，一种阻断两种T细胞的试剂 共刺激与树突状细胞成熟和迁移。第一个具体 目的是确定导致CD8或CD4长期抑制的药物 体内T细胞介导的排斥反应。然后这些代理的组合将被 在野生型小鼠身上进行测试，试图设计一种临床适用的 免疫抑制疗法。测试的试剂将包括单抗。 和阻止CD28/B7，CD54/CD4O的融合蛋白，以及新描述的 LIGH-LT/HVEM-LTR共刺激通路。第二个具体目标是 确定这些药物抑制CD8和CD8功能的机制 CD4T细胞和防止同种异体排斥反应。经处理的细胞的功能 小鼠将在体外和体内进行检测。这些研究还将提供 关于T细胞激活所必需的事件的信息以及 效应器功能的发展。第三个具体目标是定义 抗原提呈的直接途径和间接途径的相对重要性 同种异体移植排斥反应中的ANC共刺激作用。使用ELISPOT分析，MUC和 树突状细胞缺陷小鼠和tcp转基因小鼠的作用 CD8和CD4T细胞排斥反应的间接途径将被确定 细胞。

DESCRIPTION: (Verbatim from the applicant's abstract) Transpiantation is definitive therapy for many types of organ failure. However, results of intestinal transplantation are inferior to other transplanted organs due to the unique severity of intestinal rejection. To understand the factors responsibk hr this unusually severe rejection the results of intestinal and cardiac transplantation in mice were compared. CD8 T cells, while not sufficient for rejection of cardiac allografis, were sufficient to reject intestinal allografts. This observation highlights the important role that CD8 T cells can play in allograft rejection and demonstrates that the differing immunogenicity of cardiac and intestinal allografis is at least in part due to different mechanisms ofrejection. These data illustrate the need to identify immunosuppressive agents that inhibit CD8 T cells. The murme intestinal transplant model is an excellent tool for both this purpose and to study the immunobiology of CD8 T cells in vivo. Blockade of T cell costimulatory signals has been shown to prevent rejection in several experimental models. However, although blockade )f the CD28/B7 or CD154/CD4O costimulatory pathways using CTLA4Ig or MR1 prevented rejection of cardiac allografts, it did not inhibit rejection of intestinal allografls. Importantly, both agents inhibited intestinal allograft rejection by CD4, but not CD8, T cells. These data provide direct evidence of the differing costimulatory requirements of CD4 anc CD8 T cells in vivo. New data show that CD8 T cell-mediated rejection was inhibited in short-term experiments by LTbRIg, an agent that blocks both T cell costimulation and dendritic cell maturation and migration. The FIRST SPECIFIC AIM is to identify agents that result in the long-term inhibition of CD8 or CD4 T cell-mediated rejection in vivo. Combinations of these agents will then be tested in wild-type mice in an attempt to design a clinically applicable immunosuppressive regimen. Reagents tested will include monoclonal antibodies and fusion proteins that block the CD28/B7, CD! 54/CD4O, and newly described LIGHT-LT/HVEM-LTR costimulatory pathways. The SECOND SPECIFIC AIM is to determine the mechanism by which these agents inhibit the function ofCD8 and CD4 T cells and prevent allograf rejection. The function of cells from treated mice will be determined in vitro and in vivo. These studies will also provide information about the requisite events necessary for T cell activation and the development of effector function. The THIRD SPECIFIC AIM is to define the relative importance of the direct and indirect pathways of antigen presentation anc costimulation during allograft rejection. Using the ELISPOT assay, MUC and dendritic cell deficient mice, and TCP transgenic mice the roles of the direct and indirect pathways in rejection will be determined for both CD8 and CD4 T cells.