T CELL Costimulation in Intestinal Allograft Rejection

描述：（逐字从申请人的摘要）Transpiantation是 多种类型器官衰竭的确定性治疗。然而， 肠移植不如其他移植器官， 肠道排斥反应的严重程度为了了解导致 hr这种不寻常的严重排斥反应的结果，肠和心脏 小鼠移植进行了比较。CD 8 T细胞虽然不足以 心脏移植排斥反应，足以排斥肠 同种异体移植这一观察结果强调了CD 8 T细胞可以 在同种异体移植排斥反应中发挥作用，并证明不同的免疫原性 心脏和肠道同种异体移植的发生至少部分是由于 排斥机制这些数据表明， 抑制CD 8 T细胞的免疫抑制剂。小肠杂音 移植模型是一个很好的工具，用于这一目的，并研究 体内CD 8 T细胞的免疫生物学。T细胞共刺激信号的阻断 在几个实验模型中已经显示出防止排斥。然而，在这方面， 虽然阻断）的CD 28/B7或CD 154/CD 40共刺激途径， CTLA 4 Ig或MR 1可预防心脏移植排斥反应，但不抑制 肠同种异体移植物的排斥反应。重要的是，这两种药物都抑制了 肠移植排斥反应由CD 4，而不是CD 8，T细胞。这些数据提供 CD 4和CD 8 T细胞不同共刺激需求的直接证据 体内细胞新的数据表明，CD 8 T细胞介导的排斥反应被抑制， 在LTbRIg的短期实验中，LTbRIg是一种既能阻断T细胞， 共刺激和树突状细胞成熟和迁移。第一特定 目的是鉴定导致CD 8或CD 4的长期抑制的药剂 体内T细胞介导的排斥反应。然后将这些试剂的组合 在野生型小鼠中进行测试，试图设计一种临床适用的 免疫抑制方案。检测试剂将包括单克隆抗体 以及阻断CD 28/B7、CD的融合蛋白！54/CD 4 O，新描述 LIGHT-LT/HVEM-LTR共刺激通路。第二个具体目标是 确定这些药物抑制CD 8功能的机制， CD 4 T细胞和防止同种异体排斥反应。经处理的细胞的功能 将在体外和体内测定小鼠。这些研究还将提供 关于T细胞活化所必需的必要事件的信息， 效应器功能的发展。第三个具体目标是定义 抗原呈递的直接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。使用ELISPOT测定，MUC和 树突状细胞缺陷小鼠和TCP转基因小鼠的作用，直接 排斥反应的间接途径将确定为CD 8和CD 4 T细胞。 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.