INTESTINAL ALLOGRAFT REJECTION--MECHANISMS AND THERAPIES

描述(改编自申请人的摘要)：尽管同种异体移植 排斥反应仍然是所有器官移植的障碍，发生率很高 肠移植后排斥反应的严重程度是主要的 限制该技术在临床上统一成功应用的因素 程序。这项研究建议是基于拒绝的假设 同种异体肠移植的性质不同于其他 器官。研究人员开发了一种新的小鼠肠道模型 移植以验证这一假设，允许他们利用定义良好的 仅适用于该物种的生物试剂和转基因菌株。 他们的初步观察是，与之前描述的不同 在其他器官移植的动物模型中，CD8 T细胞发挥着关键和 体内单抗在肠道排斥反应中的重要作用 抗体耗竭研究。他们将描述CD8T的参与 CD8细胞在肠道排斥反应中的作用比较 肠道到心脏的移植排斥反应。在第二个观察中， 他们已经表明，CD8 T细胞遗传缺陷的小鼠保留了 排斥肠道移植的能力。他们将通过以下方式检查这一机制 哪种抗CD8单抗治疗可延长小鼠生存期 并将其与CD8使用的机制进行对比 基因敲除小鼠拒绝类似的移植物。最后，他们将利用 来研究CD8 T细胞在排斥反应中所起的独特作用 在活体内。他们将直接研究共刺激要求和 CD8 T细胞在介导同种异体移植排斥反应中的功能

DESCRIPTION (Adapted from applicant's abstract): Although allograft rejection remains an obstacle for all organ transplants, the high incidence and severity of rejection following intestinal transplantation is the major factor limiting the uniform successful clinical application of this procedure. This research proposal is based on the hypothesis that rejection of intestinal allograft is qualitatively different from that of other organs. The investigators have developed a novel model of mouse intestine transplant to test this hypothesis, allowing them to utilize well-defined biological reagents and transgenic strains available only for this species. Their preliminary observation is that, distinct from previously described animal models of other organ transplants, CD8 T cells play a critical and essential role in the rejection of the intestine, using in vivo monoclonal antibody depletion studies. They will characterize the involvement of CD8 T cells in the rejection of the intestine and compare the role of CD8 cells in the intestine to heart transplant rejection. In the second observation, they have shown that mice genetically deficient in CD8 T cells retain the ability to reject intestine transplant. They will examine the mechanism by which treatment with anti-CD8 monoclonal antibodies prolong survival of intestinal allografts and contrast this to the mechanism used by CD8 knockout mice to reject similar grafts. Finally, they will take advantage of their model to study the unique role that CD8 T cells play in rejection in vivo. They will directly examine the costimulatory requirements and functional properties of CD8 T cells in mediating allograft rejection.