Graft-specific factors promoting intestinal rejection

促进肠道排斥的移植物特异性因素

• 批准号: 6863092
• 负责人: KENNETH A. NEWELL
• 金额: $ 38.25万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6863092
• 关键词: Peyer' s patches; T lymphocyte; cell migration; combination chemotherapy; flow cytometry; gastrointestinal epithelium; gastrointestinal transplantation; genetically modified animals; homologous transplantation; immunomodulators; immunosuppressive; intestines; intravital microscopy; laboratory mouse; lymph nodes; monoclonal antibody; mutant; nonhuman therapy evaluation; radiotracer; transplant rejection

DESCRIPTION (provided by applicant): Results of intestinal transplantation are inferior to other transplanted organs primarily due to the greater immunogenicity of intestinal allografts and complications arising from the large amount of immunosuppression required to prevent rejection. These facts underscore the need to understand the unique mechanisms responsible for intestinal allograft rejection and to use this knowledge to design more effective immunosuppression. Studies of other transplanted organs demonstrate an important role for recipient secondary lymphoid organs in the rejection process. We hypothesize that mesenteric lymph nodes (MLN) and Peyer's patches (PP) within intestinal allografts serve as sites that uniquely and efficiently prime alloreactive T cells. By virtue of having been primed in the lymphoid organs of the intestine, recipient T cells express trafficking molecules that favor their subsequent migration to the intestinal epithelium where they mediate rejection. Specific aim 1 is to determine whether priming of recipient alloreactive T cells can occur in donor MLN and PP and if so, the contribution this process to intestinal rejection relative to the more conventional process of T cell priming in recipient lymphoid organs. For these experiments mutant mice that lack all lymph nodes and PP (LTalpha-/- and aly/aly) will be used as recipients and/or donors for intestinal allografts. T cell priming in donor and recipient lymphoid organs will be assessed by Elispot and intracellular cytokine staining. Specific aim 2 is to determine whether chemokines (CCR6 and CCR9) and integrins (CD103 and alpha4beta7) known to regulate intestinal T cell trafficking in response to environmental and microbial antigens also regulate the trafficking of recipient T cells in response to intestinal alloantigens. The role of these molecules in T cell trafficking to intestinal allografts will be examined using knockout mice and monoclonal antibodies specific for each molecule. The effects of each molecule will be quantified using intravital microscopy, accumulation of In(111) labeled cells, and flow cytometric analysis of T cells isolated from the various compartments of intestinal grafts. Specific aim 3 is to combine agents that block those steps shown to be important in aims 1 and 2 with other small molecule or biologic immunosuppressant agents in a attempt to design regimens that more specifically and effectively prevent the rejection of intestinal allografts.

描述（由申请人提供）：肠移植的结果劣于其他移植器官，主要是由于肠同种异体移植物的免疫原性更强以及预防排斥反应所需的大量免疫抑制引起的并发症。这些事实强调需要了解肠移植排斥反应的独特机制，并利用这些知识来设计更有效的免疫抑制剂。对其他移植器官的研究表明，受体次级淋巴器官在排斥过程中发挥重要作用。我们假设，肠系膜淋巴结（MLN）和派尔集合淋巴结（PP）内的肠同种异体移植物作为网站，独特和有效的总理同种异体反应性T细胞。由于已经在肠的淋巴器官中引发，受体T细胞表达有利于其随后迁移到肠上皮的运输分子，在那里它们介导排斥。具体目标1是确定受体同种异体反应性T细胞的引发是否可以在供体MLN和PP中发生，如果是这样，则相对于受体淋巴器官中T细胞引发的更常规过程，该过程对肠排斥的贡献。对于这些实验，将使用缺乏所有淋巴结和PP（LT α-/-和aly/aly）的突变小鼠作为肠同种异体移植物的受体和/或供体。将通过Elispot和细胞内细胞因子染色评估供体和受体淋巴器官中的T细胞引发。具体目标2是确定已知调节肠道T细胞运输以响应环境和微生物抗原的趋化因子（CCR 6和CCR 9）和整合素（CD 103和α 4 β 7）是否也调节受体T细胞的运输以响应肠道同种异体抗原。这些分子在T细胞运输到肠同种异体移植物中的作用将使用基因敲除小鼠和对每个分子特异性的单克隆抗体进行检查。将使用活体显微镜、In（111）标记细胞的累积和从肠移植物的各个隔室分离的T细胞的流式细胞术分析来定量每种分子的作用。具体目标3是将阻断在目标1和2中显示为重要的那些步骤的联合收割机试剂与其它小分子或生物免疫抑制剂试剂组合，以试图设计更特异性和有效地预防肠同种异体移植物排斥的方案。