Kidney-restricted CTL and Allograft Rejection

肾脏限制性 CTL 和同种异体移植排斥

基本信息

批准号：
7214640
负责人：
GREGG A HADLEY
金额：
$ 36.41万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-08-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7214640
关键词：
Allografting Atrophic CD8B1 gene Cells Chronic Clinical Data Development E-Cadherin Efferent Pathways Epithelial Epithelium Fibrosis Funding Gene Expression Generations Goals Guanine Nucleotide Dissociation Inhibitors Immunity Immunologics Immunosuppressive Agents Infiltration Inflammatory Injury Integrins Intervention Kidney Kidney Transplantation Lesion Ligands Lymphoid Modeling Mus Pathway interactions Phase Population Production Public Health Rattus Recruitment Activity Renal tubule structure Research Design Research Personnel Role Sentinel T-Lymphocyte Testing Therapeutic Therapeutic Intervention Transforming Growth Factor beta Transplantation Tubular formation base chemokine in vivo insight interstitial kidney allograft novel prevent programs selective expression

Allografting Atrophic CD8B1 gene Cells Chronic Clinical Data Development E-Cadherin Efferent Pathways Epithelial Epithelium Fibrosis Funding Gene Expression Generations Goals Guanine Nucleotide Dissociation Inhibitors Immunity Immunologics Immunosuppressive Agents Infiltration Inflammatory Injury Integrins Intervention Kidney Kidney Transplantation Lesion Ligands Lymphoid Modeling Mus Pathway interactions Phase Population Production Public Health Rattus Recruitment Activity Renal tubule structure Research Design Research Personnel Role Sentinel T-Lymphocyte Testing Therapeutic Therapeutic Intervention Transforming Growth Factor beta Transplantation Tubular formation base chemokine in vivo insight interstitial kidney allograft novel prevent programs selective expression

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项目摘要

DESCRIPTION (provided by applicant): - Project summary: The infiltration of CD8+ T effector populations (CD8 effectors) into graft renal tubules has long been recognized as a key lesion in progression of clinical renal allograft rejection. Studies resulting from the previous funding period revealed a pivotal role for the integrin CD103 in promoting destruction of the graft renal tubules by donor-specific CD8 effector populations. Based on these data, we postulate that blockade of the CD103 pathway as an adjunct to conventional immunosuppressive strategies provides a means of promoting long-term survival of renal allografts. The overall objective of this proposal is to test this hypothesis. In order to achieve this goal, we will first elucidate the mechanisms by which CD103+CD8+ effectors destroy the graft renal tubules, and identify the origin of CD103+CD8+ effector populations that infiltrate renal allografts. The information gained from these studies will be used to develop optimal strategies for abrogating the contribution of CD103+CD8+ effector mechanisms to renal allograft destruction. The studies in Aim 1 will use gene expression analyses in combination with mouse renal transplant models to define the mechanisms by which CD103 expression promotes accumulation and subsequent destruction of the graft renal tubules by donor-specific CD8 effectors in the graft renal tubules. The studies in Aim 2 will use mouse renal allograft models to identify the precursors of CD103+CD8+ effectors that infiltrate epithelial allografts, and elucidate the role of local transforming growth factor-beta activity in their generation. The studies in Aim 3 will use rat kidney transplant models to determine the impact of CD103 blockade on development of tubular atrophy and interstitial fibrosis in vascularized renal allografts. Together, the proposed studies will elucidate the mechanisms by which CD8+ T cells destroy renal allografts and identify novel targets for therapeutic intervention in the important clinical problem of late graft loss. Relevance to public health: Current immunosuppressive strategies do not reliably prevent the occurrence of rejection episodes and long-term damage to the graft. Consequently, late graft loss now represents the major rejection problem in clinical renal transplantation. Thus, a better understanding of the pathways by which this occurs is likely to reveal novel targets for therapeutic intervention in this important clinical problem.

描述（由申请人提供）： - 项目摘要：长期以来，将CD8+ T效应人群（CD8效应子）浸润到临床同种异体移植抑制临床肾脏的进展方面长期以来被认为是关键病变。从上一个资金期间产生的研究表明，整联蛋白CD103在促进供体特异性CD8效应子种群促进移植物肾小管破坏方面发挥了关键作用。基于这些数据，我们假设CD103途径作为常规免疫抑制策略的辅助性提供了一种促进肾同种异体移植长期生存的手段。该提案的总体目的是检验该假设。为了实现这一目标，我们将首先阐明CD103+ CD8+效应子破坏移植物肾小管的机制，并确定CD103+ CD8+ CD8+效应子种群渗透肾脏同种异体移植物的起源。从这些研究中获得的信息将用于制定最佳策略，以消除CD103+ CD8+效应子机制对肾脏同种异体移植破坏的贡献。 AIM 1中的研究将使用基因表达分析与小鼠肾移植模型结合使用，以定义CD103表达促进供体特异性CD8效应子在移植物肾小管中促进移植物肾小管的积累和随后破坏的机制。 AIM 2中的研究将使用小鼠肾脏同种异体移植模型来识别浸润上皮同种异体移植物的CD103+ CD8+效应子的前体，并阐明了局部转化生长因子-BETA活性在其一代中的作用。 AIM 3中的研究将使用大鼠肾移植模型来确定CD103阻断对血管化肾脏同种异体移植物中管道萎缩和间质性纤维化发展的影响。拟议的研究将共同阐明CD8+ T细胞破坏肾脏同种异体移植物并确定对治疗性干预的新靶标的机制，这些机制在晚期移植物损失的重要临床问题中进行了治疗干预。与公共卫生的相关性：当前的免疫抑制策略不能可靠地阻止发生拒绝发作和对移植物的长期损害。因此，晚期移植物损失现在代表了临床肾移植中的主要排斥问题。因此，更好地理解发生这种情况的途径可能会揭示有关此重要临床问题治疗干预的新目标。