Kidney-restricted CTL and Allograft Rejection

肾脏限制性 CTL 和同种异体移植排斥

• 批准号: 7793444
• 负责人: GREGG A HADLEY
• 金额: $ 31.83万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/7793444
• 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; allograft rejection; base; chemokine; in vivo; insight; interstitial; kidney allograft; novel; prevent; programs; selective expression

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：CD8+ T 效应细胞群（CD8 效应细胞）向移植肾小管的浸润长期以来被认为是临床同种异体移植肾排斥反应进展的关键病变。上一资助期的研究表明，整合素 CD103 在促进供体特异性 CD8 效应细胞群破坏移植肾小管方面发挥着关键作用。基于这些数据，我们假设阻断 CD103 通路作为传统免疫抑制策略的辅助手段提供了促进肾同种异体移植物长期存活的方法。该提案的总体目标是检验这一假设。为了实现这一目标，我们将首先阐明CD103+CD8+效应子破坏移植肾小管的机制，并确定浸润同种异体肾移植物的CD103+CD8+效应子群体的起源。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+ 效应机制对肾同种异体移植物破坏的贡献。目标 1 中的研究将结合小鼠肾移植模型使用基因表达分析来确定 CD103 表达促进移植肾小管积累和随后移植肾小管中供体特异性 CD8 效应子破坏移植肾小管的机制。目标 2 中的研究将使用小鼠肾同种异体移植模型来鉴定浸润上皮同种异体移植物的 CD103+CD8+ 效应子的前体，并阐明局部转化生长因子-β 活性在其生成中的作用。目标 3 中的研究将使用大鼠肾移植模型来确定 CD103 阻断对血管化肾同种异体移植物中肾小管萎缩和间质纤维化发展的影响。总之，拟议的研究将阐明 CD8+ T 细胞破坏同种异体肾移植物的机制，并确定针对晚期移植物丢失这一重要临床问题的治疗干预的新靶点。与公共卫生的相关性：当前的免疫抑制策略不能可靠地防止排斥反应的发生和移植物的长期损伤。因此，晚期移植物丢失现在成为临床肾移植中的主要排斥问题。因此，更好地了解这种情况发生的途径可能会揭示这一重要临床问题的治疗干预的新靶标。