KIDNEY RESTRICTED CTL AND ALLOGRAFT REJECTION

肾脏限制性 CTL 和同种异体移植物排斥

基本信息

批准号：
6740244
负责人：
GREGG A HADLEY
金额：
$ 29.7万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
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 2005-04-30
项目状态：
已结题

项目摘要

The interaction of CD8+ CTL with epithelial layers is an important but poorly defined aspects of renal allograft rejection. Recent studies demonstrating that the epithelial cell-specific integrin, CD103, defines a subset of CD8+ CTL potentially provides new insight into such interactions. The central hypothesis to be tested is that TGFbeta activity present at the site of rejecting allografts exerts local control over CD103 expression by a specific subset of graft infiltrating CD8+ CTL, thereby promoting the capacity of such cells for homing to, and subsequent destruction of, the graft epithelium. Mouse mixed leukocyte cultures will be utilized to elucidate mechanisms that regulate CD103 expression by peripheral CD8 cells, and a vascularized mouse kidney transplant model will be utilized to elucidate mechanisms that regulate CD103 expression. by peripheral CD8 cells, and a vascularized mouse kidney transplant model will be utilized to identify the in vivo compartment in which CD103+CTL originate during the allograft response. The stability and extended phenotyping and functional properties of CD103+CTL will be compared with those of conventional (CD103-) CTL, and the capacity of CD103 to function as tissue-restricted adhesion/co-stimulatory molecule that promotes interaction of CD103+ CTL with the graft epithelium will be defined. Transplant conditions that promote accumulation of CD103+CTL at the graft site will also be determined; specific variables to be examined include graft cell-type, type of rejection (acute, chronic, delayed), and CsA immunosuppression. Finally, to test the central hypothesis that CD103+ CTL possess a unique capacity to infiltrate and destroy the graft epithelium, these studies will determine whether: i) the appearance of CD103+CTL within rejecting allografts correlate with destruction of the graft epithelium, ii) targeted disruption of the CD103 gene (i.e., using CD103 knockout mice) prevents rejection of vascularized renal allografts, and iii) adoptively transferred CD103+ CTL home to the renal epithelium and elicit destructive lesions characteristic of rejection pathology. Together, these studies will fulfill a form of Kock's postulates to document the role of CD103+ CTL as an effector mechanism in renal allograft rejection. Human MLC cultures and clinical transplant nephrectomy specimens will be utilized to confirm relevance to the human system. These studies will provide new insight into the immunologic basis of renal allograft rejection and have the potential to identify novel targets for therapeutic intervention in rejection events.

CD8+ CTL 与上皮层的相互作用是肾同种异体移植排斥的一个重要但定义不明确的方面。最近的研究表明，上皮细胞特异性整合素 CD103 定义了 CD8+ CTL 的一个子集，这可能为此类相互作用提供新的见解。要测试的中心假设是，排斥同种异体移植物部位存在的 TGFbeta 活性通过移植物浸润 CD8+ CTL 的特定子集对 CD103 表达进行局部控制，从而促进此类细胞归巢并随后破坏移植物的能力。移植上皮。小鼠混合白细胞培养物将用于阐明外周 CD8 细胞调节 CD103 表达的机制，血管化小鼠肾移植模型将用于阐明调节 CD103 表达的机制。通过外周 CD8 细胞，血管化小鼠肾移植模型将用于识别同种异体移植反应期间 CD103+CTL 起源的体内隔室。 CD103+CTL 的稳定性、扩展表型和功能特性将与传统 (CD103-) CTL 进行比较，以及 CD103 作为组织限制性粘附/共刺激分子促进 CD103+ CTL 与细胞相互作用的能力。将定义移植上皮。还将确定促进移植部位 CD103+CTL 积累的移植条件；要检查的具体变量包括移植细胞类型、排斥类型（急性、慢性、迟发）和 CsA 免疫抑制。最后，为了检验 CD103+ CTL 具有渗透和破坏移植上皮的独特能力这一中心假设，这些研究将确定是否：i) 排斥同种异体移植物中 CD103+CTL 的出现与移植上皮的破坏相关，ii) 靶向CD103 基因的破坏（即使用 CD103 敲除小鼠）可防止血管化肾同种异体移植物的排斥，以及 iii) 过继转移CD103+ CTL 位于肾上皮细胞并引起排斥病理学特征的破坏性病变。总之，这些研究将满足 Kock 假设的一种形式，以记录 CD103+ CTL 作为肾同种异体移植排斥反应机制的作用。人类 MLC 培养物和临床移植肾切除标本将用于确认与人体系统的相关性。这些研究将为肾同种异体移植排斥的免疫学基础提供新的见解，并有可能确定排斥事件治疗干预的新靶点。