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脏同种异体移植排斥的重要方面。最近的研究表明，上皮细胞特异性整联蛋白CD103定义了CD8+ CTL的子集，潜在地为这种相互作用提供了新的见解。要测试的中心假设是，拒绝同种异体移植物的部位存在的TGFBETA活性通过特定的移植物浸润CD8+ CTL对CD103表达产生局部控制，从而促进了此类细胞的能力，从而促进了归巢的能力，并随后破坏了嫁接上皮。小鼠混合的白细胞培养物将用于阐明通过外围CD8细胞调节CD103表达的机制，并将使用血管化的小鼠肾移植模型来阐明调节CD103表达的机制。通过外围CD8细胞，将利用血管化的小鼠肾移植模型来识别在同种异体移植响应期间CD103+CTL起源的体内室。 CD103+ CTL的稳定性和扩展表型和功能特性将与常规（CD103-）CTL的稳定性和功能特性进行比较，并且CD103的能力充当组织限制的粘附/共刺激分子，该分子促进CD103+ CTL与Graft上皮的相互作用的相互作用。还将确定促进CD103+CTL在移植部位积累的移植条件。要检查的特定变量包括移植细胞类型，排斥类型（急性，慢性，延迟）和CSA免疫抑制。最后，为了检验CD103+ CTL具有浸润和破坏移植物上皮的独特能力的中心假设，这些研究将确定：i）CD103+ CTL在拒绝同种异体移植物相关的拒绝中与Graft上皮的破坏相关的术语，靶向CD103 GENE的限制（I.E.E）的限制（I.E.E.E）的限制（I.E.E.同种异体移植物和iii）通过过继于肾上皮的CD103+ CTL转移到拒绝病理学的特征。总之，这些研究将实现Kock的假设形式，以记录CD103+ CTL作为肾脏同种异体移植排斥的效应机制的作用。人类MLC培养物和临床移植肾切除术标本将用于确认与人类系统的相关性。这些研究将为肾脏同种异体移植排斥的免疫学基础提供新的见解，并有潜力确定对排斥事件中治疗性干预的新目标。