MECHANISMS OF INTERSTITIAL INJURY IN GLOMERULONEPHRITIS

肾小球肾炎间质损伤的机制

基本信息

批准号：
2905745
负责人：
CATHERINE M. MEYERS
金额：
$ 18.15万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-05-01 至 1999-10-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2905745
关键词：
MHC class II antigen T cell receptor autoantigens autoimmunity cellular immunity cellular pathology cytokine cytotoxic T lymphocyte disease /disorder model glomerulonephritis graft versus host disease helper T lymphocyte immunogenetics immunopathology inflammation interstitial nephritis laboratory mouse systemic lupus erythematosus

项目摘要

DESCRIPTION (Adapted from Investigator's Abstract): Technological advances of the past decade have allowed a more thorough analysis of immune-mediated mechanisms of renal injury in experimental models of glomerulonephritis. Although the histologic pattern of glomerulonephritis is a phenotypically complex lesion involving both glomerular and interstitial compartments, clinicopathologic analyses suggest that severity and chronicity of interstitial inflammation correlates well with ultimate progression of renal disease. While many disease models have focused on humorally-mediated mechanisms of glomerular injury, the pathogenic role of cell-mediated interstitial events has been largely unexplored. The primary objective of the studies outlined in this proposal is to examine cell-mediated mechanisms of interstitial injury in murine model of lupus nephritis, chronic graft-vs- host disease. Preliminary studies in this model have demonstrated that a subset of autoreactive T cell clones derived from nephrotic kidneys adoptively transfers interstitial injury to naive syngeneic recipients. To more precisely define the nephritogenic T cell response in susceptible animals, the studies in this proposal include a comprehensive phenotypic and functional characterization of T cell clones isolated from diseased kidneys at distinct time intervals in the progression of glomerulonephritis. These studies will include both in vitro and in vivo analyses. Lymphocyte function studies, such as proliferation assays, helper function studies, and cytotoxicity assays will evaluate MHC restriction and antigen specificity of isolated T cell clones. Cytokine analysis will examine whether these clones correspond to a TH1 or Th2 phenotype. The nephritogenic potential of isolated clones will also be assessed with comprehensive histologic and functional studies of adoptively transferred renal lesions. Characterization of T cell receptor (TCR) gene usage in disease-associated clones will determine frequency and/or preferential usage of TCR variable region families. Comparative analysis of nucleotide sequences of TCR antigen-binding regions derived from distinct nephritogenic clones will also be conducted. Examination of T cell and MHC interaction at a molecular level will better define immune interactions which might propagate inflammatory lesions within the kidney and facilitate the design of treatment modalities that downregulate injurious host immune responses. In aggregate, this analysis should comprehensively characterize a T cell phenotype that elicits interstitial injury in a model of glomerulonephritis and provide novel insights into the pathogenesis of interstitial injury in lupus nephritis.

描述（根据研究者的摘要改编）：技术过去十年的进步允许对在实验模型中的免疫介导的肾损伤机制肾小球肾炎。虽然是组织学模式肾小球肾炎是一种表型复杂的病变，涉及肾小球和间质室，临床病理分析表明间质性炎症的严重程度和慢性与肾脏疾病的最终进展很好地相关。而很多疾病模型的重点是幽默介导的机制肾小球损伤，细胞介导的间隙的致病作用事件在很大程度上没有探索。研究的主要目标该提案中概述的是检查细胞介导的机制狼疮肾炎的鼠模型，慢性移植-VS-的间隙损伤宿主病。该模型的初步研究表明源自肾病肾脏的自动反应性T细胞克隆的子集通过过渡地将间质损伤转移给天真的合成性接受者。更精确地定义了易感性的肾病性T细胞反应动物，该提案中的研究包括全面的表型从患病分离的T细胞克隆的功能表征肾脏在不同的时间间隔肾小球肾炎。这些研究将包括体外和体内分析。淋巴细胞功能研究，例如增殖分析，辅助功能研究和细胞毒性测定将评估MHC 分离的T细胞克隆的限制和抗原特异性。细胞因子分析将检查这些克隆是否对应于TH1或TH2 表型。孤立克隆的肾病潜力也将是通过全面的组织学和功能研究评估采用转移肾脏病变。 T细胞的表征疾病相关克隆中的受体（TCR）基因使用将确定频率和/或优先使用TCR变量区域家族。 TCR抗原结合的核苷酸序列的比较分析从不同的肾病克隆中得出的区域也将是实施。在分子上检查T细胞和MHC相互作用水平将更好地定义可能传播的免疫相互作用肾脏内的炎症病变，并促进下调有害宿主免疫反应的治疗方式。总体而言，该分析应全面表征T细胞在模型中引起间质损伤的表型肾小球肾炎，并提供新的见解狼疮肾炎中的间质损伤。