INDUCTION AND REGULATION OF IMMUNE NEPHRITIS

免疫性肾炎的诱导和调节

• 批准号: 3086238
• 负责人: MICHAEL D CLAYMAN
• 金额: $ 7.69万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1987-06-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3086238
• 关键词: B lymphocyte; T lymphocyte; affinity chromatography; antiantibody; antiidiotype antibody; autoimmune disorder; basement membrane; genetic strain; glomerulonephritis; humoral immunity; hybridomas; immunofluorescence technique; immunoglobulin genes; immunoregulation; interstitial nephritis; monoclonal antibody; radioimmunoassay; renal tubule

This project seeks to utilize didactic and research experiences to provide a program for the development of an effective independent investigator in the field of renal immunology. Phase 1 will establish an educational foundation as well as create a formulative research and methodologic experience. the former will be accomplished through seminars in the Immunology Graduate Group, lectures, conferences, and journal clubs. The latter will evolve from the further study of an already operational model of anti-tubular basement membrane (AlphaTBM) disease producing interstitial nephritis in mice. This project will initially examine the qualitative and quantitative aspects of the AlphaTBM B cell repertoire. Such an analysis will require the generation of a library of monoclonal AlphaTMB antibodies (AlphaTBM-Ab), as well as an evaluation of B cell precursor frequencies. The immunogenetics of the B cell response will be examined utilizing congenic mice to assess the relationship between heavy-chain allotype, haplotype, paratypic and idiotypic composition of AlphaTBM-Ab, and disease susceptibility. Further analysis of the immunoregulation of AlphaTBM disease will examine both the humoral and cellular arms of the idiotypic network and will employ anti-idiotypic antisera to polymorphic and broadly cross-reactive idiotypes. Solid phase radioimmunoassay will be used extensively to allow a fine analysis of the AlphaTBM serology. Finally, the further purification of nephritogenic TBM antigens will utilize monoclonal AlphaTBM-Ab affinity columns and an intensive analytical biochemical approach to isolate distinct epitopes. At the conclusion of Phase 1, it is anticipated that a more independent effort will be undertaken. This will consist of a detailed analysis of the afferent and immunoregulatory phase of experimental membranous nephritis, a model analogous to one of the most common causes of adult nephrotic syndrome. Since the relevant antigen can be readily isolated, and because the antibody response is critical to the nephritogenic immune response, many of the studies outlined for Phase 1 should be both feasible and easily applicable. A detailed immunogenetic analysis will be undertaken utilizing congenic rodents and variables described for AlphaTBM disease above. In sum, it is felt that Phase 2 has great potential to further understanding regarding induction and control of this experimental form of membranous glomerulonephritis.

该项目旨在利用教学和研究经验， 一个有效的独立调查员的发展计划， 肾脏免疫学领域。 第一阶段将建立一个教育 基础，并创建一个公式化的研究和方法论 体验. 前一项工作将通过在 免疫学研究生组，讲座，会议和期刊俱乐部。 的 后者将从对一个已经运作的模型的进一步研究中发展而来 抗肾小管基底膜（AlphaTBM）疾病产生间质性 小鼠肾炎。 该项目将首先审查质量和 AlphaTBM B细胞库的定量方面。 这种分析 将需要产生单克隆AlphaTMB抗体文库 （AlphaTBM-Ab），以及评估B细胞前体频率。 B细胞应答的免疫遗传学将利用 同类小鼠来评估重链同种异型之间的关系， AlphaTBM-Ab单倍型、特异性和独特型组成与疾病 易感性 进一步分析AlphaTBM的免疫调节作用 疾病将检查独特型的体液和细胞臂 网络，并将采用抗独特型抗血清多态性和广泛 交叉反应的独特型。 将使用固相放射免疫测定法 以允许对AlphaTBM血清学进行精细分析。 最后， 致肾炎性TBM抗原的进一步纯化将利用 单克隆AlphaTBM-Ab亲和柱和一个密集的分析 生物化学方法分离不同的表位。 在第一阶段结束时，预计将有一个更加独立的 将作出努力。 这将包括详细分析 实验性膜性肾炎的传入和免疫调节相 模型类似于成人肾病最常见的原因之一， 综合征 因为相关抗原可以容易地分离，并且因为 抗体应答对于致肾炎免疫应答是关键的， 第一阶段概述的许多研究应该既可行又容易 适用因 详细的免疫遗传学分析将利用 同类啮齿动物和上述AlphaTBM疾病的变量。 在 总之，我们认为第二阶段有很大潜力进一步了解 关于诱导和控制这种实验形式的膜 肾小球肾炎