ANTI-GLOMERULAR BASEMENT MEMBRANE DISEASE

抗肾小球基底膜疾病

• 批准号: 2905918
• 负责人: RAGHU KALLURI
• 金额: $ 16.94万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2905918
• 关键词: B lymphocyte; Goodpasture's syndrome; T lymphocyte; autoantibody; basement membrane; collagen; cytokine; disease /disorder model; gene targeting; genetically modified animals; glomerulonephritis; immunopathology; laboratory mouse; laboratory rabbit; laboratory rat; monoclonal antibody; renal glomerulus

DESCRIPTION (Adapted from Investigator's Abstract): Anti-GBM disease in humans is associated with rapidly progressive glomerulonephritis, anti-a3(IV)NC1 collagen antibodies, and sometimes pulmonary hemorrhage. Anti-GBM disease with kidney and lung involvement is typically referred to as Goodpasture syndrome. Although the primary target for autoantibodies from patients with anti-GBM disease has been identified as the a3(IV)NC1 collagen, its role in the immunopathology of this disease has not been investigated. The long term objective of this proposal is to study the pathogenesis of anti-glomerular basement membrane (GBM) disease in mice immunized with a3 chain of type IV collagen. Initially, as part of specific aim 1, the investigators will continue the characterization of murine anti-GBM disease. Their preliminary experiments show that immunization with a3(IV) collagen produces organ specific inflammatory renal disease mimicking human anti-GBM disease in Goodpasture syndrome in genetically susceptible inbred mice. While all inbred strains of mice immunized with the antigen produced IgG1/Th2-like anti-GBM antibodies that cross react with human Goodpasture autoantibodies, only a select few major histocompatibility complex haplotypes (MHC) developed inflammatory disease in organ tissues. Crescentic glomerulonephritis and lung hemorrhage were restricted to MHC haplotypes H-2 s,b, and d that express additional IL-2 and IgG2a/Th1-like responses which map to the Ab/Aa region of H-2s; immune response genes in HLA-DR/DQ correspond to this region in humans predisposed to Goodpasture syndrome. As the second part of this aim, antibodies and immune cells from mice with anti-GBM disease will be passively and adoptively transferred, respectively, into native recipients. The transfer of disease, will evaluate the contribution of various effector mechanisms. Knockout mice deficient in B cells, T cells and cytokines will also be used to further investigate the contributions of these immune cells and cytokines on disease expression. The molecular determinants of the B-lymphocyte response in mice with nephritis will be examined in specific aim 2. In the first part of the second specific aim we will make a3(IV)NC1 collagen-specific monoclonal antibodies from susceptible and non-susceptible mice. The monoclonal antibodies will be tested in passive transfer experiments for their capacity to induce anti-GBM disease. The disease-inducing and/or non-inducing monoclonals will be further studied to identify the antigen-binding epitopes using synthetic peptides derived from the murine a3(IV)NC1 collagen amino acid sequence. A select panel of monoclonals will be used as immunogens in rabbits and rats to in the hopes of identifying a cross-reactive idiotype. The mouse model described in this proposal closely resembles human anti-GBM disease and Goodpasture syndrome in is immunopathology and in the specificity of its polyclonal autoantibody repertoire. Successful completion of this project should provide new experimental information regarding the processes that govern the pathogenesis of human anti-GBM disease.

描述(改编自《调查者摘要》)：中国的抗GBM病 人类与快速进行性肾小球肾炎有关， 抗A3(IV)NC1型胶原抗体，有时可见肺出血。 抗肾小球基底膜病累及肾脏和肺是典型的 就像古德帕斯图尔综合症。尽管自身抗体的主要靶点 来自抗GBM病的患者已被确认为A3(IV)NC1 胶原蛋白，其在本病免疫病理中的作用一直未见报道 调查过了。这项建议的长远目标是研究 小鼠抗肾小球基底膜病的发病机制 用IV型胶原蛋白A3链免疫。最初，作为特定内容的一部分 目标1，调查人员将继续对小鼠进行表征 抗GBM病。他们的初步实验表明，用 A3(IV)胶原可模拟器官特异性炎性肾病 人抗GBM病在古德帕斯普综合征中的遗传易感性 近亲繁殖的小鼠。而所有近交系小鼠都用该抗原免疫 产生与人交叉反应的IgG1/Th2样抗GBM抗体 GoodPasure自身抗体，仅有少数几种主要组织相容性 复杂单倍型(MHC)在器官组织中发展为炎症性疾病。 新月体肾炎和肺出血仅限于MHC 表达额外IL-2和IgG2a/Th1样蛋白的单倍型H-2 S、b和d 映射到H-2S的抗体/AA区的反应；免疫反应基因 在有好牧场倾向的人中，这一区域对应于HL-DR/DQ 综合症。作为这一目标的第二部分，来自 抗-GBM病小鼠将被被动和过继转移， 分别发送到本地接收方。疾病的转移，将 评估各种效应器机构的贡献。基因敲除小鼠 缺乏B细胞、T细胞和细胞因子也将被用来进一步 研究这些免疫细胞和细胞因子在疾病中的作用 表情。 多发性硬化小鼠B淋巴细胞反应的分子决定因素 肾炎将有针对性地进行检查2。在第一部分中 第二个特定目标是我们将制备A3(IV)NC1胶原蛋白特异性单抗 来自敏感和不敏感小鼠的抗体。单克隆化 抗体将在被动转移实验中进行能力测试 诱导产生抗GBM病。致病和/或非致病 将进一步研究单克隆以鉴定抗原结合表位。 利用小鼠A3(IV)NC1胶原蛋白氨基合成多肽 酸序列。一组精选的单克隆体将被用作 兔子和大鼠希望能鉴定出一种交叉反应的独特型。 这项建议中描述的小鼠模型与人类抗GBM非常相似。 IS免疫病理学中的疾病和Goodppure综合征 其多克隆自身抗体库的特异性。成功 该项目的完成将提供新的实验信息 关于人类抗GBM发病机制的研究进展 疾病。