CELL MEDIATED GLOMERULONEPHRITIS IN A NEW MODEL

描述（改编自申请人摘要）：人肾小球肾炎 是患者发病、死亡和需要透析的主要原因 支持和移植。 人类肾小球肾炎出现在大多数，如果 并不是所有的病例都与自身免疫性疾病有关。 许多间接证据 表明细胞介导的免疫在 肾小球肾炎的发展。 有广泛的研究模型， 实验性肾小球肾炎 肾脏成分的抗体，随后抗原沉积 通过抗体在肾脏中的沉积或循环进行免疫 配合物 系统性免疫复合物疾病的其他内源性模型 在其旁观者角色中损害肾脏。 这些模型不出借 他们自己的研究涉及细胞介导的致病事件 免疫在自身免疫性肾小球肾炎产生时肾 本身就是目标。 一种增殖性实验性自身免疫模型 肾小球肾炎以前从未在近亲繁殖的哺乳动物中发生过 物种 我们利用一种新的方法， 抗原，并开发了一种新的实验性自身免疫模型， 近交系同系大鼠肾小球肾炎。 该模型允许，对于 第一次应用生物学工具研究发病机制， 增殖性肾小球肾炎的产生机制 以前可用的。 本建议的长远目标是 继续研究细胞介导的 免疫有助于肾小球肾炎的发病机制，在这个新的 模型，并进一步描绘细胞介导的免疫的相互作用， 和经典的抗体介导的损伤。 的具体目标 目前的建议是：1）更好地描述发展的特点， 这种实验性自身免疫性肾小球肾炎随时间的自然过程 剂量临床病理学研究; 2）检查抗体在 开发和评估抗体单独和与 使用被动转移的抗体检测产生疾病的细胞， 3）检查细胞介导的免疫在 通过过继转移研究确定发病机制，在B细胞缺陷型中诱导 大鼠，并与抗原特异性T细胞克隆的研究; 4），以确定 致肾炎肽负责诱导实验性 自身免疫性肾小球肾炎，fractionalthese肽成最小 免疫原性片段，并确定其氨基酸序列，然后 生成肽和类似物，并检测它们的生产和预防 疾病。 间接证据有力地表明， 实验性自身免疫性肾小球肾炎在他们的动物模型是 与人类Goodpastures综合征的抗原相同。这种哺乳动物 模型提供了一种独特的格式来检查自身免疫性疾病的发病事件， 肾小球肾炎，以前没有，因为缺乏一个 合适的动物模型。 从这个模型中得到的信息可能是 直接适用于人类疾病对应物，Goodpastures 综合征，可能还有其他类型的肾小球肾炎。

DESCRIPTION (Adapted from Applicant's Abstract): Glomerulonephritis in man is a major cause of patient morbidity, mortality, and need for dialysis support and transplantation. Human glomerulonephritis appears in most, if not all, cases to be related to autoimmune causes. Much indirect evidence suggests that cell mediated immunity plays an important role in the development of glomerulonephritis. There are extensively studied models of experimental glomerulonephritis induced by administration of performed antibodies to constituents of the kidney, deposition of antigens followed by antibody in the kidney, or deposition of circulating performed immune complexes. Other endogenous models of systemic immune complex disease damage the kidney in its by stander role. These models do not lend themselves to the study of pathogenetic events involved with cell mediated immunity in the production of autoimmune glomerulonephritis when the kidney itself is the target. A model of proliferative experimental autoimmune glomerulonephritis has not previously been developed in an inbred mammalian species. We have utilized a novel approach to expose a nephritogenic antigen and have developed a new model of experimental autoimmune glomerulonephritis in inbred syngeneic rats. This model allows, for the first time, application of biologic tools to investigate pathogenetic mechanisms in the production of proliferative glomerulonephritis not previously available. The long term objectives of the present proposal are to continue their investigations into the mechanisms by which cell mediated immunity contributes to the pathogenesis of glomerulonephritis in this new model and to further delineate the interaction of cell mediated immunity and classic antibody mediated damage in this process. The specific aims of the present proposal are: 1) to better characterize the development and natural course of this experimental autoimmune glomerulonephritis with time dose clinicopathologic studies; 2) to examine the role of antibody in development and assess the independent role of antibody alone and with cells in production of disease using passively transferred antibody and hybridomas; 3) to examine the role of cell mediated immunity in pathogenesis by adoptive transfer studies, induction in B cell deficient rats, and studies with antigen specific T cell clones; 4) to identify nephitogenic peptide(s) responsible for induction of experimental autoimmune glomerulonephritis, fractionate these peptide into minimal immunogenic fragments, and determine their amino acid sequence, then generate peptide and analog and examine them for production and prevention of disease. Indirect evidence strongly suggests that the antigen which causes experimental autoimmune glomerulonephritis in their animal model is the same antigen that causes Goodpastures syndrome in man. This mammalian model provides a unique format to examine pathogenetic events in autoimmune glomerulonephritis not previously available because of lack of an appropriate animal model. Information derived from this model may be directly applicable to the human disease counter part, Goodpastures syndrome, and possibly other types of glomerulonephritis.