IMMUNOPATHOLOGIC STUDIES OF HEYMANN NEPHRITIS

本提案的主要目的是确定 影响免疫复合物的肾小球上皮下定位。 这些 研究将利用良好表征的膜性Heymann大鼠模型， 肾病 此前的调查引发了关于 原位与循环免疫复合物机制对上皮下 存款形成。 我们实验室最近的数据证实， 这两种机制都在Heymann肾炎的发展中起作用。 初步结果表明，抗原独特的化学特征， 海曼肾炎，以及抗体的性质可能有利于 该动物中免疫复合物的上皮下定位部位 膜性肾病模型。 该提案旨在澄清 这些因素。 肾小球毛细血管壁和血管壁之间的相互作用 肾小管抗原将在进一步纯化 抗原。 抗体亲和力对抗体清除率的影响 循环复合物的单核吞噬细胞系统和网站的 将确定组织定位。 了解抗体的作用 亲和力对人膜性肾病具有治疗意义。 证实较高抗体亲和力与较温和抗体亲和力之间的关联。 疾病将表明产生高亲和力的免疫刺激 抗体可能是成功的治疗方法。 这将是一 作为包括免疫抑制在内所有当前治疗的重要进展 只带来了一定的好处 本提案的最终目标是 确定上皮下存款的每种机制的相对贡献 形成，循环免疫复合物和原位结合，以充分 发展疾病。

The primary objective of this proposal is to define the factors that influence glomerular subepithelial localization of immune complexes. These studies will utilize the well characterized Heymann rat model of membranous nephropathy. Prior investigations have generated controversy regarding the in situ versus circulating immune complex mechanisms for subepithelial deposit formation. Recent data from our laboratory have confirmed that both mechanisms play a role in the development of Heymann nephritis. Preliminary results suggest that chemical features unique to the antigen in Heymann nephritis, as well as properties of the antibody may favor the subepithelial site of localization of the immune complexes in this animal model of membranous nephropathy. This proposal is designed to clarify these factors. Interactions between the glomerular capillary wall and the renal tubular antigen will be evaluated following further purification of the antigen. The influence of antibody affinity on the clearance of the circulating complexes by the mononuclear phagocyte system and site of tissue localization will be determined. Understanding the role of antibody affinity has therapeutic implications for human membranous nephropathy. Confirmation of the association of higher antibody affinity with milder disease would suggest that immunostimulation of production of high affinity antibody may be successful therapeutic approach. This would be an important advance as all current treatment which includes immunosuppression has been only moderately beneficial. The final goal of this proposal is to define the relative contribution of each mechanism of subepithelial deposit formation, circulating immune complex and in situ binding, to the full development disease.