PATHOGENESIS OF EXPERIMENTAL GLOMERULONEPHRITIS

这项建议的主要目标是研究 对肾脏的免疫损伤负责。 虽然抗体介导 肾小球疾病已经在实验动物中成功地建模 我们对细胞介导的损伤的认识 涉及外源抗原的研究受到缺乏 合适的实验模型。 几种形式的人类肾脏疾病是 据信是由细胞介导的免疫损伤引起的， 然而，由外来抗原引起的， 损伤的类型，以及可以调节这种表达的条件， 肾脏损伤的认识很少。 最近的细胞培养研究 已经阐明了有效抗原所需的许多关键步骤， 通过巨噬细胞和其他细胞类型呈递。 这些新见解 应该证明在设计旨在证明 选择的肾单位节段的内在细胞的潜在能力， 成为致敏T细胞的目标，并积极参与 由迟发型超敏反应引发的疾病。 双 体内和细胞培养超敏实验方法 反应. 具有体内和细胞培养实验的双重方法将 在这些研究中进行跟踪，以证实潜在的 在这些研究中将遵循重要性，以努力证实 体外观察在发病机制中的潜在意义 发生在完整动物器官上的疾病过程。 细胞 肾小球将以纯的形式和在完整的动物中分离。 来自肾小球的细胞将以纯的形式分离并培养在培养皿中。 影响以下基因产物的细胞表面表达的条件 主要组织相容性复合体 抗原摄取、加工和 将研究肾小球细胞对纯化的T细胞的呈递 遵循旨在影响细胞内重新路由的策略，或 抗原的溶酶体加工过程。 最佳抗原的条件 然后将在培养细胞中的呈递应用于体内实验。 在完整动物中用抗原或半抗原靶向选定细胞 将通过化学修饰和/或通过偶联 适当选择的抗原与已知的 的特异性 通过各种途径主动免疫动物的研究， 用纯化的效应细胞或T细胞系的过继转移实验 将探讨各种类型的淋巴细胞在结构和 疾病的功能表达。 其他体内研究旨在 在评估选定的细胞因子的潜在调节作用。 这些 这些研究应该为细胞介导的 对肾脏的免疫损伤。

The broad objective of this proposal is the study of the mechanisms responsible for immunologic damage to the kidney. While antibody-mediated glomerular diseases have been modeled successfully in experimental animals and studied in detail, advances in our knowledge of cell-mediated injury involving foreign antigens have bee hampered substantially by the lack of suitable experimental models. Several forms of human renal diseases are believed to results from a cell-mediated immune injury, possibly-activated by foreign antigens, however, the precise mechanisms responsible for this type of damage, and conditions that could modulate the expression of such injury in the kidney are poorly understood. Recent cell culture studies have unraveled many of the critical steps required for effective antigen presentation by macrophages and other cell types. These new insights should prove useful in the design of studies aimed at demonstrating the potential capacity of intrinsic cells of selected nephron segments to become the target for sensitized T cells and to actively participate in diseases triggered by delayed type hypersensitivity reactions. A dual approach with in vivo and cell culture experiments hypersensitivity reactions. A dual approach with in vivo and cell culture experiments will be followed in these studies in an effort to corroborate a potential significance will be followed in these studies in an effort to corroborate a potential significance of in vitro observations in the pathogenesis of disease processes that befall an organ in the intact animal. Cells from the glomerulus will be isolated in pure form and in the intact animal. Cells from the glomerulus will be isolated in pure form and cultured under conditions that influence cell surface expression of the gene products of the major histocompatibility complex. Antigen uptake, processing, and presentation to purified T cells by glomerular cells will be studied following strategies designed to influence the intracellular re-routing or the lysosomal processing of antigens. Conditions for optimal antigen presentation in cultured cells will then be applied to in vivo experiments. Targeting of selected cells with antigens or haptens in the intact animal will be accomplished by chemical modification and/or by coupling of appropriately selected antigens to monoclonal antibodies of known specificity. Studies on animals actively immunized by various routes and adoptive transfer experiments with purified effectors cells or T cell lines will explore the role of various types of lymphocytes in the structural and functional expression of the disease. Additional in vivo studies are aimed at evaluating potential modulating effects by selected cytokines. These studies should provide key new insights into mechanisms of cell-mediated immune injury to the kidney.