PATHOGENESIS OF EXPERIMENTAL GLOMERULONEPHRITIS

这项建议的总体目标是研究这些机制 对肾脏的免疫损伤负责。而抗体介导的 肾小球疾病已经在实验动物身上成功地建立了模型 并详细研究了我们对细胞介导的损伤知识的进展 涉及外来抗原的问题由于缺乏 合适的实验模型。人类肾脏疾病有几种形式 被认为是细胞介导的免疫损伤的结果，可能是被激活的 然而，通过外来抗原，导致这一现象的确切机制 损伤的类型，以及可能调节这种表达的条件 人们对肾脏损伤知之甚少。细胞培养研究近况 已经解开了有效抗原所需的许多关键步骤 巨噬细胞和其他细胞类型的呈递。这些新见解 应该被证明在设计研究的目的是证明 所选肾单位节段固有细胞的潜在能力 成为致敏T细胞的靶点并积极参与 由迟发性超敏反应引发的疾病。双人对决 体内和细胞培养实验超敏反应的探讨 反应。体内和细胞培养实验的双重方法将 在这些研究中被跟踪，以努力证实一个潜在的 在这些研究中将遵循重要意义，以努力证实 体外观察在急性髓系白血病发病机制中的潜在意义 疾病发生在完好动物的器官上的疾病过程。单元格来自 肾小球将以纯净的形式在完好的动物体内被分离。 来自肾小球的细胞将以纯形式分离并在 影响细胞表面表达基因产物的条件 主要组织相容性复合体。抗原摄取、处理和 将研究肾小球细胞对纯化T细胞的呈递 遵循旨在影响小区内重新路由或 抗原的溶酶体加工。最佳抗原的条件 然后，在培养细胞中的呈现将被应用于体内实验。 用抗原或半抗原在完整动物体内靶向选定的细胞 将通过化学修饰和/或通过偶联 已知的单抗的适当选择的抗原 专一性。不同途径主动免疫动物的研究和应用 纯化效应细胞或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免疫反应中的作用 疾病的功能性表达。旨在进行更多的体内研究 在评估选定的细胞因子的潜在调节作用方面。这些 研究应该为细胞介导的机制提供关键的新见解 对肾脏造成免疫损伤。

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.