Experimental Autoimmune Nephritis: Epitope Spreading in Pathogenesis and Control

实验性自身免疫性肾炎：发病机制和控制中的表位扩散

基本信息

批准号：
8033245
负责人：
Warren Kline BOLTON
金额：
$ 30.69万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-07 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8033245
关键词：
Address Amino Acids Animal Model Animals Antigens Autoimmune Diseases Autoimmune Process B-Lymphocytes Back Cartoons Cells Collagen Type IV Data Deposition Detection Disease Disease Progression Down-Regulation End stage renal failure Environment Epitopes Equilibrium Equipment Event Excision Experimental Animal Model Experimental Models Feedback Future Generations Glomerulonephritis Healthcare Heymann Nephritis Antigenic Complex Histology Human Immune Immune System Diseases Immune response Immunization Immunosuppression Inbred WKY Rats Injury Interferons Interleukin-2 Interleukin-4 Interruption Intervention Investigation Kidney Knowledge Laboratories Lead Literature Modeling Molecular Molecular Mimicry Morbidity - disease rate Nephritis Nephrotoxic Operative Surgical Procedures Pathogenesis Patients Peptides Phenotype Principal Investigator Process Proteins Rat Protein Rattus Regulation Regulatory Element Regulatory T-Lymphocyte Renal function Research Resources Role Site Study Section Suggestion System T cell response T-Lymphocyte T-Lymphocyte Epitopes TNF gene Therapeutic Time Tissues Up-Regulation Work antigen processing cytokine enzyme linked immunospot assay feeding glomerular basement membrane human disease lymph nodes man mimetics novel strategies programs response

项目摘要

DESCRIPTION (provided by applicant): End stage renal disease is a major health care problem in the U.S. Glomerulonephritis is the third leading cause of end stage renal disease. Most cases of glomerulonephritis are of autoimmune origin but the etiologic antigen is usually not known. In the autoimmune glomerulonephritis Goodpasture's disease, the etiologic antigen is known to be a chain of type IV collagen, a3(IV) NC1, found in the glomerular basement membrane of the kidney. Despite identification of this antigen, much remains unknown about initiation, disease progression, and control. We have developed a model, experimental autoimmune glomerulonephritis, which recapitulates Goodpasture's disease. We have identified the immunodominant T cell epitope on a3(IV) NC1 and showed that the antigen causes spreading to other epitopes on a3 and a4 (IV)NC1 but not to additional glomerular antigens, (intra- and intermolecular epitope spreading). We also present evidence that a feedback loop between the kidney and its draining lymph node may be involved in epitope spreading and generation of regulatory T cells which appear in the nephritic kidneys. Other models have shown that epitope spreading is associated with amplification of immune response and disease progression, and that interruption of epitope spreading can ameliorate disease expression. We hypothesize that epitope spreading occurs to a discrete number of identifiable epitopes, that recruitment of effector and regulatory T-cells in the closed-loop environment of the kidney and kidney draining lymph node with local antigen processing are mechanisms of disease induction and regulation, and that induction of an early regulatory T cell response may ameliorate the natural course of the disease. In the present proposal we will 1) identify T cell immunodominant and subdominant spread epitopes on a3(IV) and a3(IV)NC1 proteins, 2) study the mechanisms involved in epitope spreading, and 3) assess the effect of regulatory T cells on the initiation and progression of experimental autoimmune glomerulonephritis. We hypothesize that interruption of the local kidney lymph node feed back loop and amplification of regulatory T cell response will ameliorate the course and down-regulate disease expression. Since experimental autoimmune glomerulonephritis recapitulates Goodpasture's disease in man, the information should lead to a better understanding of the pathogenesis and possible intervention in human disease.

描述（由申请人提供）：在美国肾小球肾上腺炎中，末期肾脏疾病是末期肾脏疾病的第三主要原因。肾小球肾炎的大多数病例都是自身免疫性起源，但病因学抗原通常尚不清楚。在自身免疫性肾小球肾炎善良疾病中，病因学抗原是IV型胶原蛋白A3（iv）NC1的链条，在肾脏的肾小球基底膜中发现。尽管鉴定出这种抗原，但在开始，疾病进展和控制方面仍不清楚。我们已经开发了一种模型，实验性自身免疫性肾小球肾炎，该肾上腺炎概括了Goodpasture病。我们已经确定了A3（IV）NC1上的免疫主导T细胞表位，并表明抗原引起的原因扩散到A3和A4（IV）NC1上的其他表位，但未向其他肾小球抗原（内部和分子性表现力扩散）。我们还提供了证据表明，肾脏及其排水淋巴结之间的反馈回路可能参与了出现在肾肾脏中的调节性T细胞的表位扩散和产生。其他模型表明，表位扩散与免疫反应和疾病进展的扩增有关，并且表位扩散的中断可以改善疾病的表达。 We hypothesize that epitope spreading occurs to a discrete number of identifiable epitopes, that recruitment of effector and regulatory T-cells in the closed-loop environment of the kidney and kidney draining lymph node with local antigen processing are mechanisms of disease induction and regulation, and that induction of an early regulatory T cell response may ameliorate the natural course of the disease.在本提案中，我们将1）确定T细胞免疫主导和亚抑制剂扩散表位在A3（IV）和A3（IV）NC1蛋白上，2）研究涉及表位扩散所涉及的机制，以及3）评估调节性T细胞对实验自身自身自身免除肾小球肾小球的启动和进展的作用。我们假设当地肾脏淋巴结向后循环中断，调节性T细胞反应的扩增将改善病程并下调疾病的表达。由于实验性自身免疫性肾小球肾炎概括了人类中的良好疾病，因此该信息应更好地理解对人类疾病的发病机理和可能的干预。