EICOSANOID MODULATION IN RAT RENAL ALLOGRAFT REJECTION

二十烷酸在大鼠肾同种异体移植排斥反应中的调节

• 批准号: 3463529
• 负责人: MARTIN D JENDRISAK
• 金额: $ 11.11万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-01 至 1993-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3463529
• 关键词: arachidonate; cell mediated lymphocytolysis test; cellular immunity; dendritic cells; disease /disorder model; dyes; eicosanoid metabolism; high performance liquid chromatography; histocompatibility; immunopharmacology; immunosuppression; kidney function; kidney transplantation; laboratory rat; lipoxygenase; mixed lymphocyte reaction test; prostaglandin endoperoxide synthase; radioimmunoassay

Renal allografts undergoing acute rejection demonstrate augmented metabolism of arachidonic acid (AA) to form a variety of cyclooxygenase (CO) and lipoxygenase (LO) products. These products of AA metabolism, or eicosanoids, exert powerful effects on net renal function as well as directly on the immune system (initial pilot studies in the mouse model). This proposal investigates the role of altered eicosanoid production on immune cell function during renal allograft rejection in the rat model with the specific aim that a novel form of controlled immunosuppression can be achieved. Additionally, a new concept is proposed whereby an efficient means of mesangial dendritic cell depletion from donor renal tissue can be accomplished via pharmacologic manipulation a AA metabolism prior to allotransplantation. The relationship between localization of these resident leukocytes and eicosanoid production has been demonstrated but remains incompletely understood. The effects of alterations in AA metabolism directly upon immune active cells in the rat spleen will initially be studied by lectin proliferation assays, cell mediated cytotoxicity assays, mixed lymphocyte reactions, and interleukin-2 production. Using a rat renal allograft mode, similar immunologic studies as well as subset analysis of graft infiltrating cells will be performed. Qualitative and quantitative changes in AA metabolism will be monitored by RP-HPLC profiles of radiolabeled products derived from 3H-AA substrate and radioimmunoassay, respectively. The strategy will be to inhibit "pro-rejection" eicosanoids (TXA2, LO products) and enhance "anti-rejection" eicosanoids PGI2, PGE2) by administering compounds which alter AA metabolism either alone or in combination. It is hypothesized that controlled alterations in AA metabolism can yield a controlled downregulation of the rejection response with improvement in allograft survival. Correlations of alterations in immune cell function through manipulations in eicosanoid production may enhance our understanding of mechanisms involved in acute rejection. Through this unique model of altered AA metabolism, the role of donor tissue dendritic cells can also be assessed.

发生急性排斥反应的肾移植 增强花生四烯酸（AA）的代谢，形成多种 环氧合酶（CO）和脂氧合酶（LO）产物。 这些 AA代谢产物或类二十烷酸， 对净肾功能的影响以及对免疫系统的直接影响 系统（小鼠模型中的初步试验研究）。 这项建议 研究了改变类花生酸的产生对免疫系统的作用， 大鼠肾移植排斥反应中细胞功能的变化 一种新形式受控的特定目标是， 可以实现免疫抑制。 此外，一个新概念 提出了一种有效的手段，系膜树突状细胞， 从供体肾组织中去除细胞可以通过 药理学操作AA代谢之前， 同种异体移植 本土化与 这些固有的白细胞和类花生酸的产生， 已被证明，但仍不完全理解。 的影响 AA代谢的改变直接影响免疫活性 大鼠脾脏中的细胞最初将通过凝集素 增殖试验，细胞介导的细胞毒性试验，混合 淋巴细胞反应和白细胞介素-2的产生。 使用大鼠 肾移植模型，类似的免疫学研究以及 进行移植物浸润细胞的亚群分析。 AA代谢的质和量的变化将是 通过放射性标记产物的RP-HPLC图谱进行监测， 分别从~ 3 H-AA底物和放射免疫法测定。 的 策略将是抑制“促排斥”类花生酸（TXA 2，LO 产品）和增强“抗排斥”类二十烷酸PGI 2，PGE 2）， 单独给予改变AA代谢的化合物 或组合。 据推测，控制性改变 在AA代谢中可以产生一个可控的下调， 排斥反应与移植物存活率的改善。 免疫细胞功能改变的相关性 操纵类花生酸的产生可能会提高我们的 了解急性排斥反应的机制。 通过这种改变AA代谢的独特模型， 也可以评估供体组织树突细胞。