EICOSANOID MODULATION IN RAT RENAL ALLOGRAFT REJECTION

接受急性排斥反应的同种异体肾移植显示 增强花生四烯酸(AA)的代谢，形成一种 环氧合酶(CO)和脂氧合酶(LO)产物。这些 AA代谢产物，或二十烷类化合物，发挥强大的 对净肾功能的影响以及对免疫的直接影响 系统(在小鼠模型中的初步试点研究)。这项建议 研究二十烷类化合物的变化在免疫中的作用 大鼠同种异体肾移植排斥反应中的细胞功能 一种新的受控形式的具体目的是 免疫抑制是可以实现的。此外，一个新的概念 提出了一种有效的系膜树突形成方法 从供体肾组织中去除细胞可通过以下途径完成 药理操作前的AA代谢 同种异体移植。本土化与本土化的关系 这些滞留的白细胞和二十烷类化合物的产生 已证实，但仍未完全了解。其影响 AA代谢的改变直接取决于免疫活性 大鼠脾细胞最初将通过凝集素进行研究 混合细胞增殖试验、细胞介导的细胞毒性试验 淋巴细胞反应和白介素2的产生。使用老鼠 肾移植模式，类似的免疫学研究以及 将进行移植物浸润性细胞亚群分析。 AA代谢的质和量的变化将是 用反相高效液相色谱法监测衍生放射性标记产品的图谱 分别来自~3H-AA底物和放射免疫测定法。这个 策略将是抑制“促排斥”二十碳二糖(TXA2，LO 产品)，并通过以下方式增强抗排斥作用 单独应用改变AA代谢的化合物 或者组合在一起。据推测，控制了变化 在AA代谢中可以产生受控的下调 排斥反应与同种异体移植物存活率的改善。 免疫细胞功能改变的相关性通过 二十烷类化合物生产中的操纵可能会增强我们的 了解急性排斥反应的发生机制。 通过这一独特的AA代谢改变模型， 供体组织树突状细胞也可以被评估。

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.