AUGMENTATION OF THE TRANSFUSION EFFECT

输血会产生一种强大而持久的免疫抑制作用 对人和实验动物的影响都是供者特有的 而且不明确。这种免疫抑制效应早在24年就出现了。 在输血几小时后，从而使捐赠者特定的输血 在身体和活体亲属供体移植中都很有用。嫁接 与输血有关的耐受性是一种积极的 涉及特异性和非特异性免疫反应的免疫过程 特异性巨噬细胞和T淋巴细胞抑制细胞网络。这个 输血效应在一定程度上是由细胞释放的二十烷类化合物介导的。 小剂量的环孢素可增强巨噬细胞的功能。 亚油酸，前列环素类似物伊洛前列素， 稳定的前列腺素类似物16，16-二甲基前列腺素E_2和脂氧合酶 途径抑制因子NDGA。反之，输血效果降低或 通过注射吲哚美辛(一种环氧合酶途径)消除 抑制物)抗CD4单抗(它消除了 抑制诱导细胞)、高剂量环孢素和高剂量环孢素 类固醇。拟议研究的长期目标是进一步完善 提高动物体内供体特异性输血效果的方法学 它可以应用于人类以实现永久或持久的宽容 移植到有轻微或长期免疫抑制的同种异体移植。特定的 拟议研究的组成部分包括多模式的优化 治疗，首先通过定义抗CD3抗体的最佳剂量反应， 伊洛前列素、NDGA、16，16二甲基前列腺素E_2和亚油酸单独和在 联合，首先在大鼠的筛选模型中，然后在验证中 大鼠和狗的模型。调查员以前的实验室研究 已经导致了一项临床方案的开发，用于两个在世的亲属 供体和身体肾移植，涉及给药 供体特异性输血，环孢素和酮康唑开始一次 移植前一天。这项临床试验将进行 并应导致更有效、更安全和成本更低的模式 对人类免疫抑制的影响。

Blood transfusions exert a powerful and long lasting immunosuppressive effect in both man and experimental animals which is both donor specific and non-specific. This immunosuppressive effect occurs as early as 24 hours after blood administration, thus making donor specific transfusions useful in both cadaveric and living related donor transplants. Graft tolerance associated with the administration of blood is an active immunologic process involving the development of both specific and non- specific macrophage and T lymphocyte suppressor cell networks. The transfusion effect is mediated in part by eicosanoids released from the macrophages and can be augmented by low doses of cyclosporine, the administration of linoleic acid, the prostacyclin analogue Iloprost, the stable prostaglandin analogue 16, 16 dimethyl PGE2, and the lipoxgenase pathway inhibitor NDGA. Conversely, the transfusion effect is reduced or eliminated by the administration of indomethacin (a cyclooxygenase pathway inhibitor) anti-CD4 monoclonal antibodies (which eliminates a subset of suppressor inducer cells), high doses of cyclosporin and high doses of steroids. The long-term goal of the proposed studies is to further refine methodologies to augment the donor specific transfusion effect in animals which can be applied to man to achieve permanent or long-lasting tolerance to an allograft with minimal or no long-term immunosuppression. Specific components of the proposed studies include optimization of multi-modality therapy, first by defining optimal dose responses for anti-CD3 antibodies, Iloprost, NDGA, 16, 16 dimethyl PGE2, and linoleic acid alone and in combination, first in a screening model in rats and then in verification models in rats and dogs. The investigator's previous laboratory studies have led to the development of a clinical protocol for both living related donor and cadaveric renal transplants which involves the administration of donor specific transfusions, cyclosporine and ketoconazole beginning one day prior to transplant. This clinical trial will be performed concurrently and should lead to more effective, safer and less costly modes of immunosuppression in man.