AUGMENTATION OF THE TRANSFUSION EFFECT

输血发挥强大和持久的免疫抑制作用， 在人和实验动物中的作用都是供体特异性的 也不具体 这种免疫抑制作用发生早在24 在血液给药后数小时，从而使供体特异性输血 可用于尸体和活体相关供体移植。 移植物 与血液给药相关的耐受性是一种活性物质， 免疫过程，包括特异性和非特异性免疫系统的发展。 特异性巨噬细胞和T淋巴细胞抑制细胞网络。 的 输血作用部分是由释放的类二十烷酸介导的， 巨噬细胞，并可通过低剂量的环孢霉素， 给予亚油酸，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PGE2和脂氧合酶 途径抑制剂NDGA。 相反，输血效果降低或 通过给予吲哚美辛（环氧化酶途径）消除 抑制剂）抗CD4单克隆抗体（其消除了 抑制诱导细胞）、高剂量环孢菌素和高剂量 类固醇. 拟议研究的长期目标是进一步完善 在动物中增强供体特异性输血效应的方法 它可以应用于人类以获得永久或持久的耐受性 移植到具有最小或没有长期免疫抑制的同种异体移植物。 具体 拟议研究的组成部分包括优化多模态 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PGE2和亚油酸单独和联合给药 首先在大鼠筛选模型中，然后在验证中， 大鼠和犬模型。 研究者之前的实验室研究 已经导致了一个临床协议的发展， 供体和尸体肾移植，其中涉及施用 供体特异性输血，环孢素和酮康唑开始一个 移植前一天 本临床试验将在 应导致更有效、更安全和费用更低的模式 免疫抑制的作用。

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.