EFFECTS OF ORTHOTOPIC LIVER TRANSPLANTATION

实现之前的拨款目标使我们能够回到 实验室进行新的调查。第一，更好的免疫抑制 药物评估将重点放在：一种抗T淋巴细胞 药效是环孢素(FR900506)的500-1000倍， 它抑制白介素2的产生；以及脱氧精灵，一种 较弱但新型的免疫抑制剂，作用于 巨噬细胞水平的体外免疫反应技术将 用来研究其对同种异体活化的T淋巴细胞和 包括单核细胞在内的其他细胞群，固有的 待测药物的细胞毒性，其作用机制 免疫抑制以及与其他药物的协同作用的评估 毒品。大鼠移植(肾脏、异位心脏和 (肝脏)、狗(肾脏、肝脏、心脏、胰腺、肠道)和狒狒 (肾脏和肝脏)将用于测试剂量/功效关系， 协同作用，药代动力学，物种和器官特有的因素， 和毒性。这些研究的可行性和价值一直是 在初步实验中得到了明确的证明。 第二，提出了药理学技术来预防 移植肾急性或超急性排斥反应的预制细胞毒性或 使用前列腺素和其他抗移植物抗体 炎症反应的调节剂和使用抑制剂 (血小板活化因子抑制物、血栓素A2合成酶 超氧化物歧化酶)的病理生理级联反应 由于组织损伤而启动，进而导致不可逆转的 微血管损伤。测试模型将是猪对狗的 中国肾移植和异位心脏移植 预敏大鼠。预防超急性反应的惊人能力 对这种方法的拒绝已经被明确地证明了 在使用模型进行的初步实验中。 第三，将使用相同的介体、调节体和抑制物 在大鼠和狗的移植和非移植中单独和联合使用 移植模型保护肝脏免受常温和 低温损伤，目的是延长 安全保存。非移植缺血模型已经有了 在这两个物种中都是标准化的，并且是唯一的 犬对乙酰氨基酚中毒模型的建立。这项计划的可行性 建议的治疗方法已在初步研究中得到证实。 作为一个整体，这项工作的设计是为了增加安全性， 各种器官移植的成本、效率和适用性 程序，从而改善病人护理。任何一种技术的进步 任何器官(肝脏、肾脏或心脏)的建议区域 应该适用于所有的器官。

Fulfillment of previous grant objectives allows us to return to the laboratories to new inquiries. First, better immunosuppressive drugs will be assessed with emphasis upon: an anti-T lymphocyte agent 500-1000 times more potent than cyclosporine (FR900506), which inhibits interleukin 2 production; and deoxyspergualin, a weaker but novel immunosuppressant which acts at the macrophage level of the immune response in vitro techniques will be used to study the effects upon alloactivated T-lymphocytes and other cell populations including monocytes, the intrinsic cytotoxicity of agents to be tested, the mechanisms of immunosuppression, and the assessment of synergism with other drugs. Transplantation in rats (kidney, heterotopic heart, and liver), dogs (kidneys, liver, heart, pancreas, intestine) and baboons (kidney and liver) will be used to test dose/efficacy relations, synergism, pharmacokinetics, species and organ specific factors, and toxicity. The feasibility and value of these studies has been demonstrated unequivocally in preliminary experiments. Second, pharmacologic techniques are proposed to prevent the acute or hyperacute rejection of grafts by preformed cytotoxic or other antigraft antibodies by using prostaglandins and other modulators of the inflammatory response and by using inhibitors (platelet activating factor inhibitors, thromboxane A2 synthetase inhibitor, superoxide dismutase) of the pathophysiologic cascade set into motion by tissue injury which in turn leads to irreversible injury of the microvasculature. The test models will be pig to dog renal transplantation and heterotopic heart transplantation in presensitized rats. The astonishing ability to prevent hyperacute rejection with this approach has been unequivocally demonstrated in preliminary experiments using models. Third, the same mediators, modulators, and inhibitors will be used singly and in combination in rat and dog transplant and non- transplant models to protect livers from normothermic and hypothermic injury with the objective of prolonging the period of safe preservation. Non-transplant ischemia models already have been standardized in both species as well as a unique acetaminophen toxic model in dogs. The feasibility of the proposed therapy has been proved in preliminary studies. Taken as a whole, the work is designed to increase the safety, cost, efficiency, and applicability of all kinds of organ grafting procedures, thereby improving patient care. Advances in any of the proposed areas with any of the organs (liver, kidney, or heart should be applicable to all of the organs.