ORTHOTOPIC LIVER TRANSPLANTATION

实现以前的赠款目标使我们能够回到 实验室新的调查。 首先，更好的免疫抑制 药物评估的重点是：抗T淋巴细胞 比环孢菌素（FR 900506）强500-1000倍的药剂， 抑制白细胞介素2的产生;脱氧精胍菌素， 较弱但新颖的免疫抑制剂， 巨噬细胞水平的免疫反应在体外技术将 用于研究对同种异体活化的T淋巴细胞的影响， 其他细胞群，包括单核细胞、内源性 待测试剂的细胞毒性， 免疫抑制，并评估与其他 毒品 大鼠移植（肾脏、异位心脏和 肝脏）、犬（肾脏、肝脏、心脏、胰腺、肠）和狒狒 （肾脏和肝脏）将用于检验剂量/疗效关系， 协同作用、药代动力学、种属和器官特异性因素， 和毒性。 这些研究的可行性和价值已经得到 在初步实验中得到了明确的证明。 第二，提出了药物技术来防止 由于预先形成的细胞毒性或 通过使用野牡丹素和其它抗移植物抗体 炎症反应的调节剂和通过使用抑制剂 （血小板活化因子抑制剂，血栓烷A2合成酶 抑制剂，超氧化物歧化酶 通过组织损伤启动，这反过来导致不可逆的 微血管损伤。 测试模型将是猪对狗 肾移植和异位心脏移植 致敏大鼠 惊人的能力，防止超急性 对这种方法的拒绝已经被明确地证明了 在初步实验中使用模型。 第三，将使用相同的介质、调节剂和抑制剂 在大鼠和狗移植中单独和组合使用， 移植模型，以保护肝脏免受正常体温和 低温损伤，目的是延长 安全保存。 非移植缺血模型已经有 在这两个物种中已经标准化， 对乙酰氨基酚中毒模型。 的可行性 所提出的疗法已在初步研究中得到证实。 总的来说，这项工作旨在提高安全性， 各种器官移植的成本、效率和适用性 从而改善患者护理。 任何进展 任何器官（肝脏、肾脏或心脏）的拟议区域 应适用于所有机关。

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.