Basker M, Buhler L, Alwayn I P, Appel J Z, Cooper D K
Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, USA.
Expert Opin Pharmacother. 2000 May;1(4):757-69. doi: 10.1517/14656566.1.4.757.
The ability to transplant pig organs into humans would resolve the current crisis in the supply of cadaveric human organs for the treatment of end stage disease. Several immunologic barriers need to be overcome if pig-to-primate transplantation is to be successful. The presence of preformed antibodies in humans, apes and Old World monkeys directed against galactose epitopes on pig vascular endothelium provides the major barrier, as binding of antibody to antigen leads to graft destruction by complement activation and other mechanisms. Hyperacute rejection can result from the action of complement. If this is prevented, delayed antibody-mediated rejection develops, which can be associated with a state of consumptive coagulopathy (disseminated intravascular coagulation, DIC). Efforts being made to overcome antibody-mediated rejection include depletion of antibody by extracorporeal immunoadsorption, prevention of an induced antibody response by co-stimulatory blockade, B-cell and/or plasma cell depletion, depletion or inhibition of complement, or the use of organs from pigs transgenic for a human complement regulatory protein, such as hDAF. The ultimate solution would be the induction of both B- and T-cell tolerance to the transplanted pig organ, which is being explored by attempting to induce haematopoietic cell chimerism. One complication of this is a thrombotic microangiopathy, similar to thrombotic thrombocytopenic purpura. The many and diverse roles in which pharmacotherapy is involved in attempts to overcome the barriers of xenotransplantation are reviewed and current progress, particularly in our own laboratory, is discussed.
将猪器官移植到人类体内的能力将解决目前在为治疗终末期疾病提供人体尸体器官供应方面的危机。如果猪到灵长类动物的移植要取得成功，需要克服几个免疫障碍。人类、猿类和旧世界猴体内存在针对猪血管内皮上半乳糖表位的预先形成的抗体，这是主要障碍，因为抗体与抗原的结合会通过补体激活和其他机制导致移植物破坏。补体的作用可导致超急性排斥反应。如果预防了这种情况，就会发生延迟性抗体介导的排斥反应，这可能与消耗性凝血病（弥散性血管内凝血，DIC）状态有关。为克服抗体介导的排斥反应所做的努力包括通过体外免疫吸附清除抗体、通过共刺激阻断预防诱导性抗体反应、清除B细胞和/或浆细胞、清除或抑制补体，或使用转人类补体调节蛋白（如hDAF）基因的猪的器官。最终的解决方案将是诱导对移植的猪器官产生B细胞和T细胞耐受性，目前正在通过尝试诱导造血细胞嵌合体来探索这一点。其中一个并发症是血栓性微血管病，类似于血栓性血小板减少性紫癜。本文综述了药物治疗在克服异种移植障碍的尝试中所涉及的众多不同作用，并讨论了当前的进展，特别是我们自己实验室的进展。
