DISCORDANT XENOGRAFTING

移植立即血管化的器官在物种之间， 在遗传学上广泛分离的，称为不协调种 组合，导致超急性排斥反应。 超急性基础 排斥可能涉及（i）受体的天然抗体， 供体血管内皮，（ii）随后被激活的补体 与天然抗体结合或通过替代途径，和（iii） 供体器官的内皮细胞活化，导致 血管内血栓形成 超急性排斥反应的图片包括 内皮细胞激活的普遍接受的后果是什么： 细胞外渗到血管外空间，水肿， 内皮上的粒细胞和血小板以及血栓形成。 超急性排斥反应可在短至15分钟内发生，但通常是 在2小时内完成，在某种程度上取决于不和谐的 品种组合研究。 过去的研究试图，大多数 部分，干扰一个或其他三个领域有关， 超急性排斥反应如上所述。 我们的假设是为了避免 超急性排斥反应，将有必要干预的几个 排斥过程的病理特征。 尤其重要的是， 我们的想法是仔细评估可能阻止 内皮细胞活化或干扰其结果。 我们 然而，我认为必须在动物身上尝试这种干预措施， 天然的抗体作用和补体作用已经被破坏 尽可能地。 本文提出了这样的实验。 我们将把豚鼠的心脏移植给大鼠（在非常罕见的情况下，我们 将使用新生的微型猪心脏作为供体器官）。 我们计划耗尽 并试图维持非常低水平的这种抗体 抗体主要通过使用免疫抑制剂定向 产生天然抗体的B细胞。 我们应该用眼镜蛇的毒液 消除替代和经典补体作用的因子 途径。 它是在天然抗体耗尽的背景下， 我们将测试各种干预措施， 与内皮细胞活化或活化后的情况有关。 后 在对各种治疗方案进行单独评估后，我们计划将联合收割机 治疗策略主要基于免疫病理学的 拒绝心脏，从这些研究中，我们希望了解哪些策略是 真正的互补，以避免超急性排斥反应。

Transplantation of immediately vascularized organs between species that are phylogenetically widely separated, referred to as discordant species combinations, results in hyperacute rejection. The basis of hyperacute rejection likely involves (i) natural antibodies of the recipient that bind to donor vascular endothelium, (ii) complement that is activated consequent to natural antibody binding or via the alternative pathway, and (iii) activation of endothelial cells of the donor organ resulting in intravascular thrombosis. The picture of hyperacute rejection includes what are the commonly accepted consequences of endothelial activation: extravasation of cells into the extravascular space, edema, deposition of granulocytes and platelets on the endothelium and thrombosis. Hyperacute rejection can occur in as little as 15 minutes but is usually completed within 2 hours, depending in some measure on the discordant species combination studied. Past studies have attempted, for the most part, to interfere with one or the other of the three areas related to hyperacute rejection as outlined above. It is our hypothesis that to avert hyperacute rejection it will be necessary to interfere with several of the pathogenetic features of the rejection process. Especially important, to our mind, is the careful evaluation of interventions that may prevent endothelial cell activation or interfere in the consequences thereof. We believe, however, that such interventions must be attempted in animals in which natural antibody action and complement action have been compromised to the extent possible. Such experiments are proposed herein. We shall transplant guinea pig hearts to rats (n very rare instances, we shall use newborn micropig hearts as the donor organ). We plan to deplete natural antibodies and attempt to maintain very low levels of such antibodies primarily through the use of immunosuppressive agents directed at the B cells producing the natural antibodies. We shall use cobra venom factor to abrogate complement action of both the alternative and classical pathways. It is on a background of depleted natural antibodies and compromised complement that we shall test various interventions dealing with endothelial cell activation or the aftermath of activation. After the evaluation of various treatment protocols individually, we plan to combine therapeutic strategies based largely on the immunopathology of the rejecting hearts, from which studies we hope to learn which strategies are truly complementary in attempts to avert hyperacute rejection.