DISCORDANT XENOGRAFTING

在符合以下条件的物种之间进行立即血管化器官移植 在系统发育上相距甚远的，称为不协调种 联合，导致超急性排斥反应。论超急性发作的基础 排斥反应可能涉及(I)结合受体的天然抗体 对供体血管内皮细胞，(Ii)随后被激活的补体 与天然抗体结合或通过替代途径结合，以及(Iii) 供体器官内皮细胞的激活导致 血管内血栓形成。超急性排斥反应的情况包括 血管内皮细胞激活的常见后果是什么： 细胞渗入血管外间隙，浮肿，沉积 内皮上的粒细胞和血小板与血栓形成。 超急性排斥反应可以在短短15分钟内发生，但通常 在2小时内完成，在某种程度上取决于不和谐 研究了物种组合。过去的研究在大多数情况下都试图 部分，干扰三个相关领域中的一个或另一个 如上所述的超急性排斥反应。我们的假设是为了避免 超急性排斥将有必要干扰几个 排斥反应过程的发病特点。尤其重要的是， 我们认为，仔细评估干预措施可能会防止 血管内皮细胞激活或干扰其后果。我们 然而，相信这样的干预必须在动物身上尝试 哪些天然抗体作用和补体作用受到了损害 尽最大可能。这样的实验在这里被提出。 我们将把豚鼠心脏移植到大鼠身上(在非常罕见的情况下，我们 应使用新生微型猪心脏作为捐赠器官)。我们计划耗尽 天然抗体，并试图保持极低水平的这种 抗体主要通过使用免疫抑制药定向 产生天然抗体的B细胞。我们应该用眼镜蛇的毒液 消除替代性和经典性补体作用的因素 小路。它的背景是耗尽的天然抗体和 妥协的补充，我们将测试各种干预处理 伴随着内皮细胞的激活或激活的后果。后 对不同治疗方案的单独评估，我们计划联合 治疗策略在很大程度上基于免疫病理学 拒绝心，我们希望从这些研究中了解到哪些策略是 在试图避免超急性排斥反应方面真正起到补充作用。

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.