HUMAN MEDIATED XENOGRAFT REJECTION IN RAG-1 MUTANT MICE

小型猪，因为它们的体型，生理上与 人类的繁殖特点和可获得性，是一种诱人的 临床异种移植的潜在供者。然而，对其的研究 一种可接受的模型，其中人类抗猪反应可以是 直接在体内进行评估。一种研究猪皮排斥反应的小鼠模型 人类外周血细胞移植已经在这方面得到了发展。 实验室。RAG-1(重组酶激活基因-1)突变小鼠(R)， 缺乏成熟B和T细胞的人能够接受猪皮肤移植 无限期地需要免疫抑制。R-小鼠移植 猪皮肤移植及其与人外周血细胞的重组 (Hu-R)作为人类免疫系统的模型，被发现能够 拒绝猪的皮肤移植。观察到的病理变化 在排斥反应中的移植物与灵长类的移植物非常相似 抗猪异种移植排斥反应，并可由纯化的人介导 CD4T细胞。这项建议的主要目的是研究这一机制 人抗猪细胞异种移植反应的体内应用 这个HU-R小鼠模型。具体目标是：1)确定是否 人CD8 T细胞和自然杀伤(NK)细胞参与猪 异种移植；3)确定猪主要器官的相对重要性 组织相容性(MHC)I类和I类抗原识别 人T细胞在抗猪反应中的作用；以及4)确定 阻断人类表达的黏附分子之间的相互作用 白细胞和猪内皮细胞对异种移植排斥反应的影响。最新进展 以及研究细胞免疫的小动物模型的特征 人体细胞对体内非协调性异种移植的反应将提供 一种方便的方式来提出对 异种移植领域，并提供了一个实用的系统，其中 可以直接测试防止异种移植排斥反应的方法。

Miniature swine, because of their size, physiological similarity to humans, breeding characteristics and availability, are an attractive potential donor for clinical xenotransplantation. However, the study of an acceptable model in which the human anti-pig response can be evaluated directly in vivo. A mouse model to study rejection of pig skin grafts by human peripheral blood cells has been developed in this laboratory. RAG-1 (recombinase activating gene-1) mutant mice (R), lacking both mature B and T cells are able to accept porcine skin grafts indefinitely with the need of immunosuppression. R-mice engrafted with porcine skin grafts and reconstituted with human peripheral blood cells (Hu-R), as a model of the human immune system, were found to be capable of rejecting the porcine skin grafts. The pathological changes observed within rejecting grafts were remarkably similar to those seen in primate anti-porcine xenograft rejection, and can be mediated by purified human CD4 T cells. The major goal of this proposal is to study the mechanism of the human anti-porcine cellular xenograft response in vivo utilizing this Hu-R mouse model. The specific aims are to: 1) Determine whether human CD8 T cells and natural killer (NK) cells participate in pig xenografts; 3) Determine the relative importance of pig major histocompatibility (MHC) class I and class I antigen recognition by human T cells in the anti-pig response; and 4) Determine the effect of blocking the interactions between adhesion molecules expressed on human leukocytes and pig endothelium on xenograft rejection. The development and characterization of a small animal model to study cellular immune responses of human cells to discordant xenografts in vivo, will provide a convenient means to ask mechanistic questions of importance to the field of xenotransplantation, and provide a practical system in which approaches to prevent rejection of xenografts can be tested directly.