HUMAN MEDIATED XENOGRAFT REJECTION IN RAG-1 MUTANT MICE

小型猪，由于它们的体型，生理相似性， 人类，繁殖特征和可用性，是一个有吸引力的 临床异种移植的潜在供体。然而，研究 一个可接受的模型，其中人抗猪反应可以 直接在体内评价。猪皮排斥反应的小鼠模型 通过人外周血细胞的移植已经在这方面发展起来， 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物 需要免疫抑制R小鼠移植 猪皮肤移植物和用人外周血细胞重建 （Hu-R）作为人类免疫系统的模型，被发现能够 对猪皮移植物的排斥反应观察到的病理变化 在排斥移植物中的这些现象与在灵长类动物中观察到的非常相似 抗猪异种移植排斥反应，并可由纯化的人 CD 4 T细胞。这项建议的主要目的是研究机制， 的人抗猪细胞异种移植物反应， 这个Hu-R小鼠模型。具体目标是：（1）确定是否 人CD 8 T细胞和自然杀伤（NK）细胞参与猪 异种移植物; 3）确定猪主要 组织相容性（MHC）I类和I类抗原识别 人T细胞在抗猪应答中的作用;和4）确定 阻断粘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。发展 研究细胞免疫的小动物模型的特性 人细胞对体内不协调异种移植物的反应，将提供 一个方便的手段，问机械的重要问题， 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.