HUMAN MEDIATED XENOGRAFT REJECTION IN RAG-1 MUTANT MICE

RAG-1 突变小鼠中人介导的异种移植排斥

• 批准号: 6349830
• 负责人: John J Iacomini
• 金额: $ 17.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-15 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6349830
• 关键词: CD antigens; MHC class I antigen; MHC class II antigen; biological models; cell adhesion molecules; cellular immunity; cytotoxic T lymphocyte; flow cytometry; helper T lymphocyte; human tissue; immunocytochemistry; immunofluorescence technique; laboratory mouse; model design /development; mutant; natural killer cells; skin transplantation; swine; transplant rejection; vascular endothelium; xenotransplantation

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.

小型猪，由于其体型较大，生理结构与猪相似 人类、育种特征和可用性，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，其中人类抗猪反应可以 直接在体内进行评估。研究猪皮排斥反应的小鼠模型 人类外周血细胞移植物已在这 实验室。 RAG-1（重组酶激活基因-1）突变小鼠（R）， 缺乏成熟 B 细胞和 T 细胞能够接受猪皮移植 无限期地需要免疫抑制。 R-小鼠植入 猪皮移植物并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 拒绝猪皮移植物。观察到的病理变化 排斥移植物中的情况与灵长类动物中观察到的情况非常相似 抗猪异种移植排斥，并且可以由纯化的人介导 CD4 T 细胞。该提案的主要目标是研究其机制 体内人抗猪细胞异种移植反应的研究 这款 Hu-R 鼠标型号。具体目标是： 1) 确定是否 人类 CD8 T 细胞和自然杀伤 (NK) 细胞参与猪 异种移植物； 3）确定猪专业的相对重要性 组织相容性 (MHC) I 类和 I 类抗原识别 人类 T 细胞在抗猪反应中的作用； 4) 确定效果 阻断人类表达的粘附分子之间的相互作用 白细胞和猪内皮对异种移植排斥的影响。发展历程 研究细胞免疫的小动物模型的表征和表征 人类细胞对体内不一致的异种移植物的反应，将提供 提出对人们重要的机械问题的便捷方法 异种移植领域，并提供一个实用的系统 可以直接测试防止异种移植排斥的方法。