Small Animal Model of Human Immunity

人体免疫小动物模型

• 批准号: 6510071
• 负责人: SCOTT J BANUELOS
• 金额: $ 4.81万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6510071
• 关键词: MHC class I antigen; MHC class II antigen; NOD mouse; SCID mouse; T lymphocyte; antigen presenting cell; autoimmunity; disease /disorder model; flow cytometry; gene expression; gene targeting; genetically modified animals; graft versus host disease; homologous transplantation; human tissue; immune tolerance /unresponsiveness; isoantigen; major histocompatibility complex; model design /development; pancreatic islet transplantation; skin transplantation; transplant rejection; transplantation immunology

DESCRIPTION (provided by applicant): Translation of basic research to the field of clinical transplantation is difficult due to the lack of model systems that permit in vivo analysis of a human immune response without putting a patient at risk. The laboratories of Dr. Greiner (my sponsor) and Dr. Shultz (our collaborator) have developed an immunodeficient mouse that supports high levels of human lymphocyte engraftment (termed Hu-PBL-NOD-scid). We propose to establish and validate this model for the study of mechanisms of human immune function and allograft rejection. Our working hypothesis is that Hu-PBL-NOD-scid mice expressing human MHC class 1 and class II molecules will enhance the survival and function of engrafted MHC-matched human T cells. Data i.s been established in two key areas: 1) Genetic stocks of all required human MHC transgenic and murine MHC knockout mice have been assembled. 2) Human skin and islet allograft rejection in Hu-PBL-NOD-scid mice has been documented. Building on these Preliminary Data, the Specific Aims of this proposal are two-fold. Specific Aim #1 is to investigate the mechanisms that underlie the engrafiment, expansion, and survival of human lymphocytes in NOD-scid mice. We propose to test three mechanisms that may act individually or in concert. We will test the hypotheses that expansion and survival of human lymphocytes: A) Results from human anti-mouse MHC class II reactivity; B) Is due to dysregulated homeostasis in the lymphocyte-deficient scid host; C) Requires expression of human MHC class I or class II in the murine hosts for survival. Specific Aim #2 is to test the functional activity of human lymphocytes engrafted in rransgenic NOD-scid mice that express human MHC class I or class II molecules. We propose to validate our Hu-PBL-NOD-scid model as an in vivo model of a functional human immune system for the study allograft rejection. Human MHC transgenic NOD-scid mice will be used to donate allograft targets for engra.fted human lymphocytes. This will validate the functional expression of the human MHC by mouse APCs as a target alloantigen, and validate the ability of human MHC on mouse APCs to present antigen. Our long-term goal is to use the Hu-PBL-NOD-scid model to investigate the mechanisms of human allograft rejection and the modulation of human immune responses by tolerance induction protocols.

描述（由申请人提供）：将基础研究转化为该领域 由于缺乏模型系统，临床移植很困难 允许对人体免疫反应进行体内分析，而无需将患者置于 风险。 Greiner 博士（我的资助者）和 Shultz 博士（我们的资助者）的实验室 合作者）开发了一种支持高水平免疫缺陷的小鼠 人淋巴细胞植入（称为 Hu-PBL-NOD-scid）。我们建议 建立并验证该模型用于研究人体免疫机制 功能和同种异体移植排斥。我们的工作假设是 表达人类 MHC 1 类和 II 类分子的 Hu-PBL-NOD-scid 小鼠将 增强移植的 MHC 匹配的人类 T 细胞的存活率和功能。数据 已在两个关键领域建立： 1) 所有必需的人类遗传资源 MHC 转基因小鼠和小鼠 MHC 敲除小鼠已组装完毕。 2) 人体皮肤 Hu-PBL-NOD-scid 小鼠的胰岛同种异体移植排斥已被记录。 基于这些初步数据，该提案的具体目标是 双重。具体目标#1是研究潜在的机制 NOD-scid 小鼠中人类淋巴细胞的植入、扩增和存活。我们 建议测试三种可以单独或协同作用的机制。我们 将测试人类淋巴细胞的扩增和存活的假设：A) 人抗小鼠 MHC II 类反应性结果； B) 是由于 淋巴细胞缺乏的 scid 宿主体内稳态失调； C) 要求 人类 MHC I 类或 II 类在小鼠宿主中的表达以维持生存。 具体目标#2 是测试人类淋巴细胞的功能活性 移植到表达人类 MHC I 类或 I 类的转基因 NOD-scid 小鼠中 II 分子。我们建议验证我们的 Hu-PBL-NOD-scid 模型作为体内模型 用于研究同种异体移植排斥反应的功能性人类免疫系统模型。 人类 MHC 转基因 NOD-scid 小鼠将用于捐赠同种异体移植靶点 移植的人淋巴细胞。这将验证函数表达式 以小鼠APCs为靶标同种异体抗原，检测人类MHC，并验证其能力 人类 MHC 在小鼠 APC 上呈递抗原。我们的长期目标是利用 Hu-PBL-NOD-scid模型研究人类同种异体移植的机制 通过耐受诱导来排斥和调节人体免疫反应 协议。