INDUCTION OF TRANSPLANTATION TOLERANCE BY ORAL ROUTE

通过口服途径诱导移植耐受

• 批准号: 2068087
• 负责人: CHARLES B CARPENTER
• 金额: $ 30.46万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-01 至 1997-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2068087
• 关键词: MHC class I antigen; MHC class II antigen; T lymphocyte; gastrointestinal epithelium; genetically modified animals; immunosuppression; laboratory mouse; lymphocyte proliferation; lymphokines; oral administration; synthetic peptide; tissue /cell culture; transplantation immunology

Successful transplantation depends upon the development of a state of tolerance to the incompatible alloantigens of the graft, especially those of the MHC system. The current state in the clinic is one of short tcrm success, but states of tolerance not requiring the use of powerful and toxic immunosuppressive agents are not easily achievable. The intestine has an elaborate immune system which is incompletely understood. Although the oral route can be used for immunization, there are many experimental examples of tolerance induction, including prevention or treatment of autoimmune disease in animal models . There has been little reported with regard to transplantation. Advances in the molecular biology and structure of the molecules of the MHC, as well as improved definition of the functional varieties of effector and regulatory T cells, now make it possible to perform experiments which should lead to knowledge on how to take advantage of the intestinal immune system's abilities to influence immune responses in a negative direction. Synthetic peptides representing the polymorphic regions of rat class II MHC have been shown after oral feeding to partially tolerize T cells in vitro and in vivo in an antigen specific manner. The study will aim to address the questions of the relationship between immunogenicity and tolerogenicity of MHC peptides, the mode of action with regard to T cell anergy versus suppression, the uniqueness of the proliferative responses of the intestinal epithelial T cells and the peptide presenting capacity of epithelial cells, and optimization of oral feeding to the prolongation of allografts. Rat and mouse murine models will be used, including mice tolerized to Mls immunization and T cell receptor transgenic mice. Mechanisms which involve cytokines with potential downregulatory function (e.g., TGFbeta, IL-4,IL-10) will be pursued.

移植的成功与否取决于国家的发展 对移植物的不相容同种异体抗原的耐受性， 尤其是 MHC 系统。 诊所现状 是短期的中医治疗成功之一，但不需要耐受的状态 使用强力且有毒的免疫抑制剂不 很容易实现。 肠道有一个复杂的免疫系统 这是不完全理解的。 虽然口服途径可以 用于免疫接种，有很多实验例子 耐受诱导，包括预防或治疗自身免疫性疾病 动物模型中的疾病。 很少有相关报道 关于移植。 分子生物学的进展和 MHC分子结构，以及改进的 效应器和调节器功能多样性的定义 T 细胞，现在使得进行实验成为可能 引导人们了解如何利用肠道免疫 系统以负面影响免疫反应的能力 方向。 代表多态性区域的合成肽 经口喂养后，大鼠 II 类 MHC 已被证明部分 以抗原特异性方式在体外和体内耐受 T 细胞。 该研究旨在解决两国关系的问题 MHC 肽的免疫原性和耐受原性之间的模式 关于 T 细胞无反应与抑制的作用， 肠道增殖反应的独特性 上皮T细胞和上皮细胞的肽呈递能力 细胞，并优化口服喂养以延长 同种异体移植物。 将使用大鼠和小鼠模型，包括 对 MLS 免疫和 T 细胞受体转基因耐受的小鼠 老鼠。 涉及具有潜力的细胞因子的机制 将追求下调功能（例如 TGFbeta、IL-4、IL-10）。