FACTORS CONTROLLING GRAFT-HOST INTERACTIONS

控制移植物-宿主相互作用的因素

• 批准号: 2136817
• 负责人: ICHIRO NAKAMURA
• 金额: $ 18.07万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-05-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2136817
• 关键词: MHC class I antigen; bone marrow transplantation; cell mediated lymphocytolysis test; cytotoxic T lymphocyte; fusion gene; gene expression; graft versus host disease; histocompatibility; immunogenetics; immunoregulation; laboratory mouse; lymphokine activated killer cell; major histocompatibility complex; natural killer cells; tissue /cell culture; transfection

Natural resistance to hemopoietic allografts, in particular F1 hybrid resistance to parental grafts, represents one of the most puzzling immunological phenomena. The resistance is genetically specific, and is largely controlled by recessive genes located within the major histocompatibility complex (MHC). The effector mechanism, which requires natural killer (NK) cells, is poorly understood. These properties are unique, and need to be reconciled with the contemporary concepts of cellular immunology and transplantation genetics. The long-term objective of this research project is to elucidate the immunogenetic, cellular, and ultimately molecular mechanisms underlying this form of natural resistance. This application focuses on the mechanisms by which the expression of the Hh-l phenotype is regulated, particularly by MHC class I genes. Preliminary experiments demonstrate that the expression of transfected H- 2Dd gene or cDNA, but not H-2Ld gene, in H-2b/Hh-lb cells converts the cells into an Hh-lb negative phenotype, as tested in vivo. It is proposed that this model is amenable to a detailed analysis of the structural/functional requirement for the effect of Dd molecule on the Hh- lb phenotype through the use of a series of artificially constructed or naturally occurring Dd/Ld hybrid genes. These studies will determine the specificity and the potential mechanism by which the class I molecule alters the Hh-l phenotype, as opposed to the generalized effect of class I products on the susceptibility of some cells to natural killing. Further, the proposed study will test the hypothesis that the heterozygous (H-2b x H-2d) cells fail to express Hh - 1b phenotype solely due to the expression of the H - 2Dd molecule. Finally, in order to carry this project into an analysis of the biochemical events underlying the regulation of the Hh-l phenotype, an in vitro model of hybrid resistance will be developed using as effectors the adherent IL-2-activated NK cells. These studies should improve our understanding of the relationship between the classic MHC genes and the Hh system and the mechanism that underlie immune surveillance for hemopoietic neoplasms. These studies may also suggest a means of reducing bone marrow allograft failure in man.

天然对肢体同种异体移植的抗性，特别是F1杂种 对父母嫁接的抵抗是最令人困惑的 免疫学现象。 抗性在遗传上是特异的，是 主要由位于主要的隐性基因控制 组织相容性复合物（MHC）。 效应器机制，需要 天然杀手（NK）细胞知之甚少。 这些属性是 独特，需要与当代的概念一致 细胞免疫学和移植遗传学。 长期目标 该研究项目是为了阐明免疫遗传，细胞和 最终是这种自然形式的分子机制 反抗。 该应用的重点是表达的机制 HH-L表型受到调节，特别是MHC I类基因。 初步实验表明，转染的H-的表达 H-2B/HH-LB细胞中的2DD基因或cDNA，但不是H-2LD基因 如体内测试，细胞成HH-LB阴性表型。 它是提出的 该模型适合对 DD分子对HH-的影响的结构/功能要求 LB表型通过使用一系列人工构造或 天然发生的DD/LD杂化基因。 这些研究将确定 特异性和I类分子的潜在机制 改变了HH-L表型，而不是类别的普遍效应 我的产品具有某些细胞自然杀伤的敏感性。 此外，拟议的研究将检验杂合的假设 （H-2B X H-2D）细胞无法表达HH-1B表型，仅仅是由于 H -2DD分子的表达。 最后，为了携带这个 投影分析对生化事件的分析 HH-L表型的调节，一种体外的杂交电阻模型 将使用效应子开发依附的IL-2激活的NK细胞。 这些研究应提高我们对 经典的MHC基因和HH系统以及基础的机制 血压肿瘤的免疫监测。 这些研究也可能 提出一种减少人类同种异体移植衰竭的方法。