FACTORS CONTROLLING GRAFT-HOST INTERACTIONS

控制移植物-宿主相互作用的因素

• 批准号: 2136816
• 负责人: ICHIRO NAKAMURA
• 金额: $ 17.36万
• 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/2136816
• 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.

对造血同种异体移植物，特别是F1杂种的天然抗性 对亲本嫁接的抗性，代表了一个最令人困惑的 免疫现象。 抗性是基因特异性的， 主要由位于主基因组中的隐性基因控制 组织相容性复合体（MHC）。 效应器机制，这需要 自然杀伤（NK）细胞，知之甚少。 这些属性 独特的，需要与当代的概念， 细胞免疫学和移植遗传学。 长期目标 这项研究项目的目的是阐明免疫遗传学，细胞， 最终，这种形式的自然 阻力 本申请集中在表达的机制， Hh-1表型受MHC I类基因调控。 初步实验表明，转染的H- 在H-2b/Hh-lb细胞中，2Dd基因或cDNA，而不是H-2Ld基因，可以将 细胞转化为Hh-lb阴性表型，如体内测试的。 拟 这个模型可以用来详细分析 Dd分子对Hh-的作用的结构/功能要求 通过使用一系列人工构建的或 天然存在的Dd/Ld杂交基因。 这些研究将决定 特异性和I类分子的潜在机制 改变了Hh-1表型，而不是类 我的产品对某些细胞的敏感性自然杀伤。 此外，拟议的研究将检验杂合子 (H-2b x H-2d）细胞不能表达Hh-1b表型，这仅仅是由于 H-2Dd分子的表达。 最后，为了携带这个 项目对生物化学事件的分析 Hh-1表型的调节，一种杂种抗性的体外模型 将使用粘附的IL-2活化的NK细胞作为效应物来开发。 这些研究应该增进我们对 经典的MHC基因和Hh系统及其机制 造血系统肿瘤的免疫监视。 这些研究也可能 提出了一种减少人类骨髓同种异体移植失败的方法。