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.

自然抵抗造血异体移植物，特别是F1杂交