FACTORS CONTROLLING GRAFT HOST INTERACTIONS

控制移植物宿主相互作用的因素

• 批准号: 3225183
• 负责人: ICHIRO NAKAMURA
• 金额: $ 13.19万
• 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 1988-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3225183
• 关键词: bone marrow transplantation; cell cell interaction; cellular immunity; gene expression; graft versus host disease; hematopoiesis; hematopoietic stem cells; histocompatibility antigens; histocompatibility gene; homologous transplantation; immunogenetics; immunoregulation; major histocompatibility complex; radiotracer; surface antigens; tissue /cell culture

The objective of this project is to elucidate the immunogenetic, cellular, and ultimately molecular, mechanisms underlying the natural host resistance to the proliferation of foreign, parental, and possibly syngeneic or autologous, grafts of hemopoietic stem and progenitor cells. Amomg the major rationales for this project are 1) possible existence of a class of immunocompetent non-T cells capable of mediating this resistance via immunogeneticaly specific recognition of cell surface antigens controlled by hemopoietic histocompatibility (Hh) genes, 2) possible relevance of the resistance as a manifestation of cellular interactions regulating or maintaining normal hemopoiesis, and 3) possible role of such resistance in clinical bone marrow transplantation. A series of in vivo and in vitro studies are planned mainly taking advantage of an analysis of in vivo resistance and a new in vitro model of hemopoietic resistance. The in vitro model will serve for analysis of contact-dependent and independent, immunogenetically specific and nonspecific,k stimulatory and suppressive, cellular interactions between natural killer (NK) cell-like splenic effector cells and primitive hemopoietic progenitor cells of bone marrow origin. Analysis in vivo of the genetics of effector-target cell interactions will be applied to selected Hh-incompatible allogeneic and semisyngeneic (F1 hybrid-parental) host-graft donor combinations. Functional analysis in vitro of effector-target bone marrow cell interactions will focus on specific and nonspecific regulatory influences on erythroid and myeloid progenitors and relevance of such cellular interactions in normal hemopoiesis. Further studies in vitro will characterize the effector cells in relation to NK cells, and will analyze genetic and other mechanisms that modulate effector activities. In vivo studies examining the immunogenetic control of the cellular interactions between the effector cells and hemopoietic target cells are being completed with respect to the natural resistance involving the H-1D/Hh-1 locus. In vitro studies are being actively pursued in two areas; the identification of committed hemopoietic progenitors that are subjected to modulation by NK-like effector cells in vitro and further characterization of the effector cells themselves. We are also introducing two approaches that supplement the in vitro analysis, namely, analysis of the susceptibility in vivo of various types of hemopoietic colony forming cells (as detected in vitro) and the proliferative capacity in vivo of stem/progenitor cells that had been exposed in vitro to defined effector cell populations.

该项目的目的是阐明免疫遗传学、细胞、 最终是自然宿主抗性的分子机制 外来的、亲本的、可能是同基因的或同源的增殖 自体造血干细胞和祖细胞移植物。 阿莫格 该项目的主要理由是 1）可能存在一类 具有免疫活性的非 T 细胞能够通过以下方式介导这种抵抗： 控制细胞表面抗原的免疫遗传学特异性识别 通过造血组织相容性（Hh）基因，2）可能的相关性 抵抗作为细胞相互作用调节或的表现 维持正常的造血功能，以及3）这种抵抗力的可能作用 临床骨髓移植。 计划主要进行一系列体内和体外研究 体内耐药性分析和新的体外模型的优势 造血抵抗。 体外模型将用于分析 接触依赖性和独立性、免疫遗传学特异性和 非特异性，k 刺激和抑制，细胞之间的相互作用 自然杀伤（NK）细胞样脾效应细胞和原始细胞 骨髓来源的造血祖细胞。 体内分析 效应器-靶细胞相互作用的遗传学将应用于 选定的 Hh 不相容同种异体和半同种（F1 杂种亲本） 宿主-移植物供体组合。 体外功能分析 效应器-靶骨髓细胞相互作用将集中于特定的和 对红细胞和骨髓祖细胞的非特异性调节影响 这种细胞相互作用与正常造血的相关性。 更远 体外研究将表征与 NK 相关的效应细胞 细胞，并将分析调节效应器的遗传和其他机制 活动。 体内研究检查细胞的免疫遗传控制 效应细胞和造血靶细胞之间的相互作用 正在完成涉及自然阻力 H-1D/Hh-1 基因座。 体外研究正在两个领域积极进行； 鉴定所受的定型造血祖细胞 NK 样效应细胞的体外调节以及进一步 效应细胞本身的表征。 我们还介绍 补充体外分析的两种方法，即分析 体内各种类型造血集落形成的易感性 细胞（体外检测）和体内增殖能力 已在体外暴露于特定效应物的干/祖细胞 细胞群。