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.

这个项目的目标是阐明免疫遗传、细胞和 最终是自然寄主抗性的分子机制 与外来的、亲本的、可能的同基因的或 自体，移植的造血干细胞和祖细胞。令人惊讶的是 这个项目的主要理由是1)可能存在一类 免疫活性非T细胞能够通过 受控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)可能与 抗性是细胞相互作用调节或 维持正常的造血，以及3)这种抵抗在 临床骨髓移植。 计划进行一系列体内和体外研究，主要是 体内耐药性分析的优势和一种新的体外模型 造血抵抗力。该体外模型可用于分析人血清白蛋白 接触依赖和独立，免疫特异性和 细胞之间的非特异性、钾的刺激和抑制相互作用 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。黄曲霉毒素的体内分析 效应器-靶细胞相互作用的遗传学将应用于 选择HH不相容的异体和半同系(F1杂交种-亲本) 宿主-移植物供体组合。人参皂苷的体外功能分析 效应-靶骨髓细胞的相互作用将集中在特定的和 非特异性调控对红系和髓系祖细胞的影响 这种细胞相互作用与正常造血的相关性。进一步 体外研究将确定效应细胞与NK的关系 细胞，并将分析调节效应器的遗传和其他机制 活动。 检测细胞免疫遗传控制的体内研究 效应细胞和造血靶细胞之间的相互作用是 在涉及自然抵抗的情况下完成 H-1D/HH-1基因座。目前正在两个领域积极开展体外研究； 受累的承诺造血祖细胞的鉴定 NK样效应细胞在体外对其的调节作用 效应器细胞本身的特征。我们还将推出 补充体外分析的两种方法，即分析 不同类型造血集落形成的体内易感性 细胞(体外检测)和体内增殖能力 在体外暴露于特定效应物的干/祖细胞 细胞群。