FACTORS CONTROLLING GRAFT HOST INTERACTIONS

本研究项目的长期目标是阐明 免疫遗传学、细胞学以及最终的分子学机制， 天然宿主对外来、亲本和 可能是同基因或自体的造血干细胞和祖细胞移植物 细胞 该项目的主要理由包括：1）可能 存在一类能够介导 这种抗性通过细胞表面的免疫遗传特异性识别 由造血组织相容性（Hh）基因控制的抗原，2） 耐药性可能与细胞 调节或维持正常造血的相互作用，以及3）可能的 这种抵抗在临床骨髓移植中的作用。 在本提案中，进行了一系列体内和体外研究。 计划，主要是利用新开发的竞争力 体内耐药抑制分析和一种新的体外耐药模型 造血抵抗 体外模型，尽管其特性仍然是 不完全理解，将用于分析接触依赖的， 独立的、免疫遗传学特异性的和非特异性的、刺激性的和 自然杀伤（NK）细胞样细胞之间的抑制性细胞相互作用 脾效应细胞和骨原始造血祖细胞 骨髓起源 效应-靶细胞遗传学的体内分析 相互作用将应用于选定的Hh不相容的同种异体， 半同基因（F1杂种-亲本）宿主-移植供体组合。 效应靶骨髓细胞的体外功能分析 互动将重点关注特定和非特定的监管影响 对红系和髓系祖细胞的影响以及这种细胞 正常造血的相互作用。 进一步的体外研究将 表征效应细胞与NK细胞的关系，并将分析 调节效应物活性的遗传和其他机制。

It is the long-term objective of this research project 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. Among the major rationales for this project are 1) possible existence of a class of immunocompetent non T cells capable of mediating this resistance via immunogenetically 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. In the present proposal, a series of in vivo and in vitro studies are planned, mainly taking advantage of a newly developed competitive inhibition analysis of in vivo resistance and a new in vitro model of hemopoietic resistance. The in vitro model, though its properties are stil imcompletely understood, will serve for analysis of contact-dependent and independent, immunogenetically specific and nonspecific, 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.