FACTORS CONTROLLING GRAFT-HOST INTERACTIONS

对异基因造血移植物的天然抵抗力，特别是F1杂交 对亲本移植物的抵抗，代表了最令人困惑的问题之一 免疫现象。这种抗药性是基因特有的，而且是 在很大程度上受主效基因控制。 组织相容性复合体(MHC)。效应器机构，它需要 自然杀伤(NK)细胞，人们对此知之甚少。这些属性是 独一无二的，需要与当代的 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、细胞学和 归根结底，这种形式的自然的分子机制 抵抗。 这个应用程序主要关注的是 HH-L的表型受MHC-I类基因调控。 初步实验证明，转基因H-DNA的表达。 2 H-2b/HH-lb细胞中的DD基因或cDNA，而不是H-2LD基因，可将 细胞转化为HH-Lb阴性表型，如体内测试。有建议说 这个模型可以用来详细分析 DD分子对HH-的影响的结构/功能要求 通过使用一系列人工构建的或 自然产生的DD/LD杂交基因。这些研究将确定 I类分子的特异性和潜在机制 改变HH-L的表型，而不是类的普遍效应 我的产品介绍了一些细胞对自然死亡的敏感性。 此外，拟议的研究将检验杂合子的假设 (H-2b x H-2d)细胞不能表达HH-1b表型完全是因为 H-2DD分子的表达。最后，为了承载这一点 项目进入了对潜在的生化事件的分析 杂交种抗性体外模型HH-L的表型调控 将利用黏附的IL-2激活的NK细胞作为效应器来开发。 这些研究应该有助于我们更好地理解 经典的MHC基因和HH系统及其基础机制 造血肿瘤的免疫监测。这些研究还可能 建议一种减少人类骨髓移植失败的方法。

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.