FACTORS CONTROLLING GRAFT/HOST INTERACTIONS

控制移植物/宿主相互作用的因素

• 批准号: 2684068
• 负责人: ICHIRO NAKAMURA
• 金额: $ 20.91万
• 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 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2684068
• 关键词: MHC class I antigen; cell mediated lymphocytolysis test; clone cells; hematopoietic stem cells; histocompatibility; immunogenetics; laboratory mouse; lymphokine activated killer cell; major histocompatibility complex; natural killer cells; neoplasm /cancer immunology; polymerase chain reaction; receptor; receptor expression; site directed mutagenesis; tissue /cell culture

Murine natural resistance to hemopoietic allografts, including F1 hybrid resistance to parental grafts, is a manifestation of natural killer (NK) cell's alloreactivity. The genetic basis of natural resistance has long been a puzzle, because the resistance is specific and is controlled by genes linked to the H-2, the mouse major histocompatibility complex (MHC). Recent studies by us and others suggest that H-2 class I molecules are the major determinants that control the specificity of this resistance. In fact, our study suggests that the prototypical hybrid resistance of B6D2F1(H-2b/d) mice to parental B6 (H-2b) graft is mostly, although not completely, mediated by NK cells expressing Ly-49A, a receptor that receives an inhibitory signal from Dd and Dk. Thus, the absence of particular class I molecules appears to define the specificity of this resistance, rather than positive recognition of putative target determinants controlled by the Hh-1 locus. This view is also supported by another study of ours in which Dd-loss variant clones of cell lines derived from parental DBA/2 (H-2d) and syngeneic B6D2F1 mice were found to express a phenotype indistinguishable from that of parental B6. The results indicate that susceptibility to killing by B6D2F1 NK cells does not require genes specific for H-2b. This favors the concept that lack of Dd expression is the necessary and sufficient condition for the susceptible phenotype hitherto known as Hh-1b. The nature of the receptors expressed by Ly-49A subset of B6-specific B6D2F1 effectors and the structural requirements of the Dd molecule that prevents the recognition by Ly-49A+ and Ly-49A- subsets of these effectors, will be examined as one of the objectives of the proposed studies. Our preliminary results also suggest that similar resistance of B6 mice against BALB/c (H- 2d) cells may be controlled by a different mechanism, possibly involving an H-2-independent determinant and a determinant which is positively contributed by the Dd molecule. Analysis of this resistance is therefore the second main objective of the proposed studies. Finally, we propose to analyze murine NK cell alloreactivity and its relationship to the spectrum of Ly-49 family members expressed at the level of single clones. This is based on our preliminary results, in which multiple Ly-49 transcripts were detected by RT-PCR in single clones. These studies, therefore, are designed to elucidate the molecular basis of the specific murine natural resistance against hemopoietic stem cells and neoplasm, and will hopefully suggest a means of reducing bone marrow allograft failure in man.

鼠自然耐血性同种异体移植物，包括F1杂交 对父母嫁接的抵抗是自然杀手（NK）的表现 细胞的同种异体性。自然抵抗的遗传基础很长 是一个难题，因为电阻是特定的，并且由 与H-2（小鼠主要的组织相容性复合物（MHC））相关的基因。 我们和其他人最近的研究表明，H-2 I类分子是 控制这种抗性特异性的主要决定因素。在 事实，我们的研究表明 B6D2F1（H-2B/D）小鼠到父母B6（H-2B）移植物主要是，尽管不是 完全，由表达LY-49A的NK细胞介导，一种受体，该受体 从DD和DK接收抑制信号。因此，没有 特定的I类分子似乎定义了此特异性 抵抗，而不是对推定目标的积极认识 由HH-1基因座控制的决定因素。这种观点也得到了 我们对细胞系的DD-loss变体克隆的另一项研究 发现源自父母DBA/2（H-2D）和同步B6D2F1小鼠 表达与父母B6无法区分的表型。这 结果表明，B6D2F1 NK细胞对杀死的敏感性确实 不需要针对H-2B的基因。这有利于缺乏的概念 DD表达是对 迄今称为HH-1B的易感表型。 的本质 由B6特异性B6D2F1效应子的LY-49A子集表达的受体和 DD分子的结构要求阻止了 这些效应子的LY-49A+和LY-49A-子集的识别将为 被研究为拟议研究的目标之一。我们的初步 结果还表明，B6小鼠对BALB/c的抗性相似（H- 2d）细胞可以通过不同的机制控制，可能涉及 与H-2无关的决定因素和决定因素 由DD分子贡献。 因此，对这种抗性的分析是 拟议研究的第二个主要目标。最后，我们建议 分析鼠NK细胞同质反应性及其与光谱的关系 LY-49家庭成员在单个克隆的水平上表达。 这是 根据我们的初步结果，其中多个LY-49成绩单为 由RT-PCR在单个克隆中检测到。因此，这些研究是 旨在阐明特定鼠天然的分子基础 抗血有干细胞和肿瘤的能力，并希望 提出一种减少人类同种异体移植衰竭的方法。