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.

小鼠对包括F1杂交种在内的异基因造血移植物的天然抵抗力 对亲本移植的抵抗，是自然杀手(NK)的一种表现 细胞的同种异体反应性。天然抵抗力的遗传基础由来已久 一直是个谜，因为抵抗力是特定的，由 与小鼠主要组织相容性复合体(MHC)H-2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 控制这种耐药性特异性的主要决定因素。在……里面 事实上，我们的研究表明，典型的杂交抗性 B6D2F1(H-2b/d)小鼠与亲本B6(H-2b)的移植最多，尽管不是 完全由表达Ly-49A受体的NK细胞介导 接收来自DD和DK的抑制信号。因此，没有 特定的I类分子似乎定义了这一特性 抵抗，而不是对假定目标的积极认可 受HH-1基因控制的决定因素。这一观点也得到了 我们的另一项研究，其中DD-Lost变异了细胞系的克隆 来源于亲本DBA/2(H-2d)和同基因B6D2F1的小鼠被发现 表现出与亲本B6没有区别的表型。这个 结果表明，对B6D2F1 NK细胞的杀伤敏感性 不需要针对H-2b的基因。这有利于缺乏这样一个概念 DD表达式是满足以下条件的充分必要条件 迄今为止被称为HH-1b的易感表型。这个世界的本质 B6特异性B6D2F1效应子和Ly-49A亚群受体的表达 DD分子的结构要求可以防止 这些效应器的Ly-49A+和Ly-49A-子集的识别将是 作为拟议研究的目标之一进行审查。我们的预赛 结果还表明，B6小鼠对BALB/c(H-R)的抵抗力相似。 2D)单元可以由不同的机制控制，可能包括 一个H-2无关行列式和一个正行列式 由DD分子贡献。因此，对这种阻力的分析 拟议研究的第二个主要目标。最后，我们建议 小鼠NK细胞同种异体反应性及其与光谱的关系 Ly-49家族成员在单克隆水平上表达。这是 根据我们的初步结果，其中多个Ly-49转录本 用RT-PCR方法对单克隆进行检测。因此，这些研究是 旨在阐明特定的小鼠天然抗体的分子基础 对造血干细胞和肿瘤的抗药性，并有望 建议一种减少人类骨髓移植失败的方法。