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FACTORS CONTROLLING GRAFT/HOST INTERACTIONS

控制移植物/宿主相互作用的因素

基本信息

批准号：
2900113
负责人：
ICHIRO NAKAMURA
金额：
$ 21.75万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
1977
资助国家：
美国
起止时间：
1977-05-01 至 2001-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2900113
关键词：
MHC class I antigen cell mediated lymphocytolysis test clone cells hematopoietic stem cells histocompatibility immunogenetics kidney transplantation 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

项目摘要

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.

小鼠对造血同种异体移植物（包括F1杂种）的天然抗性对亲本移植物的抗性，是自然杀伤细胞（NK）的表现，细胞的同种异体反应性。天然抗性的遗传基础由来已久，一直是一个谜，因为电阻是特定的，是由控制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类分子是控制这种抗性特异性的主要决定因素。在事实上，我们的研究表明， B6 D2 F1（H-2b/d）小鼠与亲本B6（H-2b）移植物的比例大部分是，尽管不是完全由表达Ly-49 A的NK细胞介导，Ly-49 A是一种受体，接收来自Dd和Dk的抑制信号。因此，特定的I类分子似乎定义了这种特异性，抵抗，而不是积极认识到推定的目标由Hh-1基因座控制的决定因素。这一观点也得到了我们的另一项研究中，来自亲本DBA/2（H-2d）和同基因B6 D2 F1小鼠的细胞被发现表达与亲本B6无区别的表型。的结果表明，对B6 D2 F1 NK细胞杀伤的敏感性确实不需要H-2b特异性基因。这有利于缺乏的概念， Dd表达式是易感表型迄今已知为Hh-1b。的性质由B6特异性B6 D2 F1效应子的Ly-49 A亚群表达的受体和 Dd分子的结构要求，防止通过这些效应子的Ly-49 A+和Ly-49 A-亚群的识别，将是作为拟议研究的目标之一进行审查。我们的初步结果还表明，B6小鼠对BALB/c（H- 2d）细胞可能由不同的机制控制，可能涉及一个H-2-独立行列式和一个正行列式由Dd分子贡献。因此，对这种阻力的分析第二个主要目的是研究。最后，我们建议分析小鼠NK细胞同种异体反应性及其与谱的关系的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转录本被在单个克隆中通过RT-PCR检测。因此，这些研究是旨在阐明特定的小鼠天然抗造血干细胞和肿瘤，并有望提出了一种减少人类骨髓同种异体移植失败的方法。