HLA G PEPTIDES IN IMMUNE TOLERANCE

HLA G 肽在免疫耐受中的作用

• 批准号: 2673985
• 负责人: Carol A. Clayberger
• 金额: $ 24.48万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2673985
• 关键词: MHC class I antigen; SDS polyacrylamide gel electrophoresis; affinity chromatography; calcium flux; complementary DNA; cytokine; disease /disorder model; genetic transcription; human tissue; immune tolerance /unresponsiveness; in situ hybridization; laboratory mouse; leukocyte activation /transformation; molecular cloning; pregnancy immunology; protein kinase; protein sequence; protooncogene; receptor binding; spontaneous abortion; synthetic peptide

The unique pattern of class I major histocompatibility complex (MHC) antigen expression at the maternal/fetal interface is thought to play a major role in protecting the fetus from rejection by the mother's immune system. Trophoblasts, the only fetal tissue that comes into direct contact with the mother, do not express polymorphic class I and II MHC antigens. This may in part explain the lack of maternal immune response against the fetus. Recently it was found that a non-classical MHC molecule, designated HLA-G, is present on certain subpopulations of trophoblasts, suggesting that the expression of this non-polymorphic MHC molecule plays an active role in maternal/fetal tolerance. The transcript encoding HLA-G has been shown to undergo alternative splicing to give rise to a full length form as well as two smaller forms, all of which contain the alpha1 alpha helix. In addition, some of these forms have been shown to be secreted by cells. These observations, as well as studies from this laboratory using synthetic peptides corresponding to specific regions of classical MHC class I molecules, constitute the experimental basis for the hypothesis that soluble HLA-G peptides contribute to maternal immune unresponsiveness towards the fetus. A synthetic peptide corresponding to the entire alpha1 alpha helix (residues 60-84) of HLA-G inhibits T cell proliferation in vitro and also blocks IL-2 production by T cells. The aims of this proposal are to investigate the molecular mechanisms by which soluble HLA- G peptides induce unresponsiveness and to investigate their role in pregnancy. Specifically, studies are proposed: 1) to characterize the pathways by which synthetic peptides corresponding to HLA-G transduce a negative signal in human lymphocytes; 2) to identify the receptor to which these peptides bind; and 3) to examine the effects of these peptides in a rodent model of spontaneous abortion.

I类主要组织相容性复合物（MHC）的独特模式 孕产妇/胎儿界面处的抗原表达被认为可以发挥 保护胎儿免于被母亲免疫拒绝的主要作用 系统。滋养细胞，这是唯一直接接触的胎儿组织 与母亲一起，不要表达I类和II类MHC抗原。 这可能部分解释了对孕产妇免疫反应的缺乏 胎儿。最近发现，指定的非古典MHC分子 HLA-G，存在于滋养细胞的某些亚群中，表明 这种非晶状体MHC分子的表达发挥了活性 在母亲/胎儿耐受性中的作用。编码HLA-G的笔录已经 显示出可替代的剪接以产生全长形式 以及两个较小的形式，所有形式都包含alpha1 alpha螺旋。 另外，其中一些形式已被细胞分泌。 这些观察结果以及该实验室的研究 对应于经典MHC特定区域的合成肽 I类分子，构成了假设的实验基础 可溶性HLA-G肽有助于产妇免疫反应症 朝向胎儿。与整个alpha1相对应的合成肽 HLA-G的α螺旋（残基60-84）抑制T细胞增殖 体外，还可以阻止T细胞产生IL-2。这个目的 建议是研究可溶性HLA-的分子机制 G肽会引起无反应性，并调查其在 怀孕。具体而言，提出了研究：1）表征 合成肽对应于HLA-G转导A的途径 人淋巴细胞中的阴性信号； 2）识别受体 这些肽结合； 3）检查这些肽在A中的作用 自发流产的啮齿动物模型。