HLA G PEPTIDES IN IMMUNE TOLERANCE

HLA G 肽在免疫耐受中的作用

• 批准号: 2403599
• 负责人: Carol A. Clayberger
• 金额: $ 23.57万
• 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/2403599
• 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体 (MHC) 的独特模式 母体/胎儿界面的抗原表达被认为发挥着重要作用 在保护胎儿免受母亲免疫排斥方面发挥着重要作用 系统。滋养层，唯一直接接触的胎儿组织 与母亲一样，不表达多态性 I 类和 II 类 MHC 抗原。 这可能部分解释了母体缺乏针对该病毒的免疫反应。 胎儿。最近发现一种非经典MHC分子，命名为 HLA-G 存在于某些滋养细胞亚群上，表明 这种非多态性 MHC 分子的表达发挥着积极的作用 在母体/胎儿耐受性中的作用。编码 HLA-G 的转录本是 显示经过选择性剪接以产生全长形式 以及两种较小的形式，它们都包含 alpha1 α 螺旋。 此外，其中一些形式已被证明是由细胞分泌的。 这些观察结果以及该实验室使用的研究 对应于经典 MHC 特定区域的合成肽 I 类分子，构成该假设的实验基础 可溶性 HLA-G 肽会导致母体免疫无反应 朝向胎儿。对应整个 alpha1 的合成肽 HLA-G 的 α 螺旋（残基 60-84）抑制 T 细胞增殖 体外，还可以阻断 T 细胞产生 IL-2。本次活动的目的 提议是研究可溶性HLA-的分子机制 G 肽诱导无反应并研究其在 怀孕。具体来说，建议进行以下研究：1）表征 对应于HLA-G的合成肽转导a的途径 人淋巴细胞中的负信号； 2) 识别受体 这些肽结合； 3) 检查这些肽在 啮齿动物自然流产模型。