T-CELL SUBPOPULATIONS IN TRANSPLANTATION IMMUNITY

移植免疫中的 T 细胞亚群

• 批准号: 2059858
• 负责人: HARVEY CANTOR
• 金额: $ 46.81万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-07-01 至 1996-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2059858
• 关键词: B lymphocyte; Listeria; Listeria infections; Rickettsia; Rickettsiales disease; T cell receptor; antibody formation; bacterial antigens; bactericidal immunity; biological signal transduction; cell transplantation; cellular immunity; cytokine; cytokine receptors; gene expression; genetic mapping; genetically modified animals; helper T lymphocyte; histocompatibility; histocompatibility antigens; immunogenetics; laboratory mouse; leukocyte activation /transformation; macrophage; monoclonal antibody; systemic lupus erythematosus; tissue /cell culture; transfection

Eta-1 is a single copy gene encoding a 60 kD glycoprotein secreted by activated T-cells. Studies indicate the Eta-1 gene maps to a locus that confers genetic resistance to lethal infection by intracellular bacterial parasites. Inbred mouse strains bearing the Eta-1a allele display strong and rapid Eta-1 responses after bacterial infection and are resistant to intracellular bacterial growth. Conversely, inbred strains that carry the b allele exhibit delayed and reduced Eta-1 responses and are unable to contain bacterial growth. Studies of the cellular mechanism of genetic resistance conferred by Eta-1 suggest that binding of the Eta-1 protein to specific receptors on macrophages may be responsible for resistance. A second area of study comes from examination of cell surface events and intracellular signalling pathways that lead to cytokine expression in CD4+ T-cells after stimulation by bacterial and retroviral superantigens. Analysis of cytokine gene expression after T-cell activation by the two types of ligand indicates that a putative Ca2+-independent activation pathway triggered by superantigen leads to expression of the Eta-1 gene but not IFN-gamma, IL-2 or IL-3 expression. By contrast, triggering of the same clone by conventional peptide-I-A complexes results in strong induction of all of these cytokines. The proposed studies will further define and distinguish the activation pathway triggered by superantigen resulting in selective Eta-1 gene expression from the pathway coupled to TCR ligation by conventional peptide I-A complexes. A third are of study comes from the identification of an example of dysregulated Eta-1 expression. We screened a panel of inbred mouse strains that develop different types of autoimmune disorders for evidence of elevated levels of constitutive Eta-1 expression. We found that MRL/1pr mice display a selective and substantial elevation of Eta-1 gene expression. Further studies of the interaction between Eta-1 and B-cells indicate that this cytokine promotes IgM and IgG production. These observations open the possibility that dysregulated Eta-1 expression may be responsible for polyclonal B-cell activation, the hallmark of this form of murine lupus. These findings also suggest that a subset of the autoimmune diseases may be marked by dysregulated expression of Eta-1 and thus represent a discreet nosologic entity within the autoimmune disease spectrum. If so, treatment of this biochemical disorder may be directed at correction of Eta-1 overexpression rather than current approaches which employ non-specific immunosuppressive agents.

Eta-1是一个编码60 kD糖蛋白的单拷贝基因， 活化的T细胞 研究表明Eta-1基因定位于一个位点， 赋予对细胞内细菌致死性感染的遗传抗性 寄生虫 携带Eta-1a等位基因的近交系小鼠表现出强烈的 和细菌感染后的快速Eta-1反应，并对 细胞内细菌生长。 相反，携带有 B等位基因表现出延迟和降低的Eta-1应答， 含有细菌生长。 遗传的细胞机制研究 Eta-1赋予的抗性表明Eta-1蛋白与 巨噬细胞上的特异性受体可能是抗性的原因。 一 第二个研究领域来自细胞表面事件的检查， 导致CD 4+细胞中细胞因子表达的细胞内信号传导途径 细菌和逆转录病毒超级抗原刺激后的T细胞。 两种细胞因子激活T细胞后细胞因子基因表达的分析 配体的类型表明，一个假定的Ca 2+非依赖性激活 由超抗原触发的途径导致Eta-1基因的表达， 而不是IFN-γ、IL-2或IL-3表达。 相比之下， 通过常规肽-I-A复合物的相同克隆导致强的 所有这些细胞因子的诱导。 拟议的研究将进一步 定义和区分超抗原触发的激活途径 从而导致Eta-1基因从与Eta-1基因的表达相关的途径中选择性地表达， 通过常规肽I-A复合物的TCR连接。 三分之一是学习 来自于对Eta-1失调的一个例子的鉴定， 表情 我们筛选了一组近交系小鼠， 不同类型的自身免疫性疾病的证据， 组成型Eta-1表达。 我们发现MRL/1 pr小鼠表现出一种 Eta-1基因表达的选择性和实质性升高。 进一步 Eta-1和B细胞之间相互作用的研究表明， 细胞因子促进IgM和IgG产生。 这些观察打开了 Eta-1表达失调可能是导致 多克隆B细胞活化，这是这种形式的鼠狼疮的标志。 这些发现还表明，自身免疫性疾病的一个子集可能是 Eta-1的表达失调，因此代表了一种谨慎的 自身免疫性疾病谱内的疾病分类实体。 如果是，治疗 这种生化紊乱可能是针对纠正Eta-1 过表达，而不是目前的方法，采用非特异性 免疫抑制剂。