T-CELL SUBPOPULATIONS IN TRANSPLANTATION IMMUNITY

移植免疫中的 T 细胞亚群

• 批准号: 2059857
• 负责人: HARVEY CANTOR
• 金额: $ 44.48万
• 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/2059857
• 关键词: B lymphocyte; Listeria; Listeria infections; Rickettsia; Rickettsiales disease; T cell receptor; antibody formation; bacterial antigens; bactericidal immunity; biological signal transduction; 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是一个单个副本基因，编码了由60 kd的糖蛋白分泌的60 kd糖蛋白 活化的T细胞。 研究表明ETA-1基因图到一个基因座， 赋予细胞内细菌对致死感染的遗传抗性 寄生虫。 带有ETA-1A等位基因的近交小鼠菌株表现强 细菌感染后的快速ETA-1反应，对 细胞内细菌生长。 相反，携带的近交菌株 b等位基因表现出延迟和减少的ETA-1响应，无法 包含细菌生长。 遗传细胞机制的研究 ETA-1赋予的抗性表明ETA-1蛋白与 巨噬细胞上的特定受体可能导致抗药性。 一个 第二个研究领域来自对细胞表面事件的检查和 细胞内信号传导途径，导致CD4+的细胞因子表达 细菌和逆转录病毒超抗原刺激后的T细胞。 两者T细胞激活后细胞因子基因表达的分析 配体的类型表明假定的Ca2+非依赖性激活 超抗原触发的途径导致ETA-1基因的表达，但 不是IFN-GAMMA，IL-2或IL-3表达。 相比之下，触发 传统肽-I-A复合物相同的克隆导致强大 诱导所有这些细胞因子。 拟议的研究将进一步 定义和区分超抗原触发的激活途径 导致从耦合到途径的选择性ETA-1基因表达 常规肽I-A复合物的TCR连接。 三分之一是研究 来自鉴定ETA-1失调的例子 表达。 我们筛选了一个近交小鼠菌株的面板 不同类型的自身免疫性疾病，以证明升高的证据 组成型ETA-1表达。 我们发现MRL/1PR小鼠显示 ETA-1基因表达的选择性和实质性升高。 更远 研究ETA-1和B细胞之间的相互作用表明这一点 细胞因子促进IgM和IgG产生。 这些观察开始 ETA-1表达失调的可能性可能导致 多克隆B细胞激活，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部分可能是 由ETA-1的非调节表达标记，因此代表谨慎 自身免疫性疾病谱系中的病理实体。 如果是这样，请进行治疗 这种生化障碍可以针对ETA-1校正 过表达而不是采用非特异性的当前方法 免疫抑制剂。