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是一个单拷贝基因，编码60kD的糖蛋白，由 激活的T细胞。研究表明，Eta-1基因映射到一个 赋予细胞内细菌致死性感染的遗传抵抗力 寄生虫。携带Eta-1a等位基因的近交系小鼠表现出很强的 和Eta-1在细菌感染后的快速反应，并对 细胞内细菌生长。相反，近亲繁殖的品系携带 B等位基因表现出Eta-1反应延迟和减少，并且不能 抑制细菌生长。遗传致病的细胞机制研究 Eta-1产生的抗性表明Eta-1蛋白与 巨噬细胞上的特定受体可能与耐药性有关。一个 第二个研究领域来自对细胞表面事件和 导致CD4+细胞因子表达的细胞内信号通路 细菌和逆转录病毒超抗原刺激后的T细胞。 两者对T细胞活化后细胞因子基因表达的影响 配体的类型表明可能存在钙离子非依赖性激活 超抗原触发的途径导致Eta-1基因的表达，但 不表达干扰素-γ、IL-2或IL-3。相比之下，触发 同样的克隆通过常规的多肽-I-A复合体产生强大的 所有这些细胞因子的诱导。拟议的研究将进一步 界定和区分超抗原触发的激活途径 导致选择性表达Eta-1基因 用常规的多肽I-A复合体连接TCR。三分之一的人在学习 来自于一例异常调节的Eta-1的鉴定 表情。我们筛选了一组近亲交配的小鼠品系 不同类型的自身免疫性疾病寻找升高水平的证据 组成型Eta-1表达。我们发现MRL/1PR小鼠表现出 选择性地大幅上调Eta-1基因的表达。进一步 对Eta-1与B细胞相互作用的研究表明， 细胞因子促进免疫球蛋白M和免疫球蛋白的产生。这些观察结果开启了 Eta-1表达失调可能是 多克隆B细胞激活，这是这种形式的小鼠狼疮的标志。 这些发现还表明，自身免疫性疾病的一部分可能是 以Eta-1的异常表达为特征，因此代表了一种谨慎的 自身免疫性疾病谱中的病因学实体。如果是这样的话，治疗 这种生化紊乱的作用可能与Eta-1的纠正有关 过度表达，而不是使用非特定的当前方法 免疫抑制剂。