T CELL SUBPOPULATIONS IN TRANSPLANTATION IMMUNITY

移植免疫中的 T 细胞亚群

• 批准号: 6169361
• 负责人: HARVEY CANTOR
• 金额: $ 50.27万
• 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 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6169361
• 关键词: B lymphocyte; CD44 molecule; MHC class I antigen; T cell receptor; T lymphocyte; apoptosis; biological signal transduction; cell differentiation; cell migration; cell population study; cytokine; cytokine receptors; gene expression; integrins; laboratory mouse; leukocyte activation /transformation; macrophage; osteopontin; polymerase chain reaction; protein sequence; receptor binding; tissue /cell culture; transplantation immunology

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 是编码 60 kD 糖蛋白的单拷贝基因，由 激活的 T 细胞。 研究表明 Eta-1 基因定位到一个基因座 赋予对细胞内细菌致命感染的遗传抵抗力 寄生虫。 携带 Eta-1a 等位基因的近交小鼠品系显示出很强的 和细菌感染后快速的 Eta-1 反应，并且对 细胞内细菌生长。 相反，携带 b 等位基因表现出 Eta-1 反应延迟和减少，并且无法 含有细菌生长。 遗传细胞机制研究 Eta-1 赋予的抗性表明 Eta-1 蛋白与 巨噬细胞上的特定受体可能是产生耐药性的原因。 一个 第二个研究领域来自细胞表面事件的检查 导致 CD4+ 细胞因子表达的细胞内信号通路 受到细菌和逆转录病毒超抗原刺激后的 T 细胞。 两者激活T细胞后细胞因子基因表达分析 配体类型表明假定的 Ca2+ 独立激活 超抗原触发的途径导致 Eta-1 基因表达，但 不表达 IFN-γ、IL-2 或 IL-3。 相比之下，触发 传统肽-I-A复合物的相同克隆会产生强 诱导所有这些细胞因子。 拟议的研究将进一步 定义并区分超抗原触发的激活途径 导致 Eta-1 基因从偶联途径中选择性表达 通过常规肽 I-A 复合物进行 TCR 连接。 三分之一是研究 来自对 Eta-1 失调示例的识别 表达。 我们筛选了一组近交小鼠品系，这些品系发育 不同类型的自身免疫性疾病的证据水平升高 Eta-1组成型表达。 我们发现 MRL/1pr 小鼠表现出 Eta-1 基因表达的选择性和显着升高。 更远 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 的产生。 这些观察结果打开了 Eta-1表达失调可能是造成这种情况的原因 多克隆 B 细胞激活，这是这种小鼠狼疮的标志。 这些发现还表明，自身免疫性疾病的一个子集可能是 以 Eta-1 表达失调为标志，因此代表了谨慎的 自身免疫性疾病谱中的疾病实体。 如果是的话，治疗 这种生化紊乱的研究可能是针对 Eta-1 的纠正 过度表达而不是目前采用非特异性的方法 免疫抑制剂。