Rapamycin-sensitive pathway of T cell Activation

雷帕霉素敏感的 T 细胞激活途径

• 批准号: 7326111
• 负责人: Dan L. Longo
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7326111
• 关键词: Rapamycin; sensitive; pathway; cell; Activation

The CD28-mediated costimulatory signal plays a pivotal role in the outcome of many immune responses including cytolytic responses in tumor and autoimmune diseases. Depending on the primary stimulation, CD28 can initiate multiple intracellular signaling pathways including a pathway that is insensitive to immunosuppressive drug, Cyclosporin A (CsA). This CsA- insensitive pathway is believed to be involved in graft-vs-host disease (GVHD) during allogeneic bone marrow transplantation. Our current objectives focus on three areas: (1) characterization of the CsA-resistant rapamycin-sensitive pathway of T cell activation; (2) examination of the physiological significance of this pathway; and (3) the effect of aging on the rapamycin-sensitive pathway. Our recent work has demonstrated that the immunosuppressive drug rapamycin selectively affects the CsA-resistant pathway. Our initial studies have focused on the mechanism of activation of the IL-2 gene in a CsA-resistant manner. We found that the effects of rapamycin on the IL-2 expression was due to alteration in IL-2 mRNA stability. More recently, we have also shown that activation of T cells by IL-12 is resistant to CsA, but sensitive to rapamycin. As the intracellular target of rapamycin is mTOR, we are investigating the mechanism of activation of mTOR. To examine the physiological role of this resistant pathway, we are currently examining the role of this pathway in the differentiation of T cells as well as allogeneic mixed lymphocyte reactions (MLR), an in vitro model of GVHD. We have initiated studies to dissect the CsA- sensitive component of the allogeneic mixed lymphocyte reaction from the CsA-resistant one. We believe that further elucidation of this signaling pathway may assist in the identification of novel therapeutics to prevent GVHD.

CD28介导的共刺激信号在许多免疫反应的结果中发挥着关键作用，包括肿瘤和自身免疫性疾病中的细胞溶解反应。根据主要刺激，CD28 可以启动多种细胞内信号传导途径，包括对免疫抑制药物环孢菌素 A (CsA) 不敏感的途径。这种CsA不敏感途径被认为与同种异体骨髓移植过程中的移植物抗宿主病(GVHD)有关。我们当前的目标集中在三个领域：(1) CsA 耐药的雷帕霉素敏感 T 细胞激活途径的表征； (2)检验该通路的生理意义； (3)衰老对雷帕霉素敏感途径的影响。我们最近的工作表明，免疫抑制药物雷帕霉素选择性地影响 CsA 耐药途径。我们最初的研究集中在以 CsA 抗性方式激活 IL-2 基因的机制。我们发现雷帕霉素对 IL-2 表达的影响是由于 IL-2 mRNA 稳定性的改变。最近，我们还发现 IL-12 激活的 T 细胞对 CsA 具有抗性，但对雷帕霉素敏感。由于雷帕霉素的细胞内靶点是mTOR，我们正在研究mTOR的激活机制。为了研究这一耐药途径的生理作用，我们目前正在研究该途径在 T 细胞分化以及同种异体混合淋巴细胞反应 (MLR)（GVHD 的体外模型）中的作用。我们已启动研究，将同种异体混合淋巴细胞反应中的 CsA 敏感成分与 CsA 抗性成分分开。我们相信，进一步阐明该信号通路可能有助于确定预防 GVHD 的新疗法。