Do anergic T cells intensify posttrauma immunodepression

无反应性 T 细胞会加剧创伤后免疫抑制吗

• 批准号: 6526293
• 负责人: Carol L. Miller-Graziano
• 金额: $ 29.62万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6526293
• 关键词: CD28 molecule; T cell receptor; T lymphocyte; anergy; apoptosis; biological signal transduction; clinical research; clone cells; dendritic cells; human subject; interleukin 2; leukocyte activation /transformation; protein tyrosine kinase; receptor expression; trauma

Multiple Organ Dysfunction Syndrome (MODS) in trauma patients is linked to a subset of trauma patients who develop global T cell anergy and are at highest risk of mortality and morbidity. Some trauma patients' T lymphocytes become unresponsive (anergic), then recover from anergy but others do not perhaps because their anergic T cells are actively maintaining their anergy, thereby increasing their risk of MODS. We hypothesize that the subset of trauma patients who develop MODS and experience long-term T cell global anergy activate a repertoire of inhibitory signaling pathways actively perpetuating their T cell anergy. We also postulate that altered receptor expression is both causal and/or typical of these long-term anergic and anergy inducing T cells. We further contend that multiple different pathways of T cell anergy can occur post- injury and that these anergy inducing triggers will act through defined but characteristically different inhibitory block in signal transduction pathways critical to T cell activation and cytokine production. Three recently described long-term anergy- inducing, T cell signaling pathways have been targeted for investigation based on our preliminary patient T cell data. Reduced CD28 co-stimulation during activation through T cell receptor complex (TCR); Failed T cell downregulation of CTLA4 expression resulting in CTLA4 triggering of negative signaling; Upregulation of T cell inhibitory receptors activating SHP-1 phosphatase with consequent dephosphorylation of critical TCR associated phosphotyrosine kinases (PTK). Our Specific Aims are: 1) Determine if known T cell inhibitory signaling pathways are activated in trauma patients' anergic T cells and corresponds to prolonged anergy and increasing Marshall's MODS scores. 2) Delineate if reversal of post-trauma T cell anergy by exogenous cytokines and/or exogenous co-stimulation varies depending on the mechanisms of anergy induction. 3) Determine if patients' anergic T lymphocytes actively immunosuppress normal T lymphocyte activation or mediate Dendritic cell (DC) dysfunction disrupting both T cell immune function and monocyte/macrophage inflammatory/immunostimulatory balances thereby pivotally contributing to post trauma pathology.

创伤患者的多个器官功能障碍综合征（MOD）与发生全球T细胞消极且死亡率和发病率最高的创伤患者的一部分有关。 一些创伤患者的T淋巴细胞变得无反应（厌食症），然后从厌食症中恢复过来，但其他可能不是因为他们的厌食症T细胞正在积极地保持其厌食状态，从而增加了MOD的风险。我们假设开发MOD并经历长期T细胞全球性的创伤患者的子集激活了抑制性信号传导途径的曲目，积极延续其T细胞消极。 我们还假设，这些长期厌食和厌氧诱导T细胞的受体表达改变是因果和/或典型的。 我们进一步争辩说，在损伤后可能发生多种T细胞消极的途径，并且这些诱导的触发器将通过定义但特征不同的抑制性阻滞在信号转导途径中起作用，这对于T细胞激活和细胞因子产生至关重要。 最近描述了三个长期诱导的长期诱导，T细胞信号通路已根据我们的初步患者T细胞数据进行了研究。通过T细胞受体复合物（TCR）激活过程中CD28的共刺激降低； CTLA4表达的T细胞下调失败，导致CTLA4触发负信号传导； T细胞抑制受体的上调激活SHP-1磷酸酶，从而导致关键TCR相关的磷酸酪氨酸激酶（PTK）的去磷酸化。 我们的具体目的是：1）确定在创伤患者的厌食T细胞中是否激活已知的T细胞抑制信号通路，并对应于延长的厌食和增加Marshall的MOD得分。 2）描绘出外源性细胞因子和/或外源共刺激对创伤后T细胞消极的逆转会取决于反应诱导的机制。 3）确定患者的厌氧性T淋巴细胞是否积极免疫免疫抑制正常T淋巴细胞激活或介导树突状细胞（DC）功能障碍会破坏T细胞免疫功能和单核细胞/巨噬细胞炎症/巨噬细胞炎症/免疫抑制性平衡，从而对Trauma post Trauma pod tale pivot造成了促进。