Do Anergic T Cells Intensify Post Trauma Immunodepression?

无能 T 细胞会增强创伤后免疫抑制吗？

基本信息

批准号：
7266543
负责人：
Carol L. Miller-Graziano
金额：
$ 29.72万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7266543
关键词：
Antibodies Antigen-Presenting Cells Antigens Apoptosis Apoptotic Binding Biochemical Biological CD47 gene Cell model Cell physiology Chemicals Chimeric Proteins Chronic Clinical Trials Complex Dendritic Cells Development Environment Equilibrium Failure Functional disorder Human Immune Immune System Diseases Immunosuppression Inflammation Injury Interleukin-2 Ligands Link Lymphocyte Mediating Mediator of activation protein Modeling Morbidity - disease rate Multiple Organ Failure Paralysed Pathway interactions Patients Proteins Receptor Signaling Refractory Research Personnel Sepsis Signal Pathway Signal Transduction Signal Transduction Alteration Signal Transduction Pathway Signaling Molecule Signaling Protein Surface T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Therapeutic immunosuppression Thinking Translating Trauma Up-Regulation anergy cancer therapy immune depression in vivo mortality novel novel therapeutics programs receptor receptor expression

项目摘要

DESCRIPTION (provided by applicant): Sepsis and multiple organ dysfunction syndrome (MODS) after trauma are a leading cause of mortality and morbidity. Post injury! lymphocyte immune paralysis, apoptosis, and loss of dendritic cell antigen presenta- tion and costimulation are associated with development of sepsis and MODS. T cell dysfunctions were thought to result solely from failure to fully activate through costimulatory surface receptors/ligands leading to apoptosis and T cell tolerance. However, T cell co-repressor receptor/ligands have been recently shown to counterbalance and overwhelm costimulator activation by inducing inhibitory signal transduction molecules which degrade and dephosphorylate the activating signal proteins. These co-repressors bidirectionally trig- ger apoptosis and tolerance in both the DC and T cells. Our global hypothesis is that this bidirectional co- repressor receptor/ligand triggering is responsible for post injury T cell paralysis and DC dysfunction. The co- repressor expressing anergic T cells induce paralysis in naive T cells and costimulation dysfunctions in DC. We further postulate that in concert with the co-repressor receptors, trauma mediators uniquely upregulate and trigger additional negative T cell signaling by increasing inflammation sensitive co-repressor receptor expression and triggering. To test these hypotheses we proposed 2 Specific Aims: First, to define how T cell costimulatory or co-repressor receptor expression and activating vs. inhibitory signaling pathways are altered when costimulation deficient and co-repressor tolerance are combined by (1) characterizing a human anergic T cell model and by comparing this model to alterations in refractory anergic patient T cells. Second, to as- sess if mechanisms by which trauma patients' refractory anergic and/or apoptotic T cells perpetuate post in- jury immunosuppression include 1) Apoptotic T cells' altering DC costimulation/co-repressor receptor/ligand balance to induce tolerizing DC and/or DC apoptosis. 2) Patients' refractory anergic T cells inducing co- repressor dominant tolerizing DC or DC apoptosis. 3) Patients' refractory anergic T cells inducing co- repressor dominance and/or elevate inhibitory signal transduction pathways in naive or activated T cells. Identification of T cell co-repressor receptors which trigger post trauma T cell refractory anergy may indicate targets for interventional biochemical and/or biological manipulation of injury induced aberrant T cell activa- tion representing a new therapeutic strategy for treating post injury sepsis and MODS.

描述（由申请人提供）：创伤后的败血症和多个器官功能障碍综合征（mod）是死亡率和发病率的主要原因。受伤后！淋巴细胞免疫瘫痪，细胞凋亡以及树突状细胞抗原的损失和共刺激与败血症和mod的发展有关。 T细胞功能障碍被认为仅是由于未能通过共刺激表面受体/配体完全激活导致细胞凋亡和T细胞耐受性而导致的。然而，最近已证明T细胞共抑制受体/配体通过诱导抑制性信号转导分子来抵消平衡和压倒性的共刺激剂激活，从而降解和去磷酸化激活信号蛋白。这些共抑制剂在DC和T细胞中双向触发凋亡和耐受性。我们的全球假设是，这种双向抑制剂受体/配体触发是损伤后细胞瘫痪和直流功能障碍的原因。表达厌食性T细胞的共阻抑制剂在天真的T细胞中诱导瘫痪和DC的共刺激功能障碍。我们进一步假设，与共抑制受体共同，创伤介质通过增加炎症敏感的共抑制受体表达和触发来唯一上调并触发了其他负T细胞信号传导。为了检验这些假设，我们提出了2个具体目的：首先，定义T细胞costimulation或co-抑制受体表达方式以及激活与抑制信号传导途径是如何在共刺激不足和（1）通过（1）将人类厌氧模型和该模型表征与反射性抗性的模型进行比较的（1）结合（1）将其结合在（1）中。其次，为了解决创伤患者难治性和/或凋亡的T细胞永久性陪审团免疫抑制的机制，包括1）凋亡T细胞改变了DC cotallation/co-Repressimulation/co-Repress-Repress受体/LIGAND的改变，以导于dc和/或dc apoptosis。 2）患者的难治性性T细胞诱导抑制剂显性耐受性直流或DC凋亡。 3）患者的难治性性T细胞诱导共阻剂优势和/或升高幼稚或活化的T细胞中的抑制信号转导途径。 T细胞共抑制受体的鉴定会触发创伤后T细胞难治性厌食症的鉴定可能表明靶向介入的生化和/或生物学操纵损伤引起的异常T细胞活化的靶标，代表了一种新的治疗策略，用于治疗后损伤后的损伤和mods。