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How Proinflammatory Cytokines Block T Cell Death In Vivo

促炎细胞因子如何阻止体内 T 细胞死亡

基本信息

批准号：
8918772
负责人：
Anthony T Vella
金额：
$ 5.78万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-07-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8918772
关键词：
Adjuvant Adverse effects Affect Agonist Antigens Autoimmunity Automobile Driving B-Lymphocytes Behavior Benchmarking CD4 Positive T Lymphocytes CXCR3 gene Caspase-1 Cell Death Cell Survival Cell physiology Cells Cervarix Clinical Clonal Expansion Communicable Diseases Data Dendritic Cells Development Disease Drug Formulations Effectiveness Environmental Risk Factor European Fractionation Funding Goals Health Heart Hepatitis B Vaccines Homing Human Human Papilloma Virus Vaccine Immune Immune response Immune system Immunity Immunization Inflammation Inflammatory Inflammatory Response Interferons Ligands Link Lipopolysaccharides Liquid substance Liver Lung Maps Mediating Methods Mining Nature Organ Pathway interactions Phase Play Population Process Proteins Proteome Proteomics Protocols documentation Research Safety Seminal Sepsis Signal Transduction Site Solid System T cell differentiation T cell response T-Lymphocyte TLR4 gene Testing Therapeutic Tissue Differentiation Toll-like receptors Toxic effect Vaccine Design Vaccines Work aluminum sulfate base cell behavior cell motility chemokine clinically significant cytokine design evidence base experience imprint improved in vivo innovation insight migration monophosphoryl lipid A new technology novel novel strategies novel therapeutics pathogen prevent programs response small molecule therapeutic development tumor vaccine development vaccine evaluation

项目摘要

DESCRIPTION (provided by applicant): Our goal is to define how pro-inflammatory cytokines and factors derived from toll-like receptor (TLR) stimulation impact specific CD4 T cell immunity in vivo. Characterizing this process will improve adjuvant development by defining new methods to control in vivo T cell responses while minimizing toxicity. This goal is based on our recent work which unveiled an unexpected division of labor between the TLR4 adaptors. One path signaled T cell effector differentiation and homing to solid organs, and the other path was responsible for clonal expansion and inducing cell survival. Therefore, uncovering how the adjuvant response emanating from the TLR4 pathway affects T cell behavior will allow vaccinologists to push desirable effects on Ag-specific CD4 T cells. This goal will be accomplished in 3 specific aims by determining the mechanism of how each adaptor impacts T cells. In Aim 1 we will determine how TRIF controls T cell effector differentiation and homing by examining an innate cytokine axis that we hypothesize potentiates both cell behaviors. Data from this aim will help design vaccine formulations that will aid in driving effector T cell migration to specific sites of the body. In Aim 2 a proteomic map of specific CD4 T cells destined to survive will be captured and contrasted to the same specific T cells programmed to die. We will accomplish this goal using an innovative liquid fractionation approach that will permit us to mine the proteome for differential changes between these populations. Aim 3 will capitalize on our novel finding demonstrating that Ag-experienced CD4 T cells can facilitate adjuvant toxicity. We will define this process and develop new approaches to counter toxicity while promoting strong adjuvant responses. Thus, the results from this proposal will provide an "adjuvant to toxicity" ratio that can be used to gauge the effectiveness and safety of TLR agonists, and importantly provide an evidence-based approach to designing adjuvant therapeutics.

描述（由申请人提供）：我们的目标是确定源自toll样受体（TLR）刺激的促炎细胞因子和因子如何影响体内特异性CD 4 T细胞免疫。表征这一过程将通过定义控制体内T细胞反应同时最小化毒性的新方法来改善佐剂开发。这一目标是基于我们最近的工作，该工作揭示了TLR 4衔接子之间的意外分工。一条通路信号T细胞效应分化和归巢到实体器官，另一条通路负责克隆扩增和诱导细胞存活。因此，揭示TLR 4途径产生的佐剂反应如何影响T细胞行为将使疫苗学家能够对Ag特异性CD 4 T细胞产生预期的效果。这一目标将通过确定每个适配器如何影响T细胞的机制在3个具体目标中实现。在目标1中，我们将确定TRIF如何控制T细胞效应分化和归巢通过检查先天细胞因子轴，我们假设这两个细胞的行为增强。来自这一目标的数据将有助于设计疫苗制剂，这将有助于驱动效应T细胞迁移到身体的特定部位。在目标2中，将捕获注定存活的特定CD 4 T细胞的蛋白质组图谱，并与编程死亡的相同特定T细胞进行对比。我们将使用一种创新的液体分离方法来实现这一目标，这将使我们能够挖掘这些人群之间差异变化的蛋白质组。目的3将利用我们的新发现，表明Ag-经验的CD 4 T细胞可以促进佐剂毒性。我们将定义这一过程，并开发新的方法来对抗毒性，同时促进强佐剂反应。因此，该提议的结果将提供“佐剂与毒性”的比率，其可用于衡量TLR激动剂的有效性和安全性，并且重要的是提供了设计佐剂治疗剂的循证方法。