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：
8434101
负责人：
Anthony T Vella
金额：
$ 35.97万
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/8434101
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）：我们的目标是定义促炎性细胞因子和因收费受体（TLR）刺激产生的影响特定的CD4 T细胞免疫。表征这一过程将通过定义新方法来控制体内T细胞反应的同时最大程度地减少毒性，从而改善辅助发育。这个目标是基于我们最近的工作，该工作揭示了TLR4适配器之间的意外劳动分裂。一条路径表明T细胞效应子分化和归巢对固体器官，另一个路径是克隆膨胀和诱导细胞存活的原因。因此，发现从TLR4途径发出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CD4 T细胞推动理想的影响。通过确定每个适配器如何影响T细胞的机制，将在3个特定目标中实现此目标。在AIM 1中，我们将通过检查先天细胞因子轴来确定TRIF如何控制T细胞效应子的分化和归纳，从而假设我们假设这两种细胞行为。来自此目标的数据将有助于设计疫苗配方，以帮助将效应的细胞迁移到人体的特定部位。在AIM 2中，将捕获和对比已编程为死亡的相同特定的T细胞的特定CD4 T细胞的蛋白质组学图。我们将使用创新的液体分馏方法来实现这一目标，该方法将使我们能够为这些人群之间的差异变化开采蛋白质组。 AIM 3将利用我们的新发现，证明AG经验的CD4 T细胞可以促进辅助毒性。我们将定义这一过程，并开发新的方法来对抗毒性，同时促进强烈的辅助反应。因此，该提案的结果将提供“毒性与毒性”比率，该比率可用于评估TLR激动剂的有效性和安全性，并且重要的是为设计辅助治疗剂提供了基于证据的方法。