Regulation of pathogen-specific T cell immunity by adenosine generation

通过腺苷生成调节病原体特异性 T 细胞免疫

基本信息

批准号：
8418688
负责人：
DIRK HOMANN
金额：
$ 33.69万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8418688
关键词：
Ablation Acute Acute Disease Acute Lung Injury Adenosine Adenosine A1 Receptor Adenosine A2A Receptor Anti-Bacterial Agents Antiviral Agents Area Autocrine Communication Binding Biological Models Boxing CD8B1 gene Cells Cessation of life Childhood Clinical Communicable Diseases Consensus Data Development Disease Documentation Elderly Foundations Generations Goals Half-Life Immune Immune response Immune system Immunity Immunosuppressive Agents In Vitro Individual Infection Influenza Label Lymphocytic choriomeningitis virus Memory Modality Modeling Molecular Morbidity - disease rate Mouse Strains Mus Nucleotidases Pathway interactions Physiological Population Prevention Process Property Public Health Purinergic P1 Receptors Regimen Regulation Research Resolution Respiratory Tract Infections Role Signal Pathway Signal Transduction System T cell response T memory cell T-Lymphocyte Therapeutic Treatment Efficacy Vaccination Viral Virus Virus Diseases effective therapy extracellular gain of function improved in vivo in vivo Model influenzavirus insight loss of function lung injury mutant neutralizing antibody novel novel therapeutic intervention novel therapeutics nucleotidase pandemic disease pathogen preclinical study prevent receptor reconstitution research study respiratory secondary infection

Ablation Acute Acute Disease Acute Lung Injury Adenosine Adenosine A1 Receptor Adenosine A2A Receptor Anti-Bacterial Agents Antiviral Agents Area Autocrine Communication Binding Biological Models Boxing CD8B1 gene Cells Cessation of life Childhood Clinical Communicable Diseases Consensus Data Development Disease Documentation Elderly Foundations Generations Goals Half-Life Immune Immune response Immune system Immunity Immunosuppressive Agents In Vitro Individual Infection Influenza Label Lymphocytic choriomeningitis virus Memory Modality Modeling Molecular Morbidity - disease rate Mouse Strains Mus Nucleotidases Pathway interactions Physiological Population Prevention Process Property Public Health Purinergic P1 Receptors Regimen Regulation Research Resolution Respiratory Tract Infections Role Signal Pathway Signal Transduction System T cell response T memory cell T-Lymphocyte Therapeutic Treatment Efficacy Vaccination Viral Virus Virus Diseases effective therapy extracellular gain of function improved in vivo in vivo Model influenzavirus insight loss of function lung injury mutant neutralizing antibody novel novel therapeutic intervention novel therapeutics nucleotidase pandemic disease pathogen preclinical study prevent receptor reconstitution research study respiratory secondary infection

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项目摘要

DESCRIPTION (provided by applicant): Infectious diseases, including virus-induced respiratory infections and resultant acute lung injury, pose a considerable challenge to afflicted individuals, to the development of effective treatment modalities and to public health initiatives at large and the effective control of viral infections will require a more detailed understanding o the immune mechanisms involved in the eradication of relevant pathogens. An essential component of most antiviral and many antibacterial immune responses is the generation of pathogen-specific CD8+T cell immunity. Following resolution of acute disease or successful vaccination regimens, specific CD8+ effector T cells (CD8+TE) are subject to a gradual differentiation process that culminates in the establishment of specific CD8+T cell memory. Upon re-infection with the same or related viral pathogens, virus-specific CD8+ memory T cels (CD8+TM), together with neutralizing antibodies, provide enhanced protection due to their capacity to curtail viral spread, minimize clinical disease and avert potential death of infected hosts. In an effort to define the molecular, phenotypic and functional properties of highly protective CD8+TM, we have made the unexpected discovery that the development of robust secondary CD8+T cell responses is contingent upon effective adenosine generation and signaling in a "CD8+TM-intrinsic" fashion. The notion that adenosine generation/signaling can potentiate virus-specific CD8+T cell responses constitutes a novel concept, challenges the prevailing consensus about adenosine as a primarily "immunosuppressive" agent, and suggests the possibility of novel therapeutic avenues for promotion of antiviral T cell immunity. Here, we have developed a research plan that will identify, interrogate and characterize the molecular components in the adenosine generation/signaling pathway that promote secondary reactivity of virus- specific CD8+TM, that will define the precise patho-physiological context for "proinflammatory" adenosine generation and signaling (Specific Aims 1 and 2), and that will harness relevant insights obtained in the process of these studies for the development of novel therapeutic approaches that aim to amplify protective CD8+T cell immunity in a model for influenza virus-induced acute lung injury (Specific Aim 3). The continued and considerable burden of virus-induced acute lung injury, especially among pediatric and geriatric populations, emphasizes the urgent need for novel treatment approaches. We believe that the combination of mechanistic, contextual and pre-clinical studies as proposed in the present application has the potential to provide a rational foundation for the development of such therapeutic strategies.

描述（由申请人提供）：感染性疾病，包括病毒诱导的呼吸道感染和导致的急性肺损伤，对患病的个体构成了巨大挑战，对有效治疗方式的发展以及大型的公共卫生倡议以及病毒感染的有效控制，需要更详细的理解o对授予赋予相关性的免疫机制更详细地理解。大多数抗病毒和许多抗菌免疫反应的重要组成部分是病原体特异性CD8+T细胞免疫的产生。急性疾病或成功疫苗接种方案分辨率后，特定的CD8+效应T细胞（CD8+TE）受到逐渐分化过程，该过程最终在建立特定的CD8+T细胞存储器中。通过使用相同或相关的病毒病原体重新感染，病毒特异性的CD8+记忆T摄氏度（CD8+ TM）以及中和抗体，由于其减少病毒扩散的能力，最小化临床疾病并避免了受感染宿主的潜在死亡，因此提供了增强的保护。为了定义高度保护性CD8+TM的分子，表型和功能特性，我们已经意外地发现，强劲的次级CD8+T细胞反应的发展取决于“ CD8+TM- intrinsic”的有效腺苷产生和信号传导。腺苷产生/信号传导可以增强病毒特异性CD8+T细胞反应的观念构成了一种新颖的概念，挑战了关于腺苷的普遍共识，主要是一种“免疫抑制”药物，并提出了促进抗病毒T细胞免疫力的新型治疗途径的可能性。在这里，我们制定了一项研究计划，该计划将识别，询问和表征腺苷产生/信号传导途径中促进病毒特异性CD8+TM的次级反应性的分子成分，这些途径将定义“促炎性”的腺苷产生和信号（特定的目标），这些过程中的辅助性（特定于2）的过程，这些过程构成了“促进性”和“ 2）的过程，这些过程构成了这些型和2），并扎根于这些范围，这些过程对这些的过程，并介绍了这些范围。旨在在流感病毒诱导的急性肺损伤模型中扩增保护性CD8+T细胞免疫的治疗方法（特定AIM 3）。病毒引起的急性肺损伤的持续和巨大负担，尤其是在小儿和老年群体中，强调了对新型治疗方法的迫切需求。我们认为，本应用中提出的机械，背景和临床前研究的结合有可能为发展这种治疗策略的发展提供理性的基础。