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：
8848512
负责人：
DIRK HOMANN
金额：
$ 30.02万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8848512
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

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）：传染病，包括病毒引起的呼吸道感染和由此产生的急性肺损伤，对患病个体、有效治疗方式的开发、整个公共卫生举措以及病毒的有效控制构成了相当大的挑战。感染需要更详细地了解消灭相关病原体所涉及的免疫机制。大多数抗病毒和许多抗菌免疫反应的一个重要组成部分是病原体特异性 CD8+T 细胞免疫的产生。急性疾病缓解或疫苗接种方案成功后，特异性 CD8+ 效应 T 细胞 (CD8+TE) 会经历逐渐分化过程，最终建立特异性 CD8+T 细胞记忆。当再次感染相同或相关的病毒病原体时，病毒特异性 CD8+ 记忆 T 细胞 (CD8+TM) 与中和抗体一起提供增强的保护，因为它们能够减少病毒传播、最大限度地减少临床疾病并避免潜在的死亡。被感染的主机。在努力定义高度保护性 CD8+TM 的分子、表型和功能特性的过程中，我们意外地发现，强大的次级 CD8+T 细胞反应的发展取决于“CD8+TM”中有效的腺苷生成和信号传导。 -内在的“时尚”。腺苷产生/信号传导可以增强病毒特异性 CD8+T 细胞反应的概念构成了一个新概念，挑战了关于腺苷作为主要“免疫抑制”剂的普遍共识，并提出了促进抗病毒 T 细胞的新治疗途径的可能性免疫。在这里，我们制定了一项研究计划，将识别、询问和表征腺苷生成/信号通路中促进病毒特异性 CD8+TM 次级反应的分子成分，这将定义“促炎症”的精确病理生理背景。腺苷生成和信号转导（具体目标 1 和 2），并将利用这些研究过程中获得的相关见解来开发新的治疗方法，旨在增强 CD8+T 细胞的保护性免疫流感病毒引起的急性肺损伤模型（具体目标 3）。病毒引起的急性肺损伤，尤其是儿童和老年人群，持续承受着巨大的负担，这凸显了对新治疗方法的迫切需要。我们相信，本申请中提出的机械、背景和临床前研究的组合有可能为此类治疗策略的开发提供合理的基础。