Synergies among inhibitory receptors in tolerance, cancer and antiviral immunity

抑制性受体在耐受性、癌症和抗病毒免疫方面的协同作用

• 批准号: 8854446
• 负责人: Dario AA Vignali
• 金额: $ 222.34万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8854446
• 关键词: Activities of Daily Living; Antiviral Agents; Autoimmune Diseases; Autoimmunity; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Chronic; Computational Biology; Data; Development; Disease; Environment; Exhibits; Goals; Growth and Development function; Health; Homeostasis; Immune; Immune Tolerance; Immunity; In complete remission; Investigation; Lead; Malignant Neoplasms; Mediating; Molecular; Mus; Mutant Strains Mice; Operative Surgical Procedures; Pathway interactions; Play; Population; Prevention; Reagent; Regulation; Regulatory T-Lymphocyte; Relative (related person); Role; Running; Science; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Tissues; Tumor Immunity; Viral; Virus Diseases; Voting; cancer immunotherapy; cell type; clinically significant; combinatorial; early onset; exhaust; functional genomics; immunopathology; in vivo; prevent; programs; receptor; systemic autoimmune disease; therapeutic target; tool; tumor; tumor growth

DESCRIPTION (provided by applicant): The inhibitory receptors PD1 and LAG3 synergize in the regulation of immune tolerance and prevention of autoimmunity. However, they also limit tumor clearance and sterilizing immunity to chronic viral infections. PD1/LAG3 mediate T cell intrinsic control, but also modulate the development, homeostasis and function of regulatory T cells (Tregs). Thus, inhibitory receptors are critical for maintaining immune control but also represent a major barrier to effective anti-tumor and anti-viral immunity. Our recent studies have highlighted the synergistic utilization of PD1 and LAG3, in a variety of disease settings including autoimmunity, tumors and chronic viral infections. Whereas mice lacking either PD1 or LAG3 alone exhibit minimal immunopathology, mice lacking both PD1 and LAG3 develop lethal systemic autoimmune disease. We have also shown that combinatorial blockade of PD1 and LAG3 can reinvigorate exhausted T cells in mice with chronic viral infections and induce complete remission in mice with pre-existing tumors. The primary goal and long-term objective of this PPG is to determine the relative contribution of, and synergistic interaction between, inhibitory receptors in critical immune populations. The scope of the program project will focus on the interplay between PD1 and LAG3 in regulating CD4+ T cells, CD8+ T cells and Tregs in the modulation of tolerance and autoimmunity (Project 1), tumor immunity (Project 2) and chronic viral infection (Project 3). Our central hypothesis is that "PD1 and LAG3 pathways synergize through cellular and molecular crosstalk leading to both overlapping and unique mechanisms that collectively regulate CD4+ T cell, CD8+ T cell and Treg function in autoimmunity, cancer and chronic viral infections". Given that PD1/LAG3 are expressed by all T cell subsets, it is not clear what impact the loss of PD1/LAG3 has on a particular cell type in a particular disease setting. A major strength of this PPG is the available of unique tools that will facilitate the `surgical' deletion of PD1 and/or LAG3 from specific T cell subpopulations constitutively or in a temporally controlled manner. This PPG will be supported by four cores; Administrative (Core A), Mutant Mouse (Core B), Functional Genomics and Computational Biology (Core C), and Immunopathology Cores (Core D).

描述（由申请人提供）：抑制受体PD1和LAG3在调节免疫耐受性和预防自身免疫方面协同作用。但是，它们还将肿瘤清除率限制为慢性病毒感染的免疫力。 PD1/LAG3介导T细胞的内在对照，但也调节调节T细胞（Tregs）的发育，稳态和功能。因此，抑制受体对于维持免疫控制至关重要，但也代表了有效抗肿瘤和抗病毒免疫的主要障碍。我们最近的研究强调了PD1和LAG3的协同利用，包括自身免疫性，肿瘤和慢性病毒感染。仅缺乏PD1或LAG3的小鼠表现出最小的免疫病理学，而缺乏PD1和LAG3的小鼠会出现致命的全身性自身免疫性疾病。我们还表明，PD1和LAG3的联合封锁可以恢复患有慢性病毒感染的小鼠疲惫的T细胞，并在患有肿瘤的小鼠中诱导完全缓解。该PPG的主要目标和长期目标是确定关键免疫种群中抑制受体之间的相对贡献和协同相互作用。该计划项目的范围将集中在调节CD4+ T细胞，CD8+ T细胞和Treg的PD1和LAG3之间的相互作用，以调节耐受性和自身免疫性（项目1），肿瘤免疫力（项目2）和慢性病毒感染（Project 3）。我们的中心假设是“ PD1和LAG3途径通过细胞和分子串扰协同，导致重叠和独特的机制，这些机制共同调节CD4+ T细胞，CD8+ T细胞，CD8+ T细胞和Treg功能在自身免疫性，癌症和慢性病毒感染中的功能”。鉴于PD1/LAG3均由所有T细胞子集表达，因此尚不清楚PD1/LAG3在特定疾病环境中对特定细胞类型的损失有什么影响。该PPG的主要优势是可用的独特工具，可以促进特定的T细胞亚群体的“外科手术”缺失和/或lag3的组成部分或以时间控制的方式。该PPG将由四个核心支持；行政（核心A），突变小鼠（核心B），功能基因组学和计算生物学（核心C）和免疫病理学核心（核心D）。