Synergies among inhibitory receptors in tolerance, cancer & antiviral immunity

抑制性受体在耐受性、癌症方面的协同作用

• 批准号: 10470821
• 负责人: Dario AA Vignali
• 金额: $ 231.17万
• 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 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470821
• 关键词: Advanced Malignant Neoplasm; Agonist; Area; Autoimmune Diseases; Autoimmunity; Biological; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CRISPR screen; CTLA4 blockade; CTLA4 gene; Cells; Chronic; Clinical; Clinical Trials; Combination immunotherapy; Computational Biology; Data; Development; Disease; Environment; Equilibrium; Exhibits; Goals; HIV; Hepatitis C; Homeostasis; Imaging Techniques; Immune; Immune Tolerance; Immunity; Immunology; In complete remission; Individual; Infection; Lead; LoxP-flanked allele; Malignant Neoplasms; Mediating; Medicine; Molecular; Mus; Mutant Strains Mice; Nature; Nobel Prize; Operative Surgical Procedures; PD-1 blockade; PD-1 pathway; Paper; Pathway interactions; Patients; Peer Review; Population; Prevention; Publishing; Reagent; Regulation; Regulatory T-Lymphocyte; Role; Running; Science; Seminal; Signal Transduction; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Therapeutic; Time; Tumor Immunity; Virus Diseases; Voting; antiviral immunity; autoreactivity; base; cancer immunotherapy; cancer therapy; cell type; chronic infection; clinical development; clinically significant; combinatorial; exhaust; functional genomics; immune checkpoint blockade; immunopathology; immunoregulation; in vivo; innovation; overexpression; peripheral tolerance; pre-clinical; prevent; programmed cell death protein 1; programs; receptor; research and development; response; success; synergism; systemic autoimmune disease; therapeutic target; therapeutically effective; tool; tumor

PPG SUMMARY 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 conv 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).

PPG总结 抑制性受体PD 1和LAG 3在免疫耐受的调节和免疫耐受的预防中协同作用。 自身免疫然而，它们也限制了肿瘤清除和对慢性病毒感染的杀菌免疫。 PD 1/LAG 3介导T细胞的内在控制，但也调节T细胞的发育、稳态和功能。 调节性T细胞（Tcells）。因此，抑制性受体对于维持免疫控制是至关重要的，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 PD 1和LAG 3在各种疾病环境中的应用，包括自身免疫、肿瘤和慢性病毒感染。 感染.然而，单独缺乏PD 1或LAG 3的小鼠表现出最小的免疫病理学， PD 1和LAG 3发展致命的系统性自身免疫性疾病。我们还表明， PD 1和LAG 3的结合可以重振慢性病毒感染小鼠中衰竭的T细胞并诱导完全T细胞分化 在具有预先存在的肿瘤的小鼠中缓解。本PPG的主要目标和长期目标是确定 抑制性受体在关键免疫中的相对贡献和它们之间的协同相互作用 人口。该计划项目的范围将集中在PD 1和LAG 3之间的相互作用， CD 4 + T细胞、CD 8 + T细胞和T淋巴细胞在耐受和自身免疫调节中的作用（项目1），肿瘤 免疫（项目2）和慢性病毒感染（项目3）。我们的中心假设是“PD 1和LAG 3 途径通过细胞和分子串扰协同作用，导致重叠和独特的 在自身免疫、癌症和免疫性疾病中共同调节CD 4 + T转化细胞、CD 8 + T细胞和Treg功能的机制 慢性病毒感染”。鉴于PD 1/LAG 3由所有T细胞亚群表达，尚不清楚其对T细胞亚群的影响。 PD 1/LAG 3的缺失在特定疾病环境中对特定细胞类型有影响。这款PPG的主要优势在于 是可利用的独特工具，其将促进从特定T细胞中“手术”删除PD 1和/或LAG 3， 亚群组成或在时间上控制的方式。这一项目设计补助金将由四个核心支助; 管理（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）。