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

基本信息

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
项目类别：
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

项目摘要

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摘要抑制受体PD1和LAG3在调节免疫耐受性和预防方面协同作用自身免疫性。但是，它们还限制了肿瘤清除率和免疫组织性病毒感染。 PD1/lag3介导T细胞的固有控制，但也调节发育，稳态和功能调节性T细胞（Tregs）。那就是抑制受体对于维持免疫控制至关重要，但也代表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协同作用 PD1和LAG3的利用，在各种疾病环境中，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，而小鼠则缺乏两者 PD1和LAG3患有致命的全身性自身免疫性疾病。我们还表明了组合封锁 PD1和LAG3的摄入可以恢复患有慢性病毒感染的小鼠中耗尽的T细胞，并诱导完整患有预先存在的肿瘤的小鼠缓解。该PPG的主要目标和长期目标是确定临界免疫中抑制受体之间的相对贡献和协同相互作用人群。程序项目的范围将重点关注PD1和LAG3之间的相互作用 CD4+ T细胞，CD8+ T细胞和Treg在耐受性和自身免疫性的调节中（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“ PD1和LAG3 途径通过细胞和分子串扰协同作用，导致重叠和独特集体调节CD4+ T Conv细胞，CD8+ T细胞和Treg功能的机制在自身免疫性，癌症中和慢性病毒感染”。鉴于所有T细胞子集表达了PD1/LAG3，尚不清楚什么影响在特定疾病环境中，PD1/LAG3的损失在特定细胞类型上。该PPG的主要优势是否可用的独特工具可以促进特定T细胞中PD1和/或lag3的“外科手术”删除组成或以暂时控制的方式进行亚群。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）。