Modulating the Inflammasome to Generate Robust Cell Mediated Immunity

调节炎症小体以产生强大的细胞介导的免疫

• 批准号: 8958962
• 负责人: JOHN-DEMIAN SAUER
• 金额: $ 34.22万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-06 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8958962
• 关键词: Adjuvant; Antigen Presentation; Antigens; Apoptosis; Attenuated; Autoantigens; Bacteria; Biological Assay; Biological Models; Caspase-1; Cell Death; Cells; Cellular Immunity; Clinical Trials; Cytosol; Cytotoxic T-Lymphocytes; DNA; DNA Vaccines; Data; Defect; Dendritic Cells; Development; Dinoprostone; Eicosanoid Production; Eicosanoids; Engineering; Generations; Global Change; Goals; IL18 gene; Immune; Immune response; Immunity; Immunization; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Infection; Infectious Agent; Inflammation; Interferon Activation; Interleukin-1 beta; Interleukin-10; Intervention; Lead; Left; Listeria monocytogenes; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Mediating; Modeling; Multiprotein Complexes; Mus; Necrosis; Pathway interactions; Postdoctoral Fellow; Production; Role; Self Tolerance; Signal Pathway; Signal Transduction; Stimulus; T cell response; T-Cell Activation; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; Tumor Antigens; Tumor Immunity; Uric Acid; Vaccines; Vacuole; Viral; Work; adaptive immunity; aluminum sulfate; base; cancer immunotherapy; cell mediated immune response; cytokine; design; extracellular; immunogenic; improved; inhibitor/antagonist; killings; neoplasm immunotherapy; neoplastic cell; pathogen; prophylactic; prostate cancer model; public health relevance; receptor; response; secretion process; therapeutic vaccine; transgenic adenocarcinoma of mouse prostate; tumor

 DESCRIPTION (provided by applicant): The primary goal of tumor immunotherapy is the generation of a robust cell mediated immune response. Though the mechanism remains unclear, immunization with the intracellular bacterial pathogen Listeria monocytogenes results in the induction of robust cell mediated immunity. In addition to being a promising immunotherapeutic platform, L. monocytogenes represents an ideal model system for understanding how cell mediated immune responses are generated. We have previously demonstrated that activation of the inflammasome by cytosolic L. monocytogenes inhibits the generation of cell mediated immunity. The goal of this proposal is to understand the mechanism behind this observation and to identify opportunities for therapeutic intervention, including inhibition of L. monocytogenes induced inflammasome activation. We will achieve this through the following specific aims: 1) Determine if cell death (pyroptosis, apoptosis, and/or necrosis) modulates the development of tumor specific cell mediated immunity following L. monocytogenes immunization 2) Identify inflammasome dependent alterations in inflammation that influence the development of cell mediated immunity following L. monocytogenes immunization 3) Inhibit inflammasome activation during L. monocytogenes immunization to increase the development of cell mediated immunity We will use a unique set of L. monocytogenes strains engineered to specifically activate different cell death pathways to understand how pyroptosis, apoptosis and necrosis influence the generation of tumor specific cell mediated immunity in the context of infection. Specifically we will characterize antigen specific T-cells, therapeutic and prophylactic tumor regression models and finally dendritic cell antigen presentation to understand how cell death modulates the immune response. Subsequently, we will use a combination of transgenic mice and inhibitors to define the role of cytokines (eg IL10), eicosanoids (eg PGE2) T-cell activation markers in the generation of inflammasome influenced cell mediated immune responses. Finally, we will engineer L. monocytogenes to express viral and/or mammalian inhibitors of inflammasome activation, to test the hypothesis that inflammasome inhibition will lead to more robust antigen specific T-cell development and anti-tumor immunity. These studies will directly contribute to the generation of better immunotherapies in two ways. Our results will identify the negative role of the inflammasome in generation of cell mediated immunity and suggest opportunities for therapeutic intervention. This is important not only for L. monocytogenes based immunotherapies but for other vaccines and therapeutics that result in inflammasome activation including the adjuvant alum and DNA vaccines. These studies will also directly lead to the development of a more robust L. monocytogenes based immunotherapeutic platform through the design of strains that actively inhibit inflammasome activation.

 描述(由申请人提供)：肿瘤免疫治疗的主要目标是产生强大的细胞介导的免疫反应。尽管其机制尚不清楚，但单核细胞增生性李斯特菌细胞内致病菌免疫可诱导出强大的细胞免疫。除了作为一个有前景的免疫治疗平台，单核细胞增多性乳杆菌是理解细胞介导的免疫反应是如何产生的一个理想的模型系统。我们以前已经证明，胞浆单核细胞增多性李斯特菌激活炎症体会抑制细胞免疫的产生。这项建议的目的是了解这一观察背后的机制，并确定治疗干预的机会，包括抑制单核细胞增多性乳杆菌诱导的炎症小体激活。我们将通过以下特定目标来实现这一点：1)确定细胞死亡(热下垂、细胞凋亡和/或坏死)是否调节了单核细胞增多性乳杆菌免疫后肿瘤特异性细胞免疫的发展2)确定单核细胞增多性乳杆菌免疫后影响细胞免疫发展的炎性小体依赖性变化3)在单核细胞增多性乳杆菌免疫期间抑制炎小体激活以促进细胞免疫的发展我们将使用一组独特的单核细胞增多性乳杆菌工程菌株来特异性激活不同的细胞死亡途径，以了解在感染的情况下，嗜热症、细胞凋亡和坏死如何影响肿瘤细胞介导免疫的产生。具体地说，我们将描述抗原特异性T细胞、治疗性和预防性肿瘤消退模型，以及最后树突状细胞抗原提呈，以了解细胞死亡如何调节免疫反应。随后，我们将使用转基因小鼠和抑制剂的组合来确定细胞因子(如IL10)、二十碳二烯(如PGE2)T细胞激活标记物在产生炎症小体影响的细胞免疫反应中的作用。最后，我们将使单核细胞增多性乳杆菌表达病毒和/或哺乳动物的炎症体激活抑制物，以检验抑制炎症体将导致更强大的抗原特异性T细胞发育和抗肿瘤免疫的假设。这些研究将在两个方面直接促进更好的免疫疗法的产生。我们的结果将确定炎症小体在细胞免疫产生中的负面作用，并为治疗干预提供机会。这不仅对基于单核细胞增多性李斯特氏菌的免疫疗法很重要，而且对其他导致炎症体激活的疫苗和疗法也很重要，包括明矾和DNA佐剂疫苗。这些研究还将通过设计积极抑制炎症小体激活的菌株，直接导致开发更强大的基于单核细胞增多性乳杆菌的免疫治疗平台。