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

基本信息

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
项目类别：
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

项目摘要

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，但用细胞内细菌病原体单核细胞增生李斯特氏菌进行免疫还可以诱导强大的细胞介导的免疫反应。作为一个有前途的免疫治疗平台，单核细胞增生李斯特菌代表了一个理想的模型系统，用于了解细胞介导的免疫反应是如何产生的，我们之前已经证明了细胞质对炎症小体的激活。单核细胞增生李斯特菌抑制细胞介导的免疫的产生，该提案的目的是了解这一观察结果背后的机制，并确定治疗干预的机会，包括抑制单核细胞增生李斯特菌诱导的炎症小体激活。目的： 1) 确定细胞死亡（细胞焦亡、细胞凋亡和/或坏死）是否调节单增李斯特菌免疫后肿瘤特异性细胞介导的免疫的发展 2) 识别炎症中依赖于炎症的改变会影响单核细胞增生李斯特菌免疫后细胞介导的免疫的发展 3) 在单核细胞增生李斯特菌免疫期间抑制炎症小体激活，以促进细胞介导的免疫的发展我们将使用一组独特的单核细胞增生李斯特菌菌株，专门设计用于激活不同的细胞死亡途径，以了解细胞焦亡、细胞凋亡和坏死如何影响感染背景下肿瘤特异性细胞介导的免疫的产生。表征抗原特异性 T 细胞、治疗性和预防性肿瘤消退模型，最后是树突状细胞抗原呈递，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定义细胞因子（例如 IL10）的作用。）、类二十烷酸（例如 PGE2）在炎症小体影响细胞介导的免疫反应的产生中的 T 细胞激活标记最后，我们将改造单核细胞增生李斯特氏菌以表达病毒和/或哺乳动物。炎症体激活抑制剂，以检验炎症体抑制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，这些研究将通过两种方式直接有助于产生更好的免疫疗法。炎症小体在细胞介导的免疫产生中的作用，并提出了治疗干预的机会，这不仅对于基于单核细胞增生李斯特氏菌的免疫疗法很重要，而且对于导致炎症小体激活的其他疫苗和疗法（包括这些研究还将通过设计主动抑制炎症小体激活的菌株，直接导致基于单核细胞增生李斯特氏菌的免疫治疗平台的开发。