Cell-Mediated Immunity Following Listeria monocytogenes Induced Inflammasome Activation

单核细胞增生李斯特氏菌诱导炎症小体激活后的细胞介导的免疫

基本信息

批准号：
9117001
负责人：
Erin Marie Theisen
金额：
$ 3.17万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9117001
关键词：
Address Adenoviruses Affect Androgen Receptor Antigen Presentation Antigen-Presenting Cells Antigens Apoptosis Attenuated Autoantigens Bacteria Binding Proteins CD8B1 gene Caring Cells Cellular Immunity Clinical Trials Cyclooxygenase Inhibitors Cytosol DNA DNA Vaccines Development Eicosanoid Production Eicosanoids Engineering Environment Flagellin Generations Goals Human Immune Immune response Immune system Immunity Immunization Immunotherapeutic agent Immunotherapy Infection Inflammation Inflammatory Interleukin-1 beta Interleukin-18 Listeria monocytogenes Lytic Malignant Neoplasms Malignant neoplasm of prostate Measures Mediating Modeling Molecular Mus Nucleotides Outcome Pathway interactions Pattern Peptidoglycan Production Proteins Radiosurgery Research Research Personnel Role Salmonella typhimurium Self Tolerance Signal Transduction T cell response T-Cell Development T-Lymphocyte Technology Testing Toll-like receptors Tumor Antigens Tumor Burden Tumor Immunity Tumor-Infiltrating Lymphocytes Vaccine Design Vaccines Viral Work adaptive immunity aluminum sulfate antigen processing base cancer immunotherapy cell mediated immune response chemotherapy cytokine design improved inhibitor/antagonist insight marenostrin novel novel strategies pathogen prostate cancer model prostatic fraction Acid phosphatase isoenzyme public health relevance response success tumor

项目摘要

DESCRIPTION (provided by applicant): Listeria monocytogenes, a Gram-positive facultative intracellular pathogen, is capable of stimulating robust cell-mediated immunity and is currently being developed as an immunotherapeutic platform. Attenuated L. monocytogenes has shown promise as a cancer immunotherapy in recent clinical trials; however, the mechanism of how L. monocytogenes induces a cell-mediated response remains largely unknown. Previous research suggests that L. monocytogenes must reach the host cytosol to stimulate an adaptive immune response, thus leading researchers to hypothesize that cytosolic innate immune sensing is important for the development of adaptive immunity. Unexpectedly, strains of L. monocytogenes that hyper-activate innate immune systems, such as the inflammasome, generate decreased adaptive immune responses. The overarching goal of this proposal is to understand how inflammasome activation by L. monocytogenes impairs the generation of cell-mediated immunity and to modulate these consequences for improved immunotherapeutic outcomes. We have previously shown that the inflammatory milieu downstream of inflammasome activation, which consists of IL-1β, IL-18, and eicosanoids, is largely responsible for impairing cell-mediated immune responses. This research is driven by the hypothesis that inflammasome-associated inflammation, particularly eicosanoid production, impairs cell-mediated immunity. We will characterize the inflammatory milieu downstream of inflammasome activation using Luminex technologies and ELISAs for eicosanoids. We will next modulate the presence of eicosanoids following inflammasome activation and examine generation of CD8+ T- cells in a prostate cancer tumor model to both self and non-self antigens. Additionally, we will test the impact of eicosanoid inhibition on modulating anti-tumor responses through both decreasing tumor burden and increasing the formation of tumor-infiltrating lymphocytes. Finally, we will engineer L. monocytogenes to express inflammasome inhibitors known as pyrin-only proteins (POPs), and characterize these strains in their ability to inhibit IL-1β, IL-18, and eicosanoid production. Additionally, we will test these strains for their abilities to increase cell-mediated immune responses and decrease tumor burden. Completion of this work will provide insight into how inflammasome-specific inflammation impairs cell-mediated immunity and examine novel means of inhibiting inflammasome activation. These results have implications for improving not only L. monocytogenes as an immunotherapy platform, but also other pathogen-based immunotherapeutic platforms including Salmonella typhimurium and adenovirus that have been shown to activate the inflammasome. Further, this work will extend to other vaccine platforms that induce inflammasome activation including DNA vaccines and vaccines that use the adjuvant, alum.

描述（由申请人提供）：单核细胞增生李斯特菌是一种革兰氏阳性兼性细胞内病原体，能够刺激强大的细胞介导的免疫，目前正在开发作为免疫治疗平台，减毒单核细胞增生李斯特菌近年来显示出作为癌症免疫疗法的前景。临床试验；然而，单核细胞增生李斯特菌如何诱导细胞介导的反应的机制仍然很大程度上未知。宿主细胞质刺激适应性免疫反应，从而导致研究人员认为细胞质先天免疫感应对于适应性免疫的发展很重要。出乎意料的是，过度激活先天免疫系统（例如炎症小体）的单核细胞增生李斯特氏菌菌株产生的免疫应答减少。该提案的首要目标是了解单增李斯特菌激活炎症小体如何损害细胞介导的免疫的产生，并调节这些后果以改善。我们之前已经表明，炎症小体激活下游的炎症环境（由 IL-1β、IL-18 和类二十烷酸组成）在很大程度上负责损害细胞介导的免疫反应。 -相关炎症，特别是类二十烷酸的产生，会损害细胞介导的免疫，我们将使用 Luminex 技术和 ELISA 来表征炎症小体激活下游的炎症环境。接下来，我们将在炎症体激活后调节类二十烷酸的存在，并检查前列腺癌肿瘤模型中针对自身和非自身抗原的 CD8+ T 细胞的生成。此外，我们将测试类二十烷酸抑制对调节抗-的影响。通过减少肿瘤负荷和增加肿瘤浸润淋巴细胞的形成来调节肿瘤反应最后，我们将改造单核细胞增生李斯特氏菌来表达称为仅吡啶的炎性体抑制剂。此外，我们还将测试这些菌株增强细胞介导的免疫反应和减少肿瘤负荷的能力。这项工作将深入了解炎症小体特异性炎症如何损害细胞介导的免疫，并研究抑制炎症小体激活的新方法。这些结果不仅对改善单核细胞增生李斯特氏菌作为免疫治疗平台具有重要意义。基于病原体的免疫治疗平台，包括鼠伤寒沙门氏菌和腺病毒，已被证明可以激活炎症小体。此外，这项工作将扩展到诱导炎症小体激活的其他疫苗平台，包括 DNA 疫苗和使用明矾佐剂的疫苗。