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（由适用提供）：李斯特菌单核细胞增生剂，一种革兰氏阳性的辅助性细胞内病原体，能够刺激强大的细胞介导的免疫组织化学，目前正在作为免疫治疗平台开发。在最近的临床试验中，衰减的单核细胞增生李斯特氏菌已显示出作为癌症免疫疗法的希望。然而，单核细胞增生李斯特氏菌如何诱导细胞介导的反应的机制仍然很大未知。先前的研究表明，单核细胞增生李斯特氏菌必须到达宿主的细胞质以刺激适应性免疫响应，从而使研究人员假设胞质的先天免疫传感对自适应免疫的发展很重要。出乎意料的是，过度激活先天免疫抑制系统的单核细胞增生乳杆菌的菌株，例如炎性体，产生了晚期适应性免疫调查。该提案的总体目标是了解单核细胞增生李斯特氏菌的炎性体激活如何损害细胞介导的免疫组织化学的产生，并调节这些后果以改善免疫治疗结果。我们先前已经表明，由IL-1β，IL-18和类花生素组成的炎性小子激活下游的炎症环境在很大程度上损害了细胞介导的免疫呼吸。这项研究是由炎性体相关的感染（尤其是类固醇的产生）损害细胞介导的免疫共同体的假设所驱动的。我们将使用Luminex Technologies和ELISA用于类黄花素的炎症体激活下游的炎症环境。接下来，我们将调节在前列腺癌肿瘤模型中炎性体激活和检查CD8+ T细胞的生成后，将类菌烷的存在调节为自我和非自身抗原。此外，我们将通过减少肿瘤燃烧和增加肿瘤浸润淋巴细胞的形成来测试类花生酸抑制对调节抗肿瘤反应的影响。最后，我们将设计单核细胞增生李斯特氏菌，以表达称为仅吡啶蛋白（POPS）的炎性抑制剂，并以它们抑制IL-1β，IL-18和类花生酸的产生的能力来表征这些菌株。此外，我们将测试这些菌株的能力，以增加细胞介导的免疫反应并减少肿瘤伯嫩。这项工作的完成将提供有关炎性特异性炎症体如何损害细胞介导的免疫学和检查新颖的抑制炎性体激活的方法的洞察力。这些结果对不仅改善单核细胞增生李斯特氏菌作为免疫疗法平台有影响，还可以改善其他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，这些平台已被证明激活了炎症体。此外，这项工作将扩展到诱发炎症体的其他疫苗平台。激活，包括使用调节明矾的DNA疫苗和疫苗。