Molecular and Cellular Determinants of Immunity to Histoplasmosis

组织胞浆菌病免疫的分子和细胞决定因素

基本信息

批准号：
9339497
负责人：
GEORGE S. DEEPE
金额：
--
依托单位：
CINCINNATI VA MEDICAL CENTER RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9339497
关键词：
Abbreviations Adoptive Transfer Animals Antibodies Area Behavior Biological Bone Marrow CCL4 gene CCR CCR5 gene CXC Chemokines Caring Cell physiology Cells Chemotactic Factors China Clinical Coccidioides Colony-forming units Communicable Diseases Country Data Defect Dendritic Cells Development Diagnosis Disease Elements Environment Equilibrium FOXP3 gene Flow Cytometry Functional disorder Funding Generations Granulocyte-Macrophage Colony-Stimulating Factor Green Fluorescent Proteins Growth Histoplasma capsulatum Histoplasmosis Host Defense Host resistance Human Immune response Immunity Immunocompetent Immunocompromised Host Impairment India Individual Infection Inflammatory Innate Immune Response Interferon Type II Interferon-alpha Interleukin-1 Interleukin-17 Interleukins Intravenous Knockout Mice Knowledge Life Ligands Lipopolysaccharides Lung Major Histocompatibility Complex Mediator of activation protein Medical Molecular Monoclonal Antibodies Mononuclear Mus Mycobacterium tuberculosis Natural Immunity Nitric Oxide Organism Pathogenicity Phagocytes Phenotype Physicians Polymerase Chain Reaction Population Predisposition Production Progressive Disease Property Quantitative Reverse Transcriptase PCR Recruitment Activity Regulatory T-Lymphocyte Resources Risk Risk Factors Role STAT protein Signal Transduction Southeastern United States T-Lymphocyte TNF gene Therapeutic Therapeutic immunosuppression Time Training Treatment Factor Veterans Work advanced disease antitumor effect beta-Chemokines chemokine receptor cytokine design enhancing factor epidemiologic data experimental study fungus immunosuppressed inhibitor/antagonist interest macrophage medical attention medically underserved population monocyte neutralizing monoclonal antibodies neutrophil pathogen public health relevance receptor

项目摘要

DESCRIPTION (provided by applicant): The dimorphic fungus, Histoplasma capsulatum (Hc) is found world-wide, and endemic to the Midwestern and southeastern United States. The organism can cause a life-threatening infection in immunocompetent or immunosuppressed individuals. One of the major risk factors for acquisition of disseminated Hc is the use of the TNF-� antagonist. In the past 3+ years, we have examined the role of the chemokine receptor, CCR5, in hastening the clearance of Hc. Our data demonstrate that this receptor is pivotal in dictating the balance between regulatory T cells and Th17 cells. In the CCR5 knockout mice or in mice that lack one of this receptor's major ligand, CCL4, the number of regulatory T cells in lungs is diminished whereas the number of Th17 cells is elevated. Neutralization of IL-17 reverses the salutary effect of a lack of CCR5 signaling. As an extension of these studies, we examined if the inimical effects of anti-TNF-� on host defenses to Hc were mitigated in the CCR5 knockout mice. We pursued this consideration since regulatory T cells arise after anti- TNF-� treatment and are responsible, in part, for the demise of animals. The absence of CCR5 mitigated the deleterious consequence of anti-TNF-� treatment. This finding has rekindled an interest in understanding the cells that drive the expansion of regulatory T cells in Hc-infected mice given anti-TNF-� and in examining how the lack of this cytokine or regulatory T cells blunt the innate immune response. Our preliminary data demonstrate that anti-TNF-� has a profound effect on recruitment of inflammatory monocytes and dendritic cells to the infected lung. Moreover, the cells that do reach the lungs are grossly impaired in their ability to inhibit the growth of Hc. In this proposal we will pursue aims to enhance knowledge regarding how anti-TNF-� promotes Treg expansion and how the lack of this cytokine and/or regulatory T cells alter recruitment and function of mononuclear phagocytes. Specific aim 1 will endeavor to identify a population or populations of dendritic cells or monocyte/macrophages that promote expansion of regulatory T cells in the absence of TNF-� and to investigate the phenotype of regulatory T cells that arises in TNF-�-neutralized mice. Aim 2 will examine why recruitment of inflammatory monocytes and dendritic cells is defective. We will attempt to separate the contribution of the lack of this cytokine from that of regulatory T cells. Aim 3 will pursue how antibody to TNF-� or regulatory T cells cause dysfunction of monocyte/macrophages and dendritic cells. These studies will generate a better understanding of the mechanisms by which anti-TNF-� enhances susceptibility to infection.

描述（由申请人提供）：全球范围内发现了二态真菌，组织胶质囊膜（HC），并在美国中西部和东南部的内在。该生物会导致免疫能力或免疫抑制个体威胁生命的感染。获取传播HC的主要风险因素之一是使用TNF-拮抗剂。在过去的3年中，我们研究了趋化因子受体CCR5在加速HC清除率中的作用。我们的数据表明，该受体在决定调节性T细胞和Th17细胞之间的平衡方面至关重要。在CCR5敲除小鼠或缺乏该受体主要配体CCL4之一的小鼠中，肺中调节性T细胞的数量减少，而Th17细胞的数量升高。 IL-17的中和逆转了缺乏CCR5信号传导的有益作用。作为这些研究的扩展，我们检查了CCR5基因敲除小鼠中抗TNF-对宿主防御对HC的无意性影响。我们追求这种考虑，因为调节T细胞是在抗TNF-治疗后出现的，并部分负责动物的灭亡。 CCR5的缺乏减轻了抗TNF-治疗的有害后果。这一发现重新点燃了人们对驱动抗TNF-的HC感染小鼠中调节性T细胞扩张的细胞的兴趣，并研究了这种细胞因子或调节性T细胞的缺乏如何钝化了先天免疫响应。我们的初步数据表明，抗TNF-对炎症性单核细胞和树突状细胞的募集具有深远的影响。此外，确实到达肺部的细胞在抑制HC生长的能力方面严重受损。在此提案中，我们将追求旨在增强有关抗TNF-如何促进Treg扩张的知识，以及这种细胞因子和/或调节性T细胞的缺乏如何改变单核吞噬细胞的募集和功能。特定的目标1将努力识别树突状细胞的人群或种群或单核细胞/巨噬细胞在不存在TNF-�的情况下促进调节性T细胞的扩张，并研究在TNF-中和小鼠中产生的调节T细胞的表型。 AIM 2将研究为什么募集炎症单核细胞和树突状细胞有缺陷。我们将尝试将缺乏这种细胞因子的贡献与调节性T的贡献区分开 AIM 3将追求对TNF-或调节性T细胞的抗体如何引起单核细胞/巨噬细胞和树突状细胞功能障碍。这些研究将更好地理解抗TNF-增强感染敏感性的机制。