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）：荚膜组织胞浆菌 (Hc) 是一种二形性真菌，在世界各地都有发现，是美国中西部和东南部的地方病，这种生物体可在免疫功能正常或免疫抑制的个体中引起危及生命的感染，是获得播散性感染的主要危险因素之一。 Hc 是 TNF-α 拮抗剂的用途在过去 3 年多的时间里，我们研究了趋化因子受体 CCR5 在加速清除中的作用。 Hc.我们的数据表明，这种受体对于决定调节性 T 细胞和 Th17 细胞之间的平衡至关重要。在 CCR5 敲除小鼠或缺乏该受体的主要配体之一 CCL4 的小鼠中，肺部调节性 T 细胞的数量为减少而 Th17 细胞数量增加，中和 IL-17 逆转了 CCR5 信号传导缺失的有益作用，我们检查了 CCR5 信号传导是否会产生不利影响。在 CCR5 敲除小鼠中，抗 TNF-α 对 Hc 的宿主防御作用减弱，因为调节性 T 细胞在抗 TNF-α 治疗后出现，并在一定程度上导致了动物的死亡。 CCR5 减轻了抗 TNF-α 治疗的有害后果，这一发现重新激发了人们对了解接受抗 TNF-α 治疗的 Hc 感染小鼠中驱动调节性 T 细胞扩增的细胞的兴趣，并研究这种细胞的缺乏是如何造成的。细胞因子或我们的初步数据表明，抗 TNF-α 对向受感染肺部募集炎症性单核细胞和树突状细胞具有深远影响。在本提案中，我们将致力于增强有关抗 TNF-α 如何促进 Treg 扩增以及缺乏这种细胞因子和/或调节性 T 细胞如何改变单核特异性吞噬细胞的招募和功能的知识。目的1 将努力识别一个或多个树突状细胞群或单核细胞/巨噬细胞在没有 TNF-α 的情况下促进调节性 T 细胞的扩增，并研究 TNF-α 中和小鼠中出现的调节性 T 细胞的表型，目的 2 将研究为什么炎症性单核细胞和树突状细胞的募集是重要的。我们将尝试将缺乏这种细胞因子的影响与调节性 T 的影响区分开来。目标 3 将探究 TNF-α 或调节性 T 细胞的抗体如何导致单核细胞/巨噬细胞和树突状细胞功能障碍。这些研究将更好地了解抗 TNF-α 增强感染易感性的机制。