Antibody Protection in Histoplamosis

组织胞浆菌病中的抗体保护

• 批准号: 6986738
• 负责人: JOSHUA D NOSANCHUK
• 金额: $ 36.34万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6986738
• 关键词: SDS polyacrylamide gel electrophoresis; antibody formation; antifungal antibody; antigen antibody reaction; biotechnology; cellular immunity; enzyme linked immunosorbent assay; epitope mapping; fungal antigens; fungal proteins; fungal vaccines; histones; histoplasmosis; host organism interaction; immunotherapy; interferons; interleukin 4; interleukin 6; laboratory mouse; microorganism disease chemotherapy; monoclonal antibody; nonhuman therapy evaluation; opportunistic infections; vaccine development; vaccine evaluation; western blottings

DESCRIPTION (provided by applicant): Histoplasma capsulatum is an important endemic, intracellular fungal pathogen that can cause life threatening disseminated disease, particularly in individuals with impaired immunity. Despite the use of potent anti-fungal medications significant morbidity and mortality from histoplasmosis continues to occur, and current treatment regimens frequently fail to eradicate the organism in immuno-compromised individuals, particularly those with AIDS. Recent data from intracellular pathogens (i.e. Mycobacterium tuberculosis, Listeria monocytogenes) and other fungi (i.e. Cryptococcus neoformans, Candida albicans) demonstrates that specific antibody can improve the ability of the host to combat these infecting microbes. I have identified three murine monoclonal antibodies (mAb) that bind to the H. capsulatum yeast cell surface. Administration of the mAbs reduced fungal burden, decreased pulmonary inflammation, and prolonged survival in a murine infection model. MAb treatment was associated with enhanced production of lL-4, IL-6, and IFN- in the lungs of infected mice. The mAbs increased phagocytosis of yeast by macrophage via interactions dependent on CR3. Growth of mAb-opsonized H. capsulatum was inhibited after ingestion and killing of intracellular fungus occurred. The H. capsulatum-binding mAbs interact with a histone-like protein (histone H2B) expressed on the cell surface of the fungus. The goals of this application are to define the mechanism of antibody action against this fungus, to characterize the protective epitope on the antigen, and to use the protein in the generation of new mAbs and in vaccine development. Four specific Aims are proposed: 1. To map the epitope of mAb 9C7 and generate additional mAbs to H. capsulatum. 2. To investigate the mechanism(s) of antibody-mediated protection against H. capsulatum in vivo. 3. To investigate the mechanism(s) of antibody-mediated protection against H. capsulatum in vitro. 4. To determine the efficacy of the histone H2B and the mAb 9C7 epitope as vaccines. These studies are expected to lead to insights into H. capsulatum pathogenesis and initiate the development of new therapeutic and diagnostic reagents.

描述（由申请人提供）：组织囊肿是一种重要的地方性，细胞内真菌病原体，可能导致威胁生命的传播疾病，特别是在免疫力受损的人中。尽管使用有效的抗真菌药物，组织质症的显着发病率和死亡率仍在继续，并且当前的治疗方案经常无法消除免疫功能低下的个体中的生物体，尤其是患有艾滋病的人。来自细胞内病原体（即结核分枝杆菌，单核细胞增生李斯特菌）和其他真菌（即新核切片，念珠菌，白色念珠菌）的最新数据表明，特定的抗体可以提高宿主对抗这些感染的微生物的能力。我已经确定了三种鼠单克隆抗体（MAB），它们结合到囊囊酵母细胞表面。 MAB的给药减轻了真菌负担，减少了肺部炎症，并在鼠感染模型中长期存活。 MAB处理与受感染小鼠的肺中LL-4，IL-6和IFN-的产生增强有关。 mabs通过巨噬细胞通过相互作用取决于CR3来增加酵母的吞噬作用。摄入和杀死细胞内真菌后，抑制了mab opsonized H. capsulatum的生长。 H. capsulatum结合MAB与在真菌细胞表面表达的组蛋白样蛋白（组蛋白H2B）相互作用。该应用的目标是定义针对这种真菌的抗体作用机理，以表征抗原上的保护性表位，并在新的mAb和疫苗开发中使用蛋白质。提出了四个具体目的：1。绘制MAB 9C7的表位，并为H. capsulatum生成其他mAb。 2。研究抗体介导的对体内囊囊的保护的机理。 3。研究在体外对抗体介导的抗体介导的保护的机理。 4。确定组蛋白H2b和MAB 9C7表位的功效为疫苗。 这些研究预计会导致对囊囊发病机理的见解，并启动新的治疗和诊断试剂的发展。