Isotype-dependent efficacy of human mAbs against Candida

人单克隆抗体对抗念珠菌的同型依赖性功效

• 批准号: 6504613
• 负责人: MASON X ZHANG
• 金额: $ 14.3万
• 依托单位: CALIFORNIA STATE UNIVERSITY LONG BEACH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6504613
• 关键词: Candida; SDS polyacrylamide gel electrophoresis; candidiasis; cell line; clinical research; complement; enzyme linked immunosorbent assay; genetic manipulation; host organism interaction; human tissue; humoral immunity; immunoglobulin G; immunoglobulin isotypes; laboratory mouse; microorganism immunology; monoclonal antibody; nosocomial infections; transfection; western blottings

DESCRIPTION (provided by applicant): Hematogenously disseminated candidiasis has become a common and serious nosocomial infection. Recent studies established an important role for anti-Candida mannan mAb in host defense against systemic candidiasis in experimental mice. These studies are exciting and raise a possibility for prophylactic use of protective anti-Candida antibodies in patients at risk for disseminated candidiasis. However, such studies have been limited to murine antibodies and have not examined the role of antibody isotype in treatment efficacy. Our long term goal is to understand how human anti-Candida antibody participates in host defense against candidiasis. In preliminary studies, I have used bacteriophage display and DNA recombinant technology to generate human antimannan IgG antibodies. We will use these recombinant human antibodies to examine the hypothesis that antibody-mediated host defense against disseminated candidiasis is influenced by the IgG subclass. We will pursue three aims. In the first specific aim, I will construct a family of IgG-subclass variants of human antimannan antibody with the same binding specificity. To this end, a full length human recombinant IgG1 antimannan antibody has already been constructed. Studies for the second aim will analyze modulation of complement opsonization of Candida cells by IgG subclasses. In the third specific aim, I will assess protective efficacy of IgG-subclass variants of human antimannan antibody in a mouse model of homogeneously disseminated candidiasis. Data from aims 2 and 3 will set a foundation for further dissection of the mechanisms underlying antibody-mediated host defenses. Results from this study will enhance our knowledge of the role of human humoral immunity against disseminated candidiasis. Such knowledge is critical to designs of immunoprophylactics and immunotherapeutics that involve antibody-mediated effector mechanisms.

描述（申请人提供）：血源性传播念珠菌病已成为一种常见且严重的医院感染。最近的研究表明，抗念珠菌甘露聚糖单克隆抗体在实验小鼠系统性念珠菌病的宿主防御中发挥重要作用。这些研究是令人兴奋的，并提出了一种可能性，预防性使用保护性抗念珠菌抗体的患者在传播性念珠菌病的风险。然而，这些研究仅限于鼠抗体，尚未检查抗体同种型在治疗功效中的作用。我们的长期目标是了解人类抗念珠菌抗体如何参与宿主对念珠菌病的防御。 在初步研究中，我已经使用噬菌体展示和DNA重组技术产生人抗甘露聚糖IgG抗体。我们将使用这些重组人抗体来检验抗体介导的宿主对播散性念珠菌病的防御受IgG亚类影响的假设。我们将追求三个目标。在第一个具体目标中，我将构建一个具有相同结合特异性的人源抗甘露聚糖抗体IgG亚类变体家族。为此，已经构建了全长人重组IgG1抗甘露聚糖抗体。第二个目标的研究将分析IgG亚类对念珠菌细胞补体调理作用的调节。在第三个具体的目标，我将评估IgG亚类变体的人抗甘露聚糖抗体在小鼠模型的均匀播散性念珠菌病的保护效果。目标2和3的数据将为进一步剖析抗体介导的宿主防御机制奠定基础。 本研究的结果将增强我们对人类体液免疫对播散性念珠菌病的作用的认识。这些知识对于涉及抗体介导的效应器机制的免疫抑制剂和免疫治疗剂的设计至关重要。