Isotype-dependent efficacy of human mAbs against Candida

描述(申请人提供)：血源性播散性念珠菌病已成为一种常见和严重的医院感染。最近的研究证实了抗念珠菌甘露聚糖单抗在实验小鼠抵抗系统性念珠菌病的宿主防御中的重要作用。这些研究是令人兴奋的，并提出了在有播散性念珠菌病风险的患者中预防性使用保护性抗念珠菌抗体的可能性。然而，这类研究仅限于小鼠抗体，并未检查抗体同种类型在治疗效果中的作用。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，我利用噬菌体展示和DNA重组技术制备了人源性抗甘露聚糖抗体。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免疫球蛋白亚类影响的假设。我们将追求三个目标。在第一个具体目标中，我将构建一组具有相同结合特异性的人抗甘露聚糖抗体的Ig G亚类变异体。为此，我们已经构建了全长的重组人IgG1抗甘露聚糖抗体。第二个目的的研究将分析免疫球蛋白亚类对念珠菌细胞补体调理的调节作用。在第三个具体目标中，我将评估人类抗甘露聚糖抗体的Ig G亚类变种在均质播散性念珠菌病小鼠模型中的保护效果。来自AIMS 2和AIMS 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。 这项研究的结果将增强我们对人类体液免疫在预防播散性念珠菌病中的作用的认识。这些知识对于涉及抗体介导效应机制的免疫预防和免疫治疗的设计是至关重要的。

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.