Protective Human Anti-Candida Antibodies

描述（由申请人提供）：白色念珠菌是一种酵母样真菌病原体，可引起危及生命的血源性播散性念珠菌病。白色念珠菌的细胞表面富含寡糖甘露聚糖和甘露聚糖，甘露聚糖在念珠菌与人的相互作用中起重要作用。我们已经开发了首个全长人IgG1抗甘露聚糖抗体M1g1，并发现它对小鼠血源性播散性念珠菌病模型具有保护作用。该研究与小鼠抗甘露聚糖抗体的结果表明，抗甘露聚糖抗体在宿主对念珠菌病的抗性中起作用。我们的长期目标是开发保护性的人抗念珠菌抗体用于预防和治疗应用。最近的研究表明，M1g1通过Fc依赖的经典途径或通过一种新的Fc独立的fab依赖的替代途径，在白色念珠菌上启动opsonic C3片段的沉积。然而，M1g1的IgG4变体M1g4仅激活替代途径。M1g1或M1g4单独促进人中性粒细胞对酵母细胞的吞噬。然而，补体增强了m1g1 -调理酵母细胞的吞噬，而不是m1g1 -调理酵母细胞。进一步的研究揭示了M1g4在抵抗播散性念珠菌病中的保护作用。这些观察结果表明，补体片段和抗甘露聚糖IgG之间的相互作用，当作为吞噬细胞的调理素沉积在细胞上时，可能是协同的、拮抗的或无关的，因此可能影响抗甘露聚糖抗体的保护功效。这一假设将通过一套完整的人IgG亚类变体M1g1、M1g2、M1g3和M1g4进行检验，这些变体包含相同的Fab、M1，但在Fc区域和Fc介导的效应功能上有所不同。具体目标是：1)分析IgG亚类特异性对抗甘露聚糖抗体介导的白色念珠菌吞噬和杀伤的影响；2)测定人抗甘露聚糖抗体IgG亚类变体激活小鼠补体系统的能力；3)评价补体对IgG亚类介导的白色念珠菌吞噬和杀伤的影响。4)确定补体系统对抗甘露聚糖抗体IgG亚类变体保护作用的影响；5)评价补体和IgG作为调理素对Fc介导效应功能不同的基因改变M1抗体吞噬作用的相对贡献。本研究的结果将为抗甘露聚糖抗体介导的对血源性播散性念珠菌病的耐药性机制提供见解。这些见解对开发用于免疫预防和免疫治疗的人类保护性抗甘露聚糖抗体具有重要价值。

DESCRIPTION (provided by applicant): Candida albicans is a yeast-like fungal pathogen and can cause life-threatening hematogenously disseminated candidiasis. The cell surface of C. albicans is enriched with manose oligosaccharides and polysaccharides known as mannan that plays an important role in Candida-human interactions. We have developed the first full length human IgG1 antimannan antibody, M1g1, and found it to be protective in a mouse model of hematogenously disseminated candidiasis. This study along with results from murine antimannan antibodies indicate a role for antimannan antibody in host resistance to candidiasis. Our long term goal is to develop protective human anti-Candida antibodies for prophylactic and therapeutic applications. Recent studies have demonstrated that M1g1 initiates deposition of opsonic C3 fragments on C. albicans through the classical pathway in an Fc-dependent manner or through the alternative pathway in a novel Fc- independent Fab-dependent manner. However, M1g4, an IgG4 variant of M1g1, activates the alternative pathway only. M1g1 or M1g4 alone promotes phagocytosis of yeast cells by human neutrophils. However, complement enhanced phagocytosis of M1g4-opsonized yeast cells, not M1g1-opsonized yeast. Additional studies revealed a protective role for M1g4 in resistance to disseminated candidiasis. These observations suggest that the interplay between complement fragments and antimannan IgG, when deposited on cells as opsonins for phagocytes, may be synergistic, antagonistic, or indifferent and thus may influence the protective efficacy of an antimannan antibody. This hypothesis will be examined using a complete set of human IgG subclass variants, M1g1, M1g2, M1g3, and M1g4, that contain the same Fab, M1, but differ in the Fc region and Fc-mediated effector functions. The specific aims are: 1) To analyze the influence of IgG subclass specificity on antimannan antibody-mediated phagocytosis and phagocytic killing of C. albicans, 2) To determine the ability of IgG subclass variants of human antimannan antibody to activate the murine complement system, 3) To assess the effect of complement on IgG subclass-mediated phagocytosis and phagocytic killing of C. albicans, 4) To determine the influence of the complement system on the protective efficacy of IgG subclass variants of antimannan antibody, and 5) To evaluate the relative contribution of complement and IgG as opsonins for phagocytosis with genetically altered M1 antibodies that differ in Fc- mediated effector functions. Results from this study will provide insights into the mechanisms of antimannan antibody-mediated resistance to hematogenously disseminated candidiasis. These insights are valuable to the development of human protective antimannan antibodies for immunoprophylactic and immunotherapeutic applications. PUBLIC HEALTH RELEVANCE: Candida albicans is a yeast-like fungal pathogen and is among the most common causes of infections in hospitalized patients. This project will study the protective mechanisms of human anti-Candida antibodies.