Protective Antibodies for Cryptococcal Infections

隐球菌感染的保护性抗体

• 批准号: 7039104
• 负责人: Arturo Casadevall
• 金额: $ 46.52万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7039104
• 关键词: Cryptococcus neoformans; X ray crystallography; animal genetic material tag; antibody specificity; antifungal antibody; cryptococcosis; electron microscopy; fungal proteins; glycosylation; hybrid antibody; immunoglobulin isotypes; immunoglobulin structure; immunotherapy; ion exchange chromatography; monoclonal antibody; passive immunization; polysaccharides; tissue /cell culture

DESCRIPTION (provided by applicant): Cryptococcosis is a life-threatening illness that occurs at high frequency in individuals with AIDS. The therapy of cryptococcosis in patients with AIDS is unsatisfactory because the disease is associated with high mortality, and even when controlled with medication, C. neoformans infections are seldom eradicable in the setting of severe immune suppression. In the past decade, this research program has supported the scientific development of a novel therapy for cryptococcosis based on administration of a protective antibody. Passive antibody therapy is currently in clinical evaluation. It is a central tenet of immunological dogma that the specificity of an antibody (Ab) for an antigen is determined solely by interactions between the epitope in the antigen and the Ab variable region. In the past funding period, we have learned that, for some Abs, the constant region can also affect specificity. If confirmed, this observation has the potential to be a major discovery in immunology because it could influence our understanding of such fundamental concepts as the origin of the secondary immune response, immunological memory, and the basis of Ab specificity. Furthermore, this finding is of great importance for the future development of Ab therapies against cryptococcosis and other conditions. This application proposes to obtain unequivocal proof for the existence of this effect and to elucidate the mechanism by which the constant region can affect specificity. Four specific Aims are proposed: 1. To determine how antibody specificity for C. neoformans polysaccharide depends on isotype; 2. To determine the mechanism by which constant region structural motifs influence antibody specificity for C. neoformans polysaccharide; 3. To establish the contribution of constant region glycosylation to specificity and complete the characterization of 18B7 glycosylation; and 4. To validate the findings made with murine mAbs on human C regions. It is anticipated that this research program will produce new insights into Ab structure and function that are relevant for Ab-based strategies against C. neoformans and also to other efforts to develop Ab therapy, vaccines and fundamental immunology.

描述（由申请人提供）：隐球菌病是一种威胁生命的疾病，在艾滋病患者中高频出现。艾滋病患者的隐球菌病的治疗是不令人满意的，因为该疾病与高死亡率有关，即使用药物控制，在严重免疫抑制的情况下，新羊角菌感染也很少消除。在过去的十年中，该研究计划支持了基于保护性抗体的施用隐孢子球病的新型疗法的科学发展。被动抗体治疗目前正在临床评估中。免疫教条的中心宗旨是，抗原的抗体（AB）的特异性仅取决于抗原和AB可变区域的表位之间的相互作用。在过去的资金期间，我们了解到，对于某些ABS，恒定区域也会影响特异性。如果得到证实，该观察结果有可能成为免疫学中的主要发现，因为它可能会影响我们对诸如次级免疫反应，免疫记忆和AB特异性基础之类的基本概念的理解。此外，这一发现对于针对隐球菌和其他疾病的AB疗法的未来发展至关重要。该应用程序建议为存在这种效果的存在而获得明确的证明，并阐明恒定区域可以影响特异性的机制。提出了四个具体目的：1。确定新甲状腺梭菌多糖的抗体特异性如何取决于同种型； 2。确定恒定区域结构基序影响新梭菌多糖的抗体特异性的机制； 3。建立恒定区域糖基化对特异性的贡献并完成18B7糖基化的表征；和4。验证人类C区域用鼠mabs做出的发现。可以预料，该研究计划将为AB结构和功能提供新的见解，这些见解与基于AB的Neoformans策略以及开发AB疗法，疫苗和基本免疫学的其他努力有关。