Tuning Fc-effector functions of HIV-specific antibodies

调节 HIV 特异性抗体的 Fc 效应器功能

• 批准号: 8691723
• 负责人: Galit Alter
• 金额: $ 84.27万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8691723
• 关键词: Aging; Antibodies; Antibody Formation; Antigens; Antiviral Agents; Area; Asparagine; Autoimmune Diseases; B-Lymphocytes; Binding; Carbohydrates; Cell Proliferation; Cellular biology; Chemosensitization; Communicable Diseases; Complement Activation; Cues; Enzymes; Exhibits; Fc domain; Future; Generations; Glycoside Hydrolases; HIV; HIV Infections; Homing; Immune; Immune response; Immune system; Immunization; In Vitro; Infection; Infection prevention; Inflammation; Inflammatory; Knowledge; Lead; Learning; Link; Malignant Neoplasms; Mediating; Memory; Molecular Profiling; Monoclonal Antibodies; Pathway interactions; Phagocytosis; Polysaccharides; Population; Pregnancy; Production; Recruitment Activity; Regulation; Research; Sentinel; Specificity; Structure; Substrate Specificity; Therapeutic; Therapeutic Monoclonal Antibodies; Therapeutic community technique; Translating; Vaccination; Vaccines; Viral Antibodies; Virus; antibody engineering; antibody-dependent cell cytotoxicity; arm; biophysical properties; cellular development; chronic autoimmune disease; cytokine; glycosylation; glycosyltransferase; in vivo; insight; mucosal site; neutralizing antibody; novel strategies; pathogen; population based; prevent; programs; response; therapeutic vaccine

DESCRIPTION (provided by applicant): In addition to neutralization, antibodies (Abs) represent a critical bridge between the adaptive and innate immune system, as they mediate their activity by harnessing and instructing the innate immune system on how to clear the antigen to which they are bound. The ability of Abs to provide specificity to the innate immune system is tightly regulated by: a) the isotype of the antibody (Ab), and b) the glycan structure attached at the asparagine 297 within the CH2-domain of the Ab heavy chain. While Ab engineering has revolutionized the efficacy of monoclonal Abs through the optimization of Ab glycan structures for the treatment of malignancies and autoimmune disorders, little is known about how Ab glycosylation may be harnessed in vivo through vaccination to provide enhanced protection against infectious diseases. Accumulating evidence suggests that natural modulation of the Ab-glycan occurs under inflammatory conditions, dramatically altering the activity of an Ab. However, little is known about the mechanism(s) that regulates Ab-glycosylation, how the immune system naturally exploits this humoral activity, and how it may be harnessed to potentiate Ab-antiviral activity. Given that innate immune recruiting Abs are detectable in early HIV infection, are enriched in long-term non-progressors, and correlate with enhanced HIV control, the PI hypothesizes that the "rules" for eliciting innate immune recruiting Abs, with specific glycans in vivo, can be learned from natural infection. Thus in this proposal, the PI will hone in on the B cell biology of glycosylation to define a) the mechanism by which Ab-glycosylation is tuned naturally in spontaneous controllers, b) define the mechanism by which glycosylation in B cells is regulated, and c) determine whether Ab-glycosylation is "remembered" following immunization. Together, knowledge gained from these studies will provide critical insights into the mechanism by which Ab-effector functions are regulated, and will lead to the generation of new strategies to potentiate the antiviral activity of vaccine inducd Abs.

描述（由申请人提供）：除了中和作用外，抗体（Ab）还代表了适应性免疫系统和先天免疫系统之间的关键桥梁，因为它们通过利用和指导先天免疫系统如何清除与其结合的抗原来介导其活性。Ab向先天免疫系统提供特异性的能力受到以下因素的严格调节：a）抗体（Ab）的同种型，和B）连接在Ab重链的CH 2结构域内的天冬酰胺297处的聚糖结构。虽然Ab工程通过优化Ab聚糖结构来治疗恶性肿瘤和自身免疫性疾病，从而彻底改变了单克隆Ab的功效，但关于Ab糖基化如何通过疫苗接种在体内利用以提供增强的抗感染性疾病的保护却知之甚少。越来越多的证据表明，Ab-聚糖的自然调节发生在炎症条件下，显著改变Ab的活性。然而，关于调节Ab-糖基化的机制、免疫系统如何自然地利用这种体液活性以及如何利用它来增强Ab-抗病毒活性知之甚少。鉴于先天免疫募集抗体在早期HIV感染中可检测到，在长期非进展者中富集，并且与增强的HIV控制相关，PI假设可以从自然感染中了解体内诱导具有特异性聚糖的先天免疫募集抗体的“规则”。因此，在本提案中，PI将 深入研究糖基化的B细胞生物学以定义a）Ab-糖基化在自发控制器中自然调节的机制，B）定义调节B细胞中糖基化的机制，和c）确定免疫后Ab-糖基化是否被“记住”。总之，从这些研究中获得的知识将提供重要的见解的机制，其中抗体效应功能的调节，并将导致产生新的策略，以加强疫苗诱导抗体的抗病毒活性。