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: 8408897
• 负责人: Galit Alter
• 金额: $ 60.99万
• 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/8408897
• 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; Property; 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; 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. PUBLIC HEALTH RELEVANCE: This proposal aims to define the mechanism(s) regulating antibody glycosylation in B cells. These studies may identify new strategies to specifically tune B cell responses during vaccination to induce antibodies with enhanced antiviral activity.

描述（由申请人提供）：除了中和之外，抗体 (Ab) 还代表了适应性免疫系统和先天免疫系统之间的重要桥梁，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 为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，b) Ab 重链 CH2 结构域内天冬酰胺 297 处附着的聚糖结构。虽然抗体工程通过优化抗体聚糖结构来治疗恶性肿瘤和自身免疫性疾病，彻底改变了单克隆抗体的功效，但人们对如何通过疫苗接种在体内利用抗体糖基化来提供针对传染病的增强保护知之甚少。越来越多的证据表明，抗体聚糖的自然调节发生在炎症条件下，极大地改变了抗体的活性。然而，人们对调节 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 感染中是可检测到的，在长期非进展者中富集，并且与增强的 HIV 控制相关，PI 假设，可以从自然感染中学习利用体内特定聚糖来引发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) 在自发控制器中自然调节 Ab 糖基化的机制，b) 定义 B 细胞中糖基化的调节机制，以及 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为抗体效应器功能的调节机制提供重要的见解，并将导致产生增强疫苗诱导抗体的抗病毒活性的新策略。 公共健康相关性：该提案旨在定义 B 细胞中抗体糖基化的调节机制。这些研究可能会确定新的策略，在疫苗接种过程中特异性调节 B 细胞反应，以诱导具有增强抗病毒活性的抗体。