Tuning Fc-effector functions of HIV-specific antibodies

描述（由申请人提供）：除了中和作用外，抗体（Abs）是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它们所结合的抗原来调节其活性。抗体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控：a)抗体的同型（Ab）和b) Ab重链ch2结构域内天冬酰胺297位点上的聚糖结构。虽然Ab工程通过优化治疗恶性肿瘤和自身免疫性疾病的Ab聚糖结构，彻底改变了单克隆抗体的疗效，但关于如何通过疫苗接种在体内利用Ab糖基化来增强对传染病的保护，我们知之甚少。越来越多的证据表明，在炎症条件下，Ab-聚糖的自然调节发生，极大地改变了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，我们知之甚少。鉴于先天免疫招募抗体在早期HIV感染中可检测到，在长期非进展者中丰富，并且与增强的HIV控制相关，PI假设，体内特异性聚糖诱导先天免疫招募抗体的“规则”可以从自然感染中学习。因此在这个提议中，PI将

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.