Dissecting The Interplay of GM-CSF and Neutrophils In IgG and IgA Responses

本研究的目的是阐明佐剂GM-CSF增强疫苗诱导的免疫应答的机制。 针对SIV的IgG和伊加应答。这些研究将利用独特的资源 由该财团提供，阿马拉和 Pulendran小组，评估新型Env免疫原诱导中和抗体（NAb） （项目1和项目2）。Ahmed/Silvestri/Crotty小组，该小组通过以下方式探索Ab反应的调节： T细胞（项目3）。Cerutti小组研究先天免疫细胞对B细胞的调节 （项目4）。B细胞通过产生NAb包封（Env）刺突来提供针对HIV的免疫保护。 病毒的表面然而，激发强有力和持续的NAb反应仍然是一个主要障碍， 由于Env是NAb诱导的唯一相关抗原，其特征在于序列变异， 缺乏免疫原性。另一个障碍是缺乏能够 有效地诱导NAb的全身和粘膜进入部位。阿马拉号的初步数据 结果表明，GM-CSF增强了疫苗诱导的SIV反应性IgG抗体的亲合力和频率 SIV特异性伊加在肠分泌物中的大量释放。这些 这些作用与增加的对肠道攻击的保护相关。在本提案中，我们假设 GM-CSF动员并激活了一个独特的脾IL-21产生NBH中性粒细胞亚群， 具有B细胞辅助功能。我们认为，NBH细胞增强全身IgG和肠道伊加反应， 通过诱导IG重链类别转换、V（D）J基因体细胞超突变和肠道归巢来抗SIV 受体在脾B细胞，包括边缘区和记忆B细胞。提出了三个目标。目标1： 阐明GM-CSF诱导脾B细胞中IgG和伊加类别转换的机制。目标二是 剖析GM-CSF诱导脾伊加类别转换的B细胞的终末归巢的机制。 目的3：探讨GM-CSF提高疫苗诱导的系统性免疫应答亲和力的机制。 IgG和肠伊加对SIV的反应。

The goal of this proposal is to elucidate the mechanisms by which the adjuvant GM-CSF enhances vaccineinduced IgG and IgA responses against SIV. These studies will take advantage ofthe unique resources made available by this consortium and ofthe complementary and integrative expertise ofthe Amara and Pulendran groups, which evaluate novel Env immunogens for the inducfion of neutralizing Abs (NAbs) (Proiect 1 and Proiect 2). the Ahmed/Silvestri/Crotty group, which explores the regulafion of Ab responses by T cells (Project 3). and the Cerutti group, which studies the regulafion of B cells by innate immune cells (Proiect 4). B cells provide immune protecfion against HIV by producing NAbs to envelope (Env) spikes on the surface ofthe virus. However, elicifing robust and sustained NAb responses remains a major obstacle, because Env, the only relevant anfigen for NAb inducfion, is characterized by sequence variafion, limited anfigenicity and scarce immunogenicity. An addifional obstacle relates to the lack of strategies capable of effectively inducing NAbs both systemically and at mucosal sites of entry. Preliminary data from the Amara group show that GM-CSF enhances the avidity and frequency of vaccine-induced SIV-reacfive IgG Abs produced in systemic lymphoid organs and elicits release of SIV-specific IgA in intesfinal secrefions. These effects correlate with increased protection against an intestinal challenge. In this proposal we hypothesize that GM-CSF mobilizes and activates a unique subset of splenic IL-21-producing NBH neutrophils equipped with B cell helper function. We contend that NBH cells enhance systemic IgG and intestinal IgA responses against SIV by inducing Ig heavy chain class switching, V(D)J gene somafic hypermutafion and gut-homing receptors in splenic B cells, including marginal zone and memory B cells. Three aims are proposed. Aim 1 is to elucidate the mechanism by which GM-CSF induces IgG and IgA class switching in splenic B cells. Aim 2 is to dissect the mechanism by which GM-CSF induces intesfinal homing of splenic IgA class-switched B cells. Aim 3 is to determine the mechanism by which GM-CSF improves the avidity of vaccine-induced systemic IgG and intesfinal IgA responses against SIV..