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

这项建议的目的是阐明佐剂GM-CSF增强疫苗诱导的机制。 SIV的免疫球蛋白和免疫球蛋白A反应。这些研究将利用独特的资源 由该联盟以及Amara和Amara的补充和综合专业知识提供 评价新的环境免疫原诱导中和抗体(NAB)的Pulendran小组 (项目1和项目2)。Ahmed/Silvestri/Crotty小组，通过以下方式探索抗体反应的规律 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细胞通过产生针对包膜(Env)的nabs来提供对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， 因为env是唯一与NAB诱导相关的构象，具有序列变异的特点，有限 形象性和稀少的免疫原性。另一个障碍是缺乏能够 有效地从系统和粘膜进入部位诱导NAB。来自Amara的初步数据 研究表明，GM-CSF增强了疫苗诱导的SIV反应Ig G抗体的亲和力和频率 在全身淋巴器官中产生，并引起最终分泌物中SIV特异性IgA的释放。这些 效果与增强对肠道挑战的保护有关。在这个提案中，我们假设 GM-CSF动员和激活一个独特的脾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细胞可增强全身免疫球蛋白和肠道免疫球蛋白A反应 通过诱导免疫球蛋白重链转换、V(D)J基因体细胞高度突变和肠道归巢来对抗SIV 脾B细胞上的受体，包括边缘带和记忆B细胞。提出了三个目标。目标1是 阐明GM-CSF诱导脾B细胞免疫球蛋白和免疫球蛋白A类转换的机制。目标2是 解剖GM-CSF诱导脾IgA类转换B细胞最终归巢的机制。 目的3确定GM-CSF提高疫苗诱导的系统亲和力的机制。 针对SIV的Ig G和INT最终的Ig A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..