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

剖析 GM-CSF 和中性粒细胞在 IgG 和 IgA 反应中的相互作用

• 批准号: 8198166
• 负责人: ANDREA CERUTTI
• 金额: $ 64.22万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-07 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8198166
• 关键词: Acids; Adjuvant; Affinity; Antigens; Avidity; B-Lymphocyte Subsets; B-Lymphocytes; Cells; Cellular biology; DNA; Data; Epitopes; Frequencies; Generations; Genes; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; HIV; HIV vaccine; Homing; Immune; Immunization; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin M; Immunoglobulin Switch Recombination; Instruction; Intestines; Ligands; Lymphocyte; Lymphoid; Memory B-Lymphocyte; Modeling; Modified Vaccinia Virus Ankara; Organ; Pathway interactions; Prevention strategy; Recombinants; Research; Resources; Role; SIV; Surface; T cell response; Tropism; Vaccines; Virion; Virus; Virus-like particle; cytokine; immunogenicity; improved; monomer; mucosal site; nanoparticle; neutralizing antibody; neutrophil; novel; receptor; response

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..

该提案的目的是阐明辅助GM-CSF增强疫苗诱导的机制 IgG和IgA对SIV的反应。这些研究将利用独特的资源 该财团以及Amara的补充和综合专业知识提供的 Pulendran组，该组评估了新型ENV免疫原子中和ABS的诱导（NABS） （proiect 1和proiect 2）。 Ahmed/Silvestri/Crotty组，通过 T细胞（项目3）。和CERUTTI组，研究了先天免疫细胞对B细胞的调节 （PROIECT 4）。 B细胞通过在包膜上（ENV）尖峰来提供对HIV的免疫蛋白质。 病毒的表面。但是，启发强大和持续的NAB反应仍然是一个主要障碍， 因为env是唯一的NAB诱导的相关Anfigen，其特征是序列变量，有限 无精性和稀缺的免疫原性。附加障碍与缺乏能够的策略有关 有效地从系统地和粘膜入口部位诱导NAB。来自Amara的初步数据 小组表明，GM-CSF增强了疫苗诱导的SIV-REACFIVE IgG ABS的亲和力和频率 在全身性淋巴器官中产生，并引起siv特异性IgA在静脉内部的脱离中产生。这些 效应与增加针对肠道挑战的保护相关。在这个建议中，我们假设 GM-CSF动员并激活了配备的脾脏IL-21的独特子集 具有B细胞辅助功能。我们认为NBH细胞增强了全身IgG和肠IgA响应 通过诱导IG重链类切换来反对SIV，V（d）J Gene Somafic Hypermutafion和肠道 脾B细胞中的受体，包括边缘区和记忆B细胞。提出了三个目标。目标1是 阐明GM-CSF诱导脾B细胞中IgG和IgA类切换的机制。目标2是 剖析GM-CSF诱导脾脏IgA类切换B细胞的详细归因的机制。 AIM 3是确定GM-CSF改善疫苗诱导的全身性感的机制 IgG和针对SIV的IgA反应。