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佐剂 GM-CSF 增强疫苗诱导的机制 针对 SIV 的 IgG 和 IgA 反应。这些研究将利用独特的资源 该联盟提供的以及阿马拉和阿马拉的互补和综合专业知识 Pulendran 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，探索了抗体反应的调节 T 细胞（项目 3）。以及研究先天免疫细胞对 B 细胞的调节的 Cerutti 小组 （项目 4）。 B 细胞通过产生 NAb 来包膜 (Env) 尖峰，从而提供针对 HIV 的免疫保护 病毒的表面。然而，引发强劲且持续的 NAb 反应仍然是一个主要障碍， 因为 Env 是 NAb 诱导的唯一相关抗原，其特点是序列变异，有限 抗原性和稀有免疫原性。另一个障碍涉及缺乏能够 有效地在全身和粘膜入口处诱导NAb。来自阿马拉的初步数据 研究小组表明，GM-CSF 增强了疫苗诱导的 SIV 反应性 IgG 抗体的亲和力和频率 在全身淋巴器官中产生并引起肠分泌物中 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 动员并激活脾脏中产生 IL-21 的 NBH 中性粒细胞的独特子集 具有B细胞辅助功能。我们认为 NBH 细胞增强全身 IgG 和肠道 IgA 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对抗 SIV 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 类别转换的机制。目标 2 是 剖析 GM-CSF 诱导脾脏 IgA 类别转换 B 细胞间归巢的机制。 目标 3 是确定 GM-CSF 提高疫苗诱导的全身性免疫反应的亲合力的机制。 针对 SIV 的 IgG 和肠道 IgA 反应。