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: 8516868
• 负责人: ANDREA CERUTTI
• 金额: $ 66.38万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516868
• 关键词: 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 Infections; HIV vaccine; Homing; Immune; Immunization; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin M; Immunoglobulin Switch Recombination; Instruction; Intestinal Secretions; Intestines; Ligands; Lymphocyte; Lymphoid; Memory B-Lymphocyte; Modeling; Modified Vaccinia Virus Ankara; Organ; Pathway interactions; Prevention strategy; Production; Recombinants; Regulation; Research; Resources; Role; SIV; Surface; T cell response; Tretinoin; Tropism; Vaccination; Vaccines; Variant; Virion; Virus; Virus-like particle; cytokine; immunogenicity; improved; monomer; mucosal site; nanoparticle; neutralizing antibody; neutrophil; novel; receptor; response; 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 Infections; HIV vaccine; Homing; Immune; Immunization; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin M; Immunoglobulin Switch Recombination; Instruction; Intestinal Secretions; Intestines; Ligands; Lymphocyte; Lymphoid; Memory B-Lymphocyte; Modeling; Modified Vaccinia Virus Ankara; Organ; Pathway interactions; Prevention strategy; Production; Recombinants; Regulation; Research; Resources; Role; SIV; Surface; T cell response; Tretinoin; Tropism; Vaccination; Vaccines; Variant; 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 vaccine induced 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 induction of neutralizing Abs (NAbs) (Project 1 and Project 2). the Ahmed/Silvestri/Crotty group, which explores the regulation of Ab responses by T cells (Project 3). and the Cerutti group, which studies the regulation of B cells by innate immune cells (Project 4). B cells provide immune protection against HIV by producing NAbs to envelope (Env) spikes on the surface ofthe virus. However, eliciting robust and sustained NAb responses remains a major obstacle, because Env, the only relevant antigen for NAb induction, is characterized by sequence variation, limited antigenicity and scarce immunogenicity. An additional 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-reactive IgG Abs produced in systemic lymphoid organs and elicits release of SIV-specific IgA in intestinal secretions. 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 hypermutation 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 intestinal 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 intestinal IgA responses against SIV..

该提案的目的是阐明辅助GM-CSF增强疫苗诱导的IgG和IgA针对SIV的机制。这些研究将利用该财团提供的独特资源以及Amara和Pulendran群体的互补和综合专业知识，这些资源评估了新颖的ENV免疫原子以诱导中和ABS（NABS）（NABS）（项目1和Project 2）。 Ahmed/Silvestri/Crotty组，探讨了T细胞对AB反应的调节（项目3）。和CERUTTI组，研究通过先天免疫细胞来调节B细胞（项目4）。 B细胞通过在病毒表面产生NABS（ENV）尖峰来提供免疫保护HIV。然而，引起健壮和持续的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，其特征是序列变化，有限的抗原性和稀缺的免疫原性。另一个障碍涉及缺乏能够有效地在粘膜入境部位有效诱导NAB的策略。来自Amara组的初步数据表明，GM-CSF增强了在全身性淋巴机构中产生的疫苗诱导的SIV反应IgG ABS的亲和力和频率，并在肠道分泌中引起SIV特异性IgA的释放。这些影响与增加对肠道挑战的保护相关。在此提案中，我们假设GM-CSF动员并激活了具有B细胞辅助功能的脾脏IL-21产生的NBH中性粒细胞的独特子集。我们认为，NBH细胞通过诱导Ig重链类转换，V（d）J基因somafif Hypmponthemponting和gene gene somafe受体（包括边际区域和记忆B细胞）中的Ig重链类转换来增强针对SIV的全身性IgG和肠IgA反应。提出了三个目标。目的1是阐明GM-CSF诱导脾脏B细胞中IgG和IgA类切换的机制。目的2是剖析GM-CSF诱导脾脏IgA类切换B细胞的肠道归位的机制。 AIM 3是确定GM-CSF改善疫苗诱导的全身IgG和针对SIV的肠IgA反应的机制。