Systems investigation of vaccine responses in B cell depleted autoimmune patients

B 细胞耗尽的自身免疫患者疫苗反应的系统研究

• 批准号: 10420326
• 负责人: David A. Hafler
• 金额: $ 34.54万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-12 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10420326
• 关键词: 2019-nCoV; Acute; Adenoviruses; Adjuvant; Affect; Antibodies; Antibody Formation; Antigens; Attenuated; Autoantibodies; Autoimmune; Autoimmune Diseases; Automobile Driving; B-Cell Activation; B-Lymphocytes; BLR1 gene; COVID-19; COVID-19 patient; COVID-19 vaccination; Cell Communication; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Clinical; DLEC1 gene; Disease; Dose; Event; Exhibits; Generations; HLA-DR Antigens; Immune; Immune response; Investigation; MF59; Measures; Messenger RNA; Oligonucleotides; Outcome; Patients; Peptides; Peripheral; Phase; Play; Production; Proteomics; RNA vaccination; RNA vaccine; Recovery; Role; SARS-CoV-2 infection; Secondary Immunization; Severe Acute Respiratory Syndrome; Site; System; Systems Analysis; T-Lymphocyte; Technology; Vaccination; Viral; Viral Vector; Vulnerable Populations; antigen-specific T cells; draining lymph node; improved; influenza virus vaccine; lymph nodes; nanoparticle; novel; pathogenic autoantibodies; response; vaccine response; vector vaccine

Elucidating mechanisms of novel mRNA nanoparticle and adenovirus-viral vector vaccine- induced T and B cell activation at the site of vaccination and lymph nodes is of critical importance. Studying patients with autoimmune disease treated with B cell depletion, we will perform a systems analysis to examine dynamics of immune response to SARS-CoV-2 vaccination in the context of B cell depletion. As part of our previous HIPC project, we studied T- B cell interactions in the acute phase of COVID-19 disease and found that PD-1high CXCR5– CD4+ peripheral helper T (Tph) cells were increased and exhibited B cell help signatures. Activated HLA-DR+CD38+ Tph cells were highly correlated with titers of anti-S1/RBD antibodies and improved clinical outcome. As Tph cells are known for supporting the generation of pathogenic autoantibodies and COVID-19 patients display autoantibody signatures, Tph cells may play dual roles in COVID-19 infection driving recovery and long-term adverse autoimmune sequel. Thus, we hypothesize that in response to vaccination, B cells affect the induction of antigen specific T cells and Tph cells required for antibody production. In Aim 1a , we will elucidate immune response signatures to SARS mRNA vaccination with B cell depletion. In depth functional profiling of immune cells will be accomplished with CyTOF, 10x scRNA sequencing with BCR/TCR analysis and CITE-seq and proteomics. Analysis of autoantibody production will be conducted with the REAP platform to determine whether SARS-CoV-2 vaccinations induce autoantibodies and whether they are attenuated with B cell depletion. In Aim 1b, early events in the immune response to vaccination in B cell depleted patients and controls will be analyzed near the inoculation site and in draining lymph nodes determining whether Tph cells involved in ectopic antibody production are induced at the site of vaccination. In Aim 1c, we will measure antigen specific responses to viral peptides using oligo-conjugated MHC tetramers with CITE-seq technology. We will elucidate immune signatures to a booster vaccination in B cell depleted patients in Aim 2a, and compare the response between MF59- adjuvanted flu vaccine and standard-dose flu vaccine in Aim 2b. We will determine whether responses to SARS-CoV-2 and flu vaccines correlate and if the MF59 adjuvant enhances immune response with B cell depletion. In total, this systems approach will allow us to elucidate the role of B cells in inducing immune responses with novel mRNA vaccines.

阐明新型mRNA纳米颗粒和腺病毒-病毒载体疫苗的机制- 在接种部位和淋巴结诱导T和B细胞活化是至关重要的 重要性研究用B细胞耗竭治疗的自身免疫性疾病患者，我们将 进行系统分析，以检查对SARS-CoV-2的免疫反应动力学 在B细胞耗竭的情况下接种。作为我们以前重债穷国项目的一部分，我们研究了T- COVID-19疾病急性期的B细胞相互作用，发现PD-1高CXCR 5- CD 4+外周辅助性T（Tph）细胞增加，并显示出B细胞辅助特征。 活化的HLA-DR+ CD 38 + Tph细胞与抗S1/RBD抗体滴度高度相关 并改善临床结果。由于已知Tph细胞支持产生 病原性自身抗体和COVID-19患者显示自身抗体特征，Tph细胞 可能在COVID-19感染中发挥双重作用，推动恢复和长期不良自身免疫性 续集因此，我们假设，在对疫苗接种的应答中，B细胞影响免疫应答的诱导。 抗原特异性T细胞和Tph细胞是产生抗体所必需的。在目标1a中，我们将 阐明了用B细胞耗竭的SARS mRNA疫苗接种的免疫应答特征。在 免疫细胞的深度功能分析将使用CyTOF，10 x scRNA 测序与BCR/TCR分析和CITE-seq和蛋白质组学。自身抗体分析 将使用REAP平台进行生产，以确定SARS-CoV-2是否 疫苗接种诱导自身抗体，以及它们是否被B细胞耗尽而减弱。在 目的1B，B细胞耗竭患者对疫苗接种免疫应答的早期事件， 对照将在接种部位附近和引流淋巴结中进行分析， 参与异位抗体产生的Tph细胞是否在接种部位被诱导。 在目标1c中，我们将使用寡聚缀合的 使用CITE-seq技术的MHC四聚体。我们将阐明免疫特征， 在Aim 2a中，在B细胞耗竭的患者中接种疫苗，并比较MF 59- 目标2b中的佐剂流感疫苗和标准剂量流感疫苗。我们将决定 对SARS-CoV-2和流感疫苗的反应相关，如果MF 59佐剂增强了 免疫应答伴随B细胞耗竭。总的来说，这种系统方法将使我们能够阐明 B细胞在新型mRNA疫苗诱导免疫应答中的作用。