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.

新型信使核糖核酸纳米粒和腺病毒-病毒载体疫苗的作用机制 在接种部位和淋巴结处诱导T和B细胞活化是至关重要的 重要性。在研究B细胞去除治疗的自身免疫性疾病患者时，我们将 进行系统分析以检查SARS-CoV-2免疫反应的动力学 在B细胞耗尽的情况下接种疫苗。作为我们之前的重债穷国项目的一部分，我们研究了T- 新冠肺炎病急性期B细胞相互作用研究发现PD-1高CXCR5- 外周血中辅助性T细胞(TPH)数量增加，并表现出B细胞的帮助特征。 活化的HLA-DR+CD38+TPH细胞与抗S1/RBD抗体滴度高度相关 并改善临床结果。因为众所周知，TPH细胞支持产生 病原性自身抗体和新冠肺炎患者表现出自身抗体特征，TPH细胞 可能在新冠肺炎感染推动康复和长期不良自身免疫中发挥双重作用 续集。因此，我们假设，作为对疫苗接种的反应，B细胞影响对 产生抗体所需的抗原特异性T细胞和TPH细胞。在目标1a中，我们将 阐明B细胞耗尽的SARS基因疫苗的免疫应答特征。在……里面 免疫细胞的深度功能分析将使用CyTOF，10x scRNA来完成 用BCR/TCR分析和Cite-Seq和蛋白质组学进行测序。自身抗体分析 将与REAP平台进行生产，以确定SARS-CoV-2 接种疫苗会诱导自身抗体，以及它们是否会随着B细胞的耗尽而减弱。在……里面 目的1b，B细胞耗竭患者接种疫苗后的早期免疫反应 将在接种地点附近分析对照并在引流淋巴结处确定 参与异位抗体产生的TPH细胞是否在疫苗接种部位被诱导。 在目标1c中，我们将使用寡聚结合的方法来测量对病毒多肽的抗原特异性反应。 采用CITE-SEQ技术的MHC四聚体。我们将向助推器阐明免疫信号 在AIM 2a的B细胞耗竭患者中接种疫苗，并比较MF59和MF59之间的反应。 目标2b中的流感佐剂疫苗和标准剂量流感疫苗。我们将确定是否 对SARS-CoV-2和流感疫苗的应答相关，如果MF59佐剂增强 B细胞耗尽的免疫反应。总而言之，这种系统方法将使我们能够澄清 B细胞在新型信使核糖核酸疫苗诱导免疫应答中的作用