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 在疫苗接种部位和淋巴结部位诱导的T和B细胞激活至关重要 重要性。研究接受B细胞耗竭治疗的自身免疫性疾病的患者，我们将 进行系统分析以检查对SARS-COV-2的免疫响应的动力学 在B细胞耗竭的背景下疫苗接种。作为我们以前的HIPC项目的一部分，我们研究了T- B细胞相互作用在Covid-19疾病的急性期，发现PD-1高CXCR5– CD4+外围辅助T（TPH）细胞增加并暴露于B细胞帮助特征。 活化的HLA-DR+ CD38+ TPH细胞与抗S1/RBD抗体的滴度高度相关 并改善临床结果。因为TPH细胞以支持生成而闻名 致病性自身抗体和COVID-19患者显示自身抗体特征，TPH细胞 可能在COVID-19感染恢复和长期不良自身免疫性中扮演双重角色 续集。这，我们假设是为了响应疫苗接种，B细胞会影响诱导 抗体产生所需的抗原特异性T细胞和TPH细胞。在AIM 1A中，我们将 阐明对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通过cytof，10 x scrna完成 通过BCR/TCR分析以及Cite-seq和蛋白质组学进行测序。自身抗体分析 将使用REAP平台进行生产，以确定SARS-COV-2是否是否 疫苗接种会诱导自身抗体以及是否因B细胞耗竭而减弱它们。在 AIM 1B，B细胞耗尽患者的免疫响应中的早期事件， 对照将在接种位点附近和排水淋巴结确定时进行分析 在疫苗接种部位是否诱导参与生态抗体产生的TPH细胞。 在AIM 1C中，我们将使用寡聚的偶联来测量抗原特异性反应 MHC四聚体具有Cite-Seq技术。我们将阐明助推器的免疫特征 在AIM 2A中，B细胞耗尽患者的疫苗接种，并比较MF59-之间的反应 AIM 2B中调整后的流感疫苗和标准剂量流感疫苗。我们将确定是否 对SARS-COV-2和流感疫苗的反应相关，如果MF59调整 B细胞耗竭的免疫反应。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疫苗诱导的免疫反应中的作用。