Deciphering the Molecular Mechanisms of Response to COVID Vaccine in Kidney Transplant Recipients

解读肾移植受者对新冠疫苗反应的分子机制

• 批准号: 10668154
• 负责人: Paolo Cravedi
• 金额: $ 25.55万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-21 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668154
• 关键词: 2019-nCoV; ATAC-seq; Address; Affect; Antibody Response; B-Lymphocytes; COVID-19; COVID-19 vaccination; COVID-19 vaccine; Cells; Chromatin; Collaborations; Cryopreservation; Data; Development; Dose; Epigenetic Process; Evaluation; Gene Expression; General Population; Genetic Transcription; Goals; Human; Immune; Immune response; Immunosuppression; Individual; Infection; Innate Immune Response; Kidney; Kidney Transplantation; Laboratories; Link; Liver; Measures; Molecular; Morbidity - disease rate; Organ; Organ Transplantation; Outcome; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Population; Productivity; Publishing; RNA vaccination; RNA vaccine; Recording of previous events; Regimen; SARS-CoV-2 spike protein; Sampling; Serology; Solid; T cell clonality; T cell response; T-Cell Activation; T-Lymphocyte; Technology; Testing; Transplant Recipients; Vaccination; Vaccines; Viral; Virus; Work; adaptive immune response; booster vaccine; cohort; coronavirus disease; experimental study; high reward; high risk; immune function; improved; liver transplantation; mortality; organ transplant recipient; post SARS-CoV-2 infection; responders and non-responders; response; response biomarker; seroconversion; single nucleus RNA-sequencing; success

PROJECT SUMMARY / ABSTRACT Solid organ transplant recipients have increased morbidity and mortality in response to infection with SARS- CoV-2, the virus responsible for COVID19. While the general population has greatly benefited from the rapid development of several vaccines that are protective against the development of severe infection, the transplant recipient population has sub-optimal responses to similar vaccination regimens. Herein, we build on our published and preliminary data on the cellular and serological responses to SARS-CoV-2 mRNA vaccination in both liver and kidney transplant recipients. Liver transplant recipients are significantly more likely to respond to a two-dose regimen with both viral specific T cells and seroconversion when compared with kidney transplant recipients. Interestingly, although both seroconversion efficiency and T cell activation are affected by the levels of immunosuppression, the organ transplanted (liver versus kidney) has an independent effect on the humoral and cellular responses. However, an in depth, mechanistic evaluation of these adaptive immune responses is lacking. We hypothesize that there are intrinsic differences in immune function, irrespective of the degree of immunosuppression, between liver and kidney transplant recipients. This proposal builds on an already productive collaboration between the laboratories of Jonathan Maltzman and Paolo Cravedi. The overall goal of this work is to use cryopreserved samples to mechanistically understand the features that characterize effective immune response to SARS-CoV-2 vaccination in kidney transplant recipients. To address this goal, we propose the following specific aims: Aim 1: Assess the differences in T cell phenotype and function between solid organ transplant (SOT) recipients that are SARS-CoV-2 vaccine responders versus non-responders; Aim 2: Determine differences in innate and adaptive immune cell populations between vaccine responders versus non-responders by measuring chromatin accessibility and gene expression. This project builds upon the productive collaboration between the Maltzman and Cravedi laboratories and leverages their expertise. Success of this high-risk proposal has the potential to comprehensively delineate the immune responses in both kidney and liver transplant recipients upon SARS- CoV-2 vaccination, a point of critical importance to define biomarkers of response and envision strategies to improve response (high reward).

项目概要/摘要 实体器官移植受者因感染 SARS 而发病率和死亡率增加 CoV-2，导致新冠肺炎 (COVID19) 的病毒。虽然广大民众已从快速发展中受益匪浅 开发几种可预防严重感染、移植的疫苗 接受人群对类似疫苗接种方案的反应不佳。在此，我们以我们的 已发表的有关 SARS-CoV-2 mRNA 疫苗接种的细胞和血清学反应的初步数据 肝脏和肾脏移植受者。肝移植受者更有可能做出反应 与肾移植相比，采用病毒特异性 T 细胞和血清转化的双剂量方案 收件人。有趣的是，虽然血清转化效率和 T 细胞活化都受到水平的影响 免疫抑制方面，移植的器官（肝脏与肾脏）对体液有独立的影响 和细胞反应。然而，对这些适应性免疫反应的深入、机制评估是 缺乏。我们假设免疫功能存在内在差异，无论免疫功能的程度如何。 肝移植和肾移植受者之间的免疫抑制。该提案建立在已经 乔纳森·马尔兹曼 (Jonathan Maltzman) 和保罗·克拉韦迪 (Paolo Cravedi) 实验室之间富有成效的合作。总体目标 这项工作的目的是使用冷冻保存的样本来机械地了解 表征肾移植受者对 SARS-CoV-2 疫苗接种的有效免疫反应。到 为了实现这一目标，我们提出以下具体目标： 目标 1：评估 T 细胞表型的差异 SARS-CoV-2 疫苗应答者实体器官移植 (SOT) 接受者之间的功能和功能 与无反应者相比；目标 2：确定先天性和适应性免疫细胞群的差异 通过测量染色质可及性和基因来区分疫苗反应者与无反应者 表达。该项目建立在 Maltzman 和 Cravedi 之间富有成效的合作基础上 实验室并利用他们的专业知识。这一高风险提案的成功有可能 全面描绘了肾移植和肝移植受者对 SARS 的免疫反应 CoV-2 疫苗接种是定义反应生物标志物和制定应对策略的关键点 提高反应（高奖励）。