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).

项目总结/摘要 实体器官移植受者感染SARS后发病率和死亡率增加- CoV-2是导致COVID-19的病毒。虽然普通民众从快速增长中受益匪浅， 开发出几种疫苗，可以防止严重感染的发展，移植 受者群体对类似的疫苗接种方案的反应不理想。在此，我们建立在我们的 已发表的和初步的数据，对SARS-CoV-2 mRNA疫苗接种的细胞和血清学反应， 肝脏和肾脏的移植者肝移植受者更有可能对 与肾移植相比，使用病毒特异性T细胞和血清转化的两次给药方案 受惠人士有趣的是，尽管血清转化效率和T细胞活化都受到水平的影响， 在免疫抑制中，移植的器官（肝脏与肾脏）对体液免疫有独立的影响。 和细胞反应。然而，对这些适应性免疫应答的深入机制评估是 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。 免疫抑制，在肝脏和肾脏移植受者之间。该提案建立在一个已经 Jonathan Maltzman和Paolo Cravedi实验室之间的富有成效的合作。总目标 这项工作的目的是使用冷冻保存的样品来机械地了解 描述肾移植受者对SARS-CoV-2疫苗接种的有效免疫应答。到 为了实现这一目标，我们提出了以下具体目标：目标1：评估T细胞表型的差异 SARS-CoV-2疫苗应答者的实体器官移植（SOT）受者之间的 目的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表达， 表情该项目建立在Maltzman和Cravedi之间富有成效的合作基础上 实验室和利用他们的专业知识。这一高风险提案的成功有可能 全面描述肾和肝移植受者对SARS的免疫反应- CoV-2疫苗接种是定义应答生物标志物和设想策略的关键点， 提高反应（高奖励）。