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

项目摘要/摘要 实体器官移植患者因感染SARS而增加了发病率和死亡率-- CoV-2，是导致COVID19的病毒。虽然普通民众从快速的 开发几种预防严重感染的疫苗，移植 接受人群对类似疫苗接种方案的反应不是最理想的。在这里，我们建立在我们的 关于SARS-CoV-2mRNA疫苗接种后的细胞和血清学反应的公布和初步数据 肝脏和肾脏移植的接受者。肝移植受者明显更有可能对 病毒特异性T细胞和血清转换双剂方案与肾移植的比较 收件人。有趣的是，尽管血清转换效率和T细胞激活都受到水平的影响 在免疫抑制方面，移植的器官(肝和肾)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、机械性评估是 缺乏。我们假设，无论疾病的程度如何，免疫功能都存在内在差异。 肝肾移植受者之间的免疫抑制。这项建议建立在一个已经存在的 乔纳森·马尔茨曼和保罗·克拉维迪的实验室之间富有成效的合作。总目标 这项工作的重点是使用低温保存的样本来机械地理解 描述肾移植受者接种SARS-CoV-2疫苗后的有效免疫反应。至 针对这一目标，我们提出了以下具体目标：目标1：评估T细胞表型的差异 和作为SARS-CoV-2疫苗应答者的固体器官移植(SOT)接受者之间的功能 目标2：确定先天免疫细胞和获得性免疫细胞群体的差异 通过测量染色质可及性和基因在疫苗应答者和无应答者之间的差异 表情。这个项目建立在Maltzman和Cravedi之间富有成效的合作之上 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 全面描述肾和肝移植受者对SARS的免疫反应- CoV-2疫苗接种，对于定义反应的生物标记物和设想战略至关重要 改进响应(高额奖励)。

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).