Mapping Immune Responses to CMV in Renal Transplant Recipients - Transplant Supplement

绘制肾移植受者对 CMV 的免疫反应 - Transplant Supplement

• 批准号: 10225673
• 负责人: ELAINE F REED
• 金额: $ 213.21万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225673
• 关键词: 2019-nCoV; Address; Administrative Supplement; Aging; Antibodies; Antibody Response; Antibody titer measurement; Avidity; Bioinformatics; Biometry; Blood; CD8-Positive T-Lymphocytes; COVID-19; COVID-19 pandemic; California; Cancer Patient; Cellular Immunity; Cessation of life; Chronic Kidney Failure; Clinical; Clinical Trials; Communities; Computer Models; Cytomegalovirus; Data; Disease; End stage renal failure; Enrollment; Evolution; Exposure to; Frequencies; Goals; Health; Human; Humoral Immunities; Immune; Immune System Diseases; Immune response; Immunity; Immunobiology; Immunocompromised Host; Infection; Kidney Transplantation; Kinetics; Knowledge; Link; Longevity; Los Angeles; Maintenance; Minority; Modeling; Molecular Profiling; Morbidity - disease rate; Outcome; Patients; Phenotype; Population; Population Heterogeneity; Populations at Risk; Research Proposals; Resources; Risk; Sampling; Seroprevalences; Suggestion; Syndrome; T cell response; T-Lymphocyte; T-cell receptor repertoire; Technology; Transplant Recipients; Transplantation; Universities; Urine; Vaccine Design; Virus; Virus Diseases; Work; adaptive immune response; antigen-specific T cells; base; clinical phenotype; clinical practice; cohort; comorbidity; ethnic diversity; experience; follow-up; high dimensionality; high risk; improved; insight; mortality; multidimensional data; multiple omics; novel; older patient; pandemic disease; pathogen; post-transplant; racial diversity; recruit; repository; response; transplant centers

SARS-CoV-2 virus infection and associated COVID-19 disease has caused unparalleled global morbidity and mortality in previously healthy patients, with over 4 million cases and 150,000 deaths in the US alone. Older patients, who experience immune dysfunction associated with aging, and patients with underlying health issues, such as chronic kidney disease, have been inequitably burdened by COVID-19. Understanding correlates of protection against SARS-CoV-2 infection and why these immunocompromised patients apparently possess deficiencies in generating these protective immune responses is critical to developing clinical practices for these at-risk populations. To address this fundamental knowledge gap, this study will characterize the natural immune response to SARS-CoV-2 virus infection in immunocompromised patients and determine whether immunity is long-lasting. Specifically, we will evaluate the quantity and quality of antibodies against SARS-CoV-2 and their relationship to frequency and functionality of SARS-CoV-2-specific T cells, therefore generating a complete picture of the adaptive immune response to SARS-CoV-2 in immunocompromised patients. To achieve our goal, we have utilized four kidney transplant centers within the University of California to establish a cohort of 2500 patients with end-stage renal disease (ESRD) awaiting transplant and 2000 renal transplant recipients with banked pre- and post-COVID-19 pandemic sera across a highly racially and ethnically diverse population, of which 40% are from minority populations that have been inequitably burdened by COVID-19. We will screen for exposure to SARS-CoV-2 in the complete cohort of 4500 patients, enrolling 100 ESRD and 76 renal transplant recipients with evidence of SARS-CoV-2-specific antibodies, based on a recent population seroprevalence estimate of 4% in Los Angeles. We will additionally recruit matched patients without evidence of SARS-CoV-2-specific antibodies. Antibody titer, isotype, subclass, avidity, infection neutralization and ability to interface with cell-mediated immunity will be determined at baseline with longitudinal follow-up 3-6 month and 9- 12 months later to assess longevity of humoral immune responses to SARS-CoV-2. Similarly, we will delineate the frequency, phenotype and longevity of SARS-CoV-2-specific cellular immune responses. This study will generate an extensive repository of clinical phenotypes, outcomes, and high-dimensional blood and urine profiling data on longitudinal samples of patients with and without exposure to SARS-CoV-2 in the California transplant population, providing an invaluable resource for the research community in understanding immunity to SARS-CoV-2. Utilizing state-of-the-art biostatistics and computational approaches, we will integrate high-dimensional data of humoral and cellular immune responses to develop models of combined adaptive immune profiles following SARS-CoV-2 exposure and assess their longevity and likelihood of protecting upon re-exposure.

SARS-COV-2病毒感染和相关的Covid-19疾病已引起无与伦比的全球发病率和 以前健康的患者的死亡率，仅美国就有超过400万例和15万例死亡。年龄较大 患者，患有与衰老有关的免疫功能障碍，以及潜在的健康问题患者， 慢性肾脏疾病造成了COVID-19的负担不足。理解相关性 防止SARS-COV-2感染，以及为什么这些免疫功能低下的患者显然拥有 产生这些保护性免疫反应的缺陷对于开发这些临床实践至关重要 高危人群。为了解决这个基本知识差距，本研究将表征自然免疫 免疫功能低下的患者对SARS-COV-2病毒感染的反应，并确定免疫力是否为 持久。具体而言，我们将评估针对SARS-COV-2及其抗体的数量和质量 与SARS-COV-2特异性T细胞的频率和功能的关系，因此产生完整的 免疫功能低下的患者对SARS-COV-2的适应性免疫反应的图片。 为了实现我们的目标，我们利用了加利福尼亚大学的四个肾脏移植中心建立 等待移植和2000肾移植的2500例终末期肾脏疾病（ESRD）的队列 在高度种族和种族多样性上，拥有前后库存前和后期大流行血清的接收者 人口，其中40％来自少数民族，而少数民族受到了Covid-19的负担。我们 将在4500名患者的全部队列中筛选接触SARS-COV-2，招募100 ESRD和76 肾移植接受者具有SARS-COV-2特异性抗体的证据，基于最近的人群 洛杉矶的血清价估计值为4％。我们将另外招募匹配的患者，而没有证据表明 SARS-COV-2特异性抗体。抗体滴度，同种型，亚类，亲和力，感染中和和能力 与细胞介导的免疫力的界面将在基线时确定，纵向随访3-6个月和9-- 12个月后，以评估对SARS-COV-2的体液免疫反应的寿命。同样，我们将描绘 SARS-COV-2特异性细胞免疫反应的频率，表型和寿命。 这项研究将产生广泛的临床表型，结果和高维血液的存储库 以及有关在有或没有暴露于SARS-COV-2的患者的纵向样本的尿液分析数据 加利福尼亚移植人口，为研究界提供了宝贵的资源 对SARS-COV-2的免疫力。利用最先进的生物统计学和计算方法，我们将整合 体液和细胞免疫反应的高维数据开发了组合自适应模型 SARS-COV-2暴露后的免疫轮廓，并评估其寿命和保护的可能性 重新暴露。