Multiparametric mapping of Covid-19 immune responses in Kidney transplant recipients

肾移植受者 Covid-19 免疫反应的多参数绘图

• 批准号: 10241179
• 负责人: Peter Scott Heeger
• 金额: $ 59.87万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-29 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241179
• 关键词: 2019-nCoV; 3-Dimensional; Address; Adult Respiratory Distress Syndrome; Affect; Antiviral Agents; Autoimmune Diseases; B-Lymphocytes; Biological Assay; Biological Markers; Biopsy; Blood; COVID-19; COVID-19 morbidity; COVID-19 patient; COVID-19 severity; Case Series; Cellular Immunity; Cessation of life; Characteristics; Chronic; Clinical; Clinical Data; Communities; Critical Illness; DNA; Data; Defect; Deterioration; Development; Disease; Disease Marker; Enzyme-Linked Immunosorbent Assay; Epidemiologic Factors; Flow Cytometry; General Population; Genotype; Goals; Graft Survival; Hospitalization; Hospitals; Human; Immune response; Immunity; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunologics; Immunology procedure; Immunophenotyping; Immunosuppression; Impairment; Incidence; Individual; Infection; Inflammatory Response; Injury; Kidney Transplantation; Kinetics; Longevity; Lymphopenia; Machine Learning; Mechanical ventilation; Medical center; Morbidity - disease rate; Organ Transplantation; Outcome; Pathogenicity; Patients; Peptides; Peripheral Blood Mononuclear Cell; Phenotype; Population; Prevalence; Production; Publications; RNA; Renal Replacement Therapy; Reporting; Resources; Risk; Risk Factors; SARS-CoV-2 immune response; SARS-CoV-2 infection; Sampling; Series; Serology; Serum; Severe Acute Respiratory Syndrome; Severity of illness; Surface; System; T memory cell; T-Lymphocyte; Testing; Time; Transplant Recipients; Transplantation; Variant; Virus; Work; base; case control; clinical biomarkers; cohort; comorbidity; coronavirus disease; cytokine; cytokine release syndrome; enzyme linked immunospot assay; exhaustion; experience; feature selection; high risk; immunosuppressed; insight; large datasets; mortality; novel; pandemic disease; response; severe COVID-19; study population; therapeutically effective; transcriptomics; transmission process

Abstract As of May 2020, over five million confirmed cases of COVID-19 have been reported globally with over 400,000 associated deaths. Around 5-20% of patients develop critical illness, which predominantly manifests as acute respiratory distress syndrome. When this develops, the estimated mortality is around 40%, and as high as 80% in ventilated patients. Several early reports describe the development of an excessive inflammatory response, the so-called `cytokine storm', which is strongly associated with rapid deterioration in clinical condition and mortality. Early reports of kidney transplant recipients, who are at high risk due to chronic immunosuppression and additional comorbid diseases, portray a concerning picture. In one series of 36 patients, 39% required mechanical ventilation, 21% required renal replacement therapy, and 28% died. Of the 11 patients that were intubated, 64% died. However, there is still an unmet need of understanding disease natural course, specific risk factors, identifying biomarkers, as well as potential impact of COVID-19 on graft/patient survival in vulnerable KTRs. To fill this information gap, we propose a comprehensive observational analysis of epidemiological factors and immunological assay results in COVID19-infected KTRs at 2 medical centers at the epicenter of COVID19 infection in NYC (Mount Sinai Hospital in Manhattan and Montefiore Hospital in the Bronx). We hypothesize that specific recipient clinical characteristics affect COVID-19 clinical course and that recipient immunosuppression in KTRs alters the ability of COVID-19 KTRs to develop protective anti-COVID-19 humoral and cell-mediated immunity that contributes to the morbidity and mortality of these individuals. We will test this hypothesis by 1) examining risk factors of COVID-19 severity in a large dataset of KTRs and individuals from the general population with COVID-19 (aim 1); 2) by characterizing the COVID-19 reactive humoral and cellular immune response in serially collected samples from COVID-19 KTRs (aim 2); and 3) by comprehensive assessment of DNA and serial serum, RNA, and PBMC from COVID-19 KTRs to identify disease mechanisms and potentially informative biomarkers for outcomes (aim 3). The proposed work is significant because of the high incidence of the disease, rate of community transmission, high mortality, and absence of clearly effective therapeutic options. Our studies will be amongst the first to define risk factors, predictors, and pathogenic mechanisms of COVID-19 in Kidney transplantation and may apply to recipients of other transplanted organs, as well as to individuals on chronic immunosuppression due to autoimmune diseases.

抽象的 截至 2020 年 5 月，全球报告的 COVID-19 确诊病例已超过 500 万例，确诊病例超过 40 万例 相关死亡。大约 5-20% 的患者会出现危重疾病，主要表现为急性 呼吸窘迫综合征。当这种情况发生时，估计死亡率约为 40%，最高可达 80% 在通气患者中。一些早期报告描述了过度炎症反应的发展， 所谓的“细胞因子风暴”，与临床状况的迅速恶化密切相关 死亡。 肾移植受者的早期报告，由于慢性免疫抑制和肾移植受者的风险较高 其他合并症，描绘出令人担忧的景象。在 36 名患者的一系列研究中，39% 需要 机械通气，21% 需要肾脏替代治疗，28% 死亡。在这 11 名患者中， 插管后，64% 死亡。然而，了解疾病的自然病程、具体情况的需求仍然没有得到满足。 风险因素、识别生物标志物以及 COVID-19 对移植物/患者生存的潜在影响 脆弱的 K​​TR。为了填补这一信息空白，我们提出了一项全面的观察分析 位于 2 个医疗中心的新冠病毒感染 KTR 的流行病学因素和免疫学检测结果 纽约市新冠病毒感染的震中（曼哈顿的西奈山医院和纽约市的蒙蒂菲奥里医院） 布朗克斯）。我们假设特定的接受者临床特征会影响 COVID-19 的临床过程 KTR 中的受体免疫抑制改变了 COVID-19 KTR 发展的能力 保护性抗 COVID-19 体液和细胞介导的免疫，有助于发病和 这些人的死亡率。 我们将通过以下方式检验这一假设：1) 在大型 KTR 数据集中检查 COVID-19 严重程度的风险因素，以及 一般人群中患有 COVID-19 的个人（目标 1）； 2) 通过表征 COVID-19 反应性 从 COVID-19 KTR 中连续收集的样本中的体液和细胞免疫反应（目标 2）； 3) 通过 对来自 COVID-19 KTR 的 DNA 和系列血清、RNA 和 PBMC 进行全面评估，以识别 疾病机制和可能提供信息的结果生物标志物（目标 3）。 由于该疾病的高发病率、社区传播率、 死亡率高，且缺乏明确有效的治疗方案。我们的研究将是最先 定义肾移植中 COVID-19 的危险因素、预测因素和致病机制，并可能 适用于其他移植器官的接受者，以及由于以下原因而长期免疫抑制的个体 自身免疫性疾病。