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，据报道，超过500万个证实的Covid案件已在全球范围内报道，超过40万 相关死亡。大约5-20％的患者出现危重疾病，主要表现为急性 呼吸窘迫综合征。当这种情况发展时，估计的死亡率约为40％，高达80％ 在通风的患者中。几份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”，在临床状况和 死亡。 肾脏移植接受者的早期报道，由于慢性免疫抑制和 其他合并症，描绘了有关图片的一份。在一系列36例患者中，需要39％ 机械通气，21％需要肾脏替代疗法，而28％的人死亡。在11例患者中 插管，有64％的人死亡。但是，仍然需要了解疾病自然病程，具体 识别生物标志物的危险因素以及Covid-19对移植/患者生存的潜在影响 脆弱的KTR。为了填补此信息差距，我们提出了对 流行病学因素和免疫学测定导致在2个医疗中心感染的KTRS中导致在2个医疗中心 纽约市Covid19感染的中心（曼哈顿山医院和蒙特菲奥尔医院 布朗克斯）。我们假设特定的受体临床特征会影响COVID-19 KTR中的接受者免疫抑制改变了Covid-19 KTR的能力 保护性抗COVID-19的体液和细胞介导的免疫力有助于发病率和 这些人的死亡率。 我们将通过1）检查该假设的1）检查在KTR的大数据集中，COVID-19的风险因素和 来自Covid-19的普通人群的个人（AIM 1）； 2）通过表征covid-19反应性 来自共同的19 ktrs的串行收集样品中的体液和细胞免疫反应（AIM 2）； 3） 从COVID-19 KTRS的DNA和系列血清，RNA和PBMC的全面评估以识别 疾病机制和可能的结果有益的生物标志物（AIM 3）。 拟议的工作很重要，因为该疾病的发生率很高，社区传播速度， 高死亡率，缺乏明显有效的治疗选择。我们的研究将是第一个 定义肾移植中Covid-19的危险因素，预测因素和致病机制，可能 适用于其他移植器官的接受者，以及由于慢性免疫抑制的人 自身免疫性疾病。