Stratifying Patient Immune Endotypes in Sepsis (SPIES Study)

脓毒症患者免疫内型分层（SPIES 研究）

基本信息

批准号：
10439853
负责人：
LYLE L MOLDAWER
金额：
$ 74.89万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-05 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10439853
关键词：
Age Animal Model Antibiotics Biological Assay Biological Markers Blood Blood specimen CD14 gene Cell physiology Cells Chronic Clinical Clinical Trials Critical Illness Data Defect Development Diagnosis Early Diagnosis Effectiveness Enrollment Ethnic Origin Exclusion Criteria Failure Functional disorder Future Genomics Goals Granulocyte-Macrophage Colony-Stimulating Factor HLA-DR Antigens Hospital Mortality Hospitalization Hospitals Hour IL7 gene Immune Immune response Immunity Immunocompetence Immunocompromised Host Immunologic Adjuvants Immunology procedure Immunosuppression Immunotherapy Impairment Incidence Incubated Individual Infection Inpatients Institution Interferon Type II Interferons Interleukin-6 Invaded Knowledge Laboratories Length of Stay Life Lymphocyte Count Measurement Measures Monoclonal Antibodies Mononuclear Natural Immunity Nosocomial Infections Nucleic Acids Oncology Organ Outcome Pathogenicity Patients Phenotype Plasma Plasma Proteins Production Proteins Proteomics Quality Control Race Randomized Randomized Clinical Trials Recurrence Sampling Savings Sepsis Severities Surrogate Markers Survivors T-Lymphocyte TNF gene TNFSF4 gene Testing Therapeutic Time Validation Whole Blood adaptive immunity aging population anti-PD-1 base clinical development comorbidity comparative efficacy design efficacy evaluation hospital readmission immune function immune stimulant immunological status immunosuppressed improved in vivo indexing individual patient monocyte mortality novel pathogen patient stratification predictive modeling prospective recidivism recurrent infection response secondary infection secondary outcome septic patients sex tertiary care transcriptomics treatment response tumor

项目摘要

ABSTRACT Sepsis remains the leading cause of hospital mortality today.1 Despite its increasing incidence due to an aging population with greater comorbidities, in-hospital mortality has significantly declined over the past decade.2 This is due in large part to earlier recognition and better compliance with best practices in early sepsis management. Despite improved in-hospital mortality, a large proportion (up to 50% in some studies)3-5 of sepsis survivors never fully recover and develop chronic critical illness (CCI), characterized by persistent immune suppression, recurrent infections, sepsis recidivism and poor long-term outcomes. There are three key challenges, however, hindering the development of immunological therapies in these sepsis survivors: i) how to endotype patients with sepsis who are immunosuppressed; ii) how to quantify the degree of immune suppression; and iii) how to identify promising immune stimulants in individual immunosuppressed patients? We believe that current efforts to endotype sepsis survivors as being immunosuppressed have not been fully successful because they fail to directly assess immune function, instead using either genomic or proteomic measures of immune status. Here we propose to: 1) assess whether stimulated T cell production of IFN-γ and stimulated monocyte production of TNF as quantitated by ELISpot, better predicts infectious and long-term outcomes in sepsis survivors than common static measurements based on protein levels, expression and nucleic acid concentrations; and 2) to employ ELISpot assessment of IFN- production by T-cells and TNF production by monocytes from sepsis survivors to examine ex vivo the comparative efficacy of different immune stimulants to reverse sepsis-induced immunosuppression. To achieve these goals, we propose a prospective, observational trial of 270 patients with sepsis (using Sepsis-3 criteria) compared to 90 patients with critical illness without sepsis (total of 390 with 30 healthy subjects for quality control and validation) at 3 academic institutions. At 1, 4 and 7 days post sepsis diagnosis, blood samples will be obtained and blood T-cell and monocyte production of IFN- and TNF, respectively, will be determined by ELISpot. In addition, samples will be obtained for other biomarkers, including plasma proteins (IL-6 and sPD-L1), CD14+ cell expression of HLA-DR, total lymphocyte count and whole blood genomics. Secondary infections will be the primary clinical index of outcome6, with secondary indices including hospital readmission, and 180 day mortality. In addition, we will evaluate in this ELISpot platform the ex vivo response of IFN- production by T-cells and TNF production by monocytes stimulated with varying concentrations of IL-7, anti-PD-1 mAb, GITRL, OX40L or 4-1BB, using a randomized block design. These immune stimulants are currently under consideration as potential therapeutics for sepsis patients. This application proposes the validation of a novel functional bioassay to identify patients who would benefit from immunotherapy, and to identify different immune therapies that would benefit the individual patient.

抽象的败血症仍然是今天医院死亡率的主要原因。在过去十年在很大程度上是由于早期认可和更好地遵守早期败血症管理的最佳实践。尽管院内死亡率有所提高，但很大一部分（在某些研究中最多50％）3-5败血症从未完全康复并发展为慢性疾病（CCI），其特征是持续的免疫抑制，复发性感染，败血症累犯和长期不良结果。但是，有三个主要挑战阻碍这些败血症生存中免疫疗法的发展：i）如何内型患者免疫抑制的败血症； ii）如何量化免疫抑制程度； iii）如何识别在个别免疫抑制患者中有希望的免疫兴奋剂？我们相信目前为内型败血症生存为免疫抑制，因为它们没有完全成功直接使用免疫状态的基因组或蛋白质组学测量值直接评估免疫功能。这里我们建议：1）评估是否刺激了IFN-γ的T细胞产生和刺激的单核细胞产生 tnf被ELISPOT定量，更好地预测败血症生存中的传染性和长期结局基于蛋白质水平，表达和核酸浓度的常见静态测量；和2）到由T细胞和TNF产生IFN-的员工ELISPOT评估败血症的单核细胞产生幸存者检查离体的相比效率不同免疫抑制。为了实现这些目标，我们提出了270名患者的前瞻性观察试验败血症（使用SEPIS-3标准），而没有败血症的90例患者（总计390例）在3个学术机构中的健康受试者进行质量控制和验证）。败血症后1、4和7天诊断，将获得血液样本，以及IFN-和TNF的血液T细胞和单核细胞的产生，此外，还将获得其他生物标志物的样品，包括血浆蛋白（IL-6和SPD-L1），CD14+ HLA-DR的细胞表达，总淋巴细胞计数和全血基因组学。继发感染将是结果6的主要临床指数，其中包括医院再入院和180天的死亡率。此外，我们将在此ELISPOT平台中进行评估。 T细胞产生IFN-的响应，由单核细胞刺激的单核细胞产生。使用随机块设计，IL-7，抗PD-1 MAB，GITRL，OX40L或4-1BB的浓度。这些免疫兴奋剂目前正在考虑为败血症患者的潜在治疗。这应用建议对新型功能生物测定的验证，以识别将受益的患者免疫疗法，并确定将受益于个体患者的不同免疫疗法。