Enabling risk-based testing through characterization of environmentally induced immune dysregulation and susceptibility to the SARS-CoV2 virus and COVID-19

通过表征环境引起的免疫失调以及对 SARS-CoV2 病毒和 COVID-19 的易感性，实现基于风险的测试

• 批准号: 10682371
• 负责人: FLORENCE BURLESON
• 金额: $ 93.56万
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-13 至 2023-08-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10682371
• 关键词: 2019-nCoV; Animals; Antibody-mediated protection; Aromatic Polycyclic Hydrocarbons; Autoimmune Diseases; Biological Assay; Blood specimen; COVID-19; Cell-Mediated Cytolysis; Chemical Agents; Chemicals; Communicable Diseases; Contracts; Data; Dermal; Development; Environmental Risk Factor; Event; Exposure to; Flow Cytometry; Food Additives; Health; Health Hazards; Hematopoietic; Human; Hypersensitivity; Immune; Immunologic Techniques; Immunologics; Immunosuppression; Immunotoxicology; In Vitro; Influenza; Measures; Methods; Molecular; Mus; National Toxicology Program; Natural Killer Cells; Neoplasms; Pharmaceutical Preparations; Positioning Attribute; Predictive Value; Predisposition; Publications; Reporting; Research; Resistance; Risk; Source; Structure; System; T-Cell Activation; Testing; Therapeutic Agents; Viral Antigens; Virus; Virus Diseases; Whole Blood; Xenobiotics; base; cytokine; dietary supplements; environmental agent; exposed human population; immune function; immune system function; immunoregulation; immunotoxicity; in vitro Model; in vivo; programs; respiratory; response

In FY 22 we continued to focus the immunotoxicology research program on in vitro approaches. A major effort involved investigating how interindividual susceptibility factors and environmental risk factors such as exposure to polyaromatic hydrocarbons impact the response to viral infection (SARS-CoV-2 and Influenza), using an in vitro human whole blood culture system. Endpoints include lymphocytotoxicity, cytokine release, and Natural Killer cell activity. In FY22, BRT performed these assays for 200 blood samples purchased from commercial sources. The data are currently being analyzed prior to reporting and publication. Efforts in FY22 to add to this toolbox of in vitro approaches resulted in the development of a flow cytometry-based assay to measure T-cell activation following in vitro stimulation with viral antigens. BRT continues to expand the toolbox and is currently testing this culture system to facilitate interrogation of humoral antibody mediated immunity to viral antigens. We have begun preliminary in vitro studies with an immunosuppressive compound that will serve as a positive control for the in vitro PAC-MAP studies. The data from these studies will be referenced against mouse in vivo data previously collected under this contract and serve to anchor human relevance and establish scientific confidence in the data that can be generated using the in vitro system. This in vitro toolbox will be critically important to identify chemicals that have the potential to modulate immune function in humans and will position NTP at the cutting edge of testing in this field.

在第22财年，我们继续将免疫毒理学研究的重点放在体外方法上。一项主要工作涉及使用体外人类全血培养系统调查个体间易感因素和环境风险因素(如暴露于多环芳烃)如何影响对病毒感染(SARS-CoV-2和流感)的反应。终点包括淋巴细胞毒性、细胞因子释放和自然杀伤细胞活性。在22财年，BRT对从商业来源购买的200份血液样本进行了这些分析。目前正在对这些数据进行分析，然后再进行报告和公布。在2012财年，为了增加这一体外方法工具箱，开发了一种基于流式细胞术的分析方法，以测量病毒抗原体外刺激后T细胞的激活情况。BRT继续扩展工具箱，目前正在测试该培养系统，以便于询问体液抗体介导的对病毒抗原的免疫。我们已经开始了一种免疫抑制化合物的初步体外研究，该化合物将作为体外PAC-MAP研究的阳性对照。来自这些研究的数据将与先前根据该合同收集的小鼠体内数据相对照，并用于锚定人类相关性，并建立对使用体外系统产生的数据的科学信心。这个体外工具箱对于识别有可能调节人类免疫功能的化学物质将是至关重要的，并将使NTP处于该领域测试的前沿。