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; 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22财年，我们继续将免疫毒理学研究计划集中在体外方法上。一项重大努力涉及调查个体易感性因素和环境风险因素，例如暴露于多芳烃，会影响对病毒感染的反应（SARS-COV-2和流感），使用体外人类全血培养系统。终点包括淋巴细胞毒性，细胞因子释放和天然杀伤细胞活性。 在22财年，BRT对从商业来源购买的200个血液样本进行了这些测定。目前正在报告和发布之前对数据进行分析。 222财年的努力增加了该工具箱的体外方法，从而开发了基于流式细胞术的测定方法，以测量病毒抗原体外刺激后的T细胞激活。 BRT继续扩展工具箱，目前正在测试该培养系统，以促进对病毒抗原的免疫力进行体液抗体的询问。我们已经开始使用免疫抑制化合物进行初步的体外研究，这将是体外PAC-MAP研究的阳性对照。这些研究的数据将针对先前根据本合同收集的小鼠数据中的小鼠数据引用，并有助于基于人类的相关性，并在可以使用体外系统生成的数据中建立科学信心。该体外工具箱对于确定具有调节人类免疫功能的化学物质至关重要，并将NTP定位在该领域测试的最前沿。