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
基本信息
- 批准号:10906729
- 负责人:
- 金额:$ 109.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-08-13 至 2024-08-12
- 项目状态:已结题
- 来源:
- 关键词:2019-nCoVAnimalsAntibody-mediated protectionAromatic Polycyclic HydrocarbonsAutoimmune DiseasesBiological AssayBlood specimenCOVID-19COVID-19 susceptibilityCell-Mediated CytolysisChemical AgentsChemicalsCommunicable DiseasesContractsDataDermalDevelopmentEnvironmentEnvironmental Risk FactorEventExposure toFlow CytometryFood AdditivesHealthHealth HazardsHematopoieticHumanHypersensitivityImmuneImmunologic TechniquesImmunologicsImmunosuppressionImmunotoxicologyIn VitroIndividualInfluenzaMeasuresMethodsMolecularMusNational Toxicology ProgramNatural Killer CellsNeoplasmsPharmaceutical PreparationsPositioning AttributePredictive ValuePredispositionPublicationsReportingResearchResistanceRiskSourceStructureSystemT-Cell ActivationTestingTherapeutic AgentsViral AntigensVirusVirus DiseasesWhole BloodXenobioticscytokinedietary supplementsenvironmental agentexposed human populationimmune functionimmune system functionimmunoregulationimmunotoxicityin vitro Modelin vivoprogramsrespiratoryresponse
项目摘要
In FY 23 we continued to focus the immunotoxicology research program within the the Division of Translation Toxicology (DTT) on in vitro approaches. A major effort involved investigating how interindividual susceptibility factors and environmental risk factors impact the response to viral infection, using an in vitro human whole blood culture system. Endpoints include lymphocytotoxicity, cytokine release, and Natural Killer cell activity. We have screened >200 individual samples to date and are analyzing in vitro data to examine how intrinsic factors such as age, gender and ethnicity influence the response of peripheral blood leukocytes to influenza and SARS-CoV-2 antigens. Preliminary results demonstrate an association between sex and NK activity with males having higher NK activity in peripheral blood than females. Immunophenotyping data are being analyzed to determine if this effect is due to males having higher abundance of NK cells or more active NK cells than females. A second phase of this study is investigating the responses to these antigens following in vitro exposure to known immunotoxicants, including PACs and how exposure to these environmental agents may affect susceptibility to viral infection. The PAC data will be referenced against mouse in vivo data previously collected in the PAC-MAP mixtures studies and serve to anchor human relevance and strengthen the data that can be generated using the in vitro system. As proof of concept, whole blood cultures were unstimulated or stimulated with anti-CD3/CD28 or viral peptide pools in the presence of dexamethasone, a known immunosuppressive drug. DEX treatment resulted in inhibition of NK activity, cytokine production, and T-cell activation following stimulation with the positive control anti-CD3/CD28. Importantly, DEX treatment also inhibited the production of cytokines stimulated by SARS-CoV-2 antigen pool in a concentration related manner. This work demonstrated that the in vitro immunotoxicity platform was capable of detecting immune suppression and alterations in responses to SARS-CoV-2 peptides. A second proof of concept study using the PAC Benzo(a)pyrene is ongoing and exposure to this compound in the present of metabolizing enzymes resulted in potent suppression in the immune endpoints measured to date. BRT is currently working on development of additional in vitro tools for this culture system that will facilitate interrogation of humoral antibody mediated immunity and T-cell driven immunity. This in vitro toolbox will be critically important to provide direct human relevance in the methods used to identify chemicals that have the potential to modulate immune function, and will reduce the use of animals in toxicology testing.
在2023财年,我们继续将翻译毒理学(DTT)部门内的免疫毒理学研究计划集中在体外方法上。一个主要的努力涉及调查个体间的易感因素和环境风险因素如何影响病毒感染的反应,使用体外人全血培养系统。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。迄今为止,我们已经筛选了超过200个个体样本,并正在分析体外数据,以研究年龄、性别和种族等内在因素如何影响外周血白细胞对流感和SARS-CoV-2抗原的反应。初步结果表明性别和NK活性之间的关联,男性外周血中的NK活性高于女性。正在分析免疫表型数据,以确定这种影响是否是由于男性比女性具有更高丰度的NK细胞或更活跃的NK细胞。本研究的第二阶段是研究体外暴露于已知的免疫毒物(包括PAC)后对这些抗原的反应,以及暴露于这些环境因子如何影响对病毒感染的易感性。PAC数据将参考先前在PAC-MAP混合物研究中收集的小鼠体内数据,并用于锚人体相关性,并加强可使用体外系统生成的数据。作为概念证明,全血培养物未受刺激或在存在地塞米松(一种已知的免疫抑制药物)的情况下用抗CD 3/CD 28或病毒肽池刺激。DEX处理导致用阳性对照抗CD 3/CD 28刺激后NK活性、细胞因子产生和T细胞活化的抑制。更重要的是,DEX处理还以浓度相关的方式抑制SARS-CoV-2抗原库刺激的细胞因子的产生。这项工作表明,体外免疫毒性平台能够检测对SARS-CoV-2肽的免疫抑制和反应变化。使用PAC苯并(a)芘的第二项概念验证研究正在进行中,在存在代谢酶的情况下暴露于该化合物导致迄今为止测量的免疫终点的强效抑制。BRT目前正在开发用于该培养系统的额外体外工具,这将有助于询问体液抗体介导的免疫和T细胞驱动的免疫。这种体外工具箱对于在用于识别具有调节免疫功能潜力的化学品的方法中提供直接的人类相关性至关重要,并将减少在毒理学测试中使用动物。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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{{ truncateString('FLORENCE BURLESON', 18)}}的其他基金
STUDIES TO EVALUATE THE POTENTIAL FOR ENVIRONMENTAL&THERAPEUTIC AGENTS TO INDUCE IMMUNOTOXICITY - In vitro hypersensitivity
评估环境潜力的研究
- 批准号:
10421165 - 财政年份:2014
- 资助金额:
$ 109.09万 - 项目类别:
STUDIES TO EVALUATE THE POTENTIAL FOR ENVIRONMENTAL&THERAPEUTIC AGENTS TO INDUCE IMMUNOTOXICITY - In vivo
评估环境潜力的研究
- 批准号:
10209928 - 财政年份:2014
- 资助金额:
$ 109.09万 - 项目类别:
STUDIES TO EVALUATE THE POTENTIAL FOR ENVIRONMENTAL&THERAPEUTIC AGENTS TO INDUCE IMMUNOTOXICITY
评估环境潜力的研究
- 批准号:
8937071 - 财政年份:2014
- 资助金额:
$ 109.09万 - 项目类别:
STUDIES TO EVALUATE THE POTENTIAL FOR ENVIRONMENTAL&THERAPEUTIC AGENTS TO INDUCE IMMUNOTOXICITY - In vivo
评估环境潜力的研究
- 批准号:
10023392 - 财政年份:2014
- 资助金额:
$ 109.09万 - 项目类别:
STUDIES TO EVALUATE THE POTENTIAL FOR ENVIRONMENTAL&THERAPEUTIC AGENTS TO INDUCE IMMUNOTOXICITY
评估环境潜力的研究
- 批准号:
9129580 - 财政年份:2014
- 资助金额:
$ 109.09万 - 项目类别:
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 - 财政年份:2014
- 资助金额:
$ 109.09万 - 项目类别:
STUDIES TO EVALUATE THE POTENTIAL FOR ENVIRONMENTAL&THERAPEUTIC AGENTS TO INDUCE IMMUNOTOXICITY - In vitro
评估环境潜力的研究
- 批准号:
10023468 - 财政年份:2014
- 资助金额:
$ 109.09万 - 项目类别:
STUDIES TO EVALUATE THE POTENTIAL FOR ENVIRONMENTAL&THERAPEUTIC AGENTS TO INDUCE IMMUNOTOXICITY - In vivo
评估环境潜力的研究
- 批准号:
10906727 - 财政年份:2014
- 资助金额:
$ 109.09万 - 项目类别:
STUDIES TO EVALUATE THE POTENTIAL FOR ENVIRONMENTAL&THERAPEUTIC AGENTS TO INDUCE IMMUNOTOXICITY - In vivo
评估环境潜力的研究
- 批准号:
10421164 - 财政年份:2014
- 资助金额:
$ 109.09万 - 项目类别:
STUDIES TO EVALUATE THE POTENTIAL FOR ENVIRONMENTAL&THERAPEUTIC AGENTS TO INDUCE IMMUNOTOXICITY - In vitro immunomodulation
评估环境潜力的研究
- 批准号:
10906728 - 财政年份:2014
- 资助金额:
$ 109.09万 - 项目类别:
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