NIEHS activities to develop new approaches for identifying potential immunotoxicants
The NIEHS Division of Translational Toxicology (DTT) conducts testing and research to determine potential human health effects of chemicals, drugs, food additives, dietary supplements, or environmental agents. One DTT area of study is how environmental factors that alter immune responses may contribute to human disease. Changes in immune function can affect susceptibility to infectious disease or cancer, contribute to the development of respiratory or dermal allergic responses resulting from xenobiotic exposures, and induce or exacerbate autoimmune disease. The DTT immunotoxicity testing and research program investigates the ability of xenobiotics to alter the normal structure and/or function of the immune system. Current efforts within the research program focus on using in vitro approaches to assessing potential immunotoxicity. A major effort during 2022 and 2023 used an in vitro human whole blood culture system to investigate how interindividual susceptibility factors and environmental risk factors impact the response to viral infection. Over 200 individual human samples have been screened, and data are being analyzed 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 suggest that males have a higher natural killer cell activity in peripheral blood than females, and data are being further analyzed to determine if this effect is due to males having higher abundance of natural killer cells or more active natural killer cells than females. A second phase of this study is investigating responses to influenza and SARS-CoV-2 antigens following in vitro exposure to known immunotoxicants and how exposure to these environmental agents may affect susceptibility to viral infection. As proof of concept, whole blood cultures were unstimulated or stimulated with anti-T-cell receptor antibodies or viral peptide pools in the presence of dexamethasone, a known immunosuppressive drug. Dexamethasone treatment resulted in inhibition of natural killer activity, cytokine production, and T-cell activation following stimulation with the positive control. This work demonstrated that the in vitro immunotoxicity platform could detect immune suppression and alterations in responses to SARS-CoV-2 peptides. A second proof-of-concept study to examine the effect of benzo(a)pyrene exposure in the presence of metabolizing enzymes resulted in potent suppression in immune endpoints. Work planned for 2024 will develop additional endpoints for this culture system to facilitate interrogation of antibody-mediated responses and cytotoxic T-cell driven immunity. This in vitro toolbox will be critically important for providing direct human relevance of methods used to identify chemicals that have the potential to modulate immune function and reduce the use of animals in toxicology testing.