Immunotoxicity testing using human primary leukocytes: An adjunct approach for the evaluation of human risk

Historically, immunotoxicity testing for chemicals, pesticides and pharmaceuticals has relied heavily on animal models to identify effects on the immune system followed by extrapolation to humans. Substantial progress has been made in the past decade on understanding human immune cell regulation, adaptive and innate immune responses and its modulation. The human immune system is complex and there exists diversity within composition, localization, and activation of different immune cell types between individuals. The inherent variation in human populations owing to genetics and environment can have a significant influence on the response of the immune system to infectious agents, drugs, chemicals and other environmental factors. Several recent reports have highlighted that mouse models of sepsis and inflammation are poorly predictive of human disease physiology and pathology. Rodent and human immune cells differ in the expression of cell surface proteins and phenotypes expressed in disease models, which may significantly influence the mechanism of action of xenobiotics and susceptibility yielding a different profile of activity across animal species. In the light of these differences and recent trends toward precision medicine, personalized therapies and the 3Rs (reduce, replace and refine animal use) approaches, the importance of using 'all human' model systems cannot be overstated. Hence, this opinion piece aims to discuss new models used to assess the effects of environmental contaminants and immune modulators on the immune response in human cells, the advantages and challenges of using human primary cells in immunotoxicology research and the implication for the future of immunotoxicity testing.