Translatability Of Non-Human Primate Cytokine Data To In-Life Parameters In Nonclinical Toxicology Studies

By C Do, V Bunker, J Forget, and T Rogers

Cytokines are crucial immunoregulatory proteins that play a significant role in safety assessments; however, interpreting cytokine data presents challenges due to the variability in their stimuli and responses. Factors contributing to this variability include species-specific reactions, individual differences, dose-response relationships, and unexpected immunotoxicity. As a result, cytokine measurements should not be used as standalone biomarkers for immunotoxicity assessment. Instead, they should be evaluated alongside clinical observations, body weight, and clinical pathology data to provide a more comprehensive safety assessment in nonclinical studies. Several case studies examined cytokine levels in non-human primates using multiplex platforms such as Luminex or MSD® to assess IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12/IL-23p40, MCP-1, IFN-γ, and TNF-α.

In many instances, measurable IL-6 or IL-12 levels correlated with clinical signs like bruising, injury, or abnormal feces, which were not necessarily related to the test article. Additionally, elevated TNF-α and IL-6 were detected in dehydrated animals with increased blood urea nitrogen (BUN), creatinine, and decreased electrolytes. In cases where test article-related effects were observed, moribund animals also exhibited elevated TNF-α and IL-6 levels. These findings emphasize the importance of interpreting cytokine variations in the context of clinical observations, body weight, and clinical pathology parameters to accurately assess potential toxicity.