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Comparing Cytokine Data to In-Life Parameters on NHPs in Nonclinical Toxicology Studies

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Comparing Cytokine Data to In-Life Parameters on Non-human Primates in Nonclinical Toxicology Studies  presented by Vivienne Bunker, Study Director, Research Scientist

Authors: V. Bunker, C. Do, J. Forget, and T. Rogers. Altasciences, Seattle, WA.

Cytokines are important immunoregulatory proteins that have gained attention in safety assessment associated with innate or adaptive immune responses. Interpreting cytokine data comes with challenges due to the variable nature of their stimuli and responses. Contributing factors to the variability in cytokine expression include species-specific reactions, individual variations, dose-response relationships, and unanticipated immunotoxicity. For these reasons, cytokine measurements should not be used as standalone biomarkers for immunotoxicity assessment. However, in conjunction with additional parameters such as clinical observations, body weights, and clinical pathology data, cytokine interpretation can be used to provide more definitive assessments in nonclinical safety studies. In several case studies, cytokines were evaluated for a dose response relationship. Multiplex platforms such as Luminex or MSD® were used to determine cytokine levels in non-human primates including IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12/IL-23p40, MCP-1, IFN-γ, and TNF-α. In several instances, measurable levels of IL-6 or IL-12 correlated with clinical observations of bruising, injury, or abnormal feces, not necessarily considered test article-related. Elevated TNF- α and IL-6, pro-inflammatory cytokines, were detected in animals observed as dehydrated with elevated BUN, creatine, and decreased electrolytes. In cases of test article-related effects, animals becoming moribund also had elevated TNF-α and IL-6 levels. Increased levels of MCP-1, a monocyte chemotactic factor, were observed in one study with an animal with petechial bruising, and another study with a cohort with test-article associated renal failure, characterized by hypoproteinemia, azotemia, and hyperkalemia. In conclusion, cytokines are useful markers when assessing potential toxicity when evaluated with other measurements. Clinical observations, body weights, and clinical pathology parameters should also be considered in addition to the test article-related effects.

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