Journal of Inflammation Research (Feb 2021)
High Concentrations of Etanercept Reduce Human Islet Function and Integrity
Abstract
Daniel Brandhorst,1,2,* Heide Brandhorst,1,2,* Samuel Acreman,1,2 Anju Abraham,1,2 Paul RV Johnson1,2 1Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK; 2Oxford Consortium for Islet Transplantation, Oxford Centre for Diabetes, Endocrinology, and Metabolism (OCDEM), Churchill Hospital, University of Oxford, Oxford, OX3 7LE, UK*These authors contributed equally to this workCorrespondence: Daniel BrandhorstNuffield Department of Surgical Sciences, John Radcliffe Hospital, Level 6, Headley Way, University of Oxford, Oxford, OX3 9DU, UKEmail [email protected]: Most islet transplant groups worldwide routinely use the TNFα inhibitor Etanercept in their peri-transplant protocols. Surprisingly, there have been no published dose-response studies on the effects of Etanercept on human islets. Our study aimed to address this by treating cultured human islets with increasing concentrations of Etanercept.Materials and Methods: Isolated human islets were cultured for 3– 4 days in normoxic (21% oxygen) or in hypoxic (2% oxygen) atmosphere using Etanercept dissolved in a range of 2.5– 40 μg/mL prior to islet characterisation.Results: In normoxic atmosphere, it was found that 5 μg/mL is the most efficient dose to preserve islet morphological and functional integrity during culture. Increasing the dose to 10 μg/mL or more resulted in detrimental effects with respect to viability and glucose-stimulated insulin release. When human islets were cultured for 3 to 4 days in clinically relevant hypoxia and treated with 5 μg/mL Etanercept, post-culture islet survival (P < 0.001) and in vitro function (P < 0.01) were significantly improved. This correlated with a substantially reduced cytokine production (P < 0.05), improved mitochondrial function (P < 0.01), and reduced production of reactive oxygen species (P < 0.001) in hypoxia-exposed islets.Conclusion: These findings suggest that the therapeutic window of Etanercept is very narrow and that this should be considered when optimising the dosage and route of Etanercept administration in islet-transplant recipients or when designing novel drug-delivering islet scaffolds.Keywords: human islet transplantation, Etanercept, inflammation, hypoxia, cytokines
