High Concentrations of Etanercept Reduce Human Islet Function and Integrity

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...

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Autores principales:	Brandhorst D, Brandhorst H, Acreman S, Abraham A, Johnson PRV
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	human islet transplantation etanercept inflammation hypoxia cytokines Pathology RB1-214 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/2a3c25709d1143d5b7625030a604adde
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spelling	oai:doaj.org-article:2a3c25709d1143d5b7625030a604adde2021-12-02T10:35:46ZHigh Concentrations of Etanercept Reduce Human Islet Function and Integrity1178-7031https://doaj.org/article/2a3c25709d1143d5b7625030a604adde2021-02-01T00:00:00Zhttps://www.dovepress.com/high-concentrations-of-etanercept-reduce-human-islet-function-and-inte-peer-reviewed-article-JIRhttps://doaj.org/toc/1178-7031Daniel 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 daniel.brandhorst@nds.ox.ac.ukBackground: 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, cytokinesBrandhorst DBrandhorst HAcreman SAbraham AJohnson PRVDove Medical Pressarticlehuman islet transplantationetanerceptinflammationhypoxiacytokinesPathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 14, Pp 599-610 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	human islet transplantation etanercept inflammation hypoxia cytokines Pathology RB1-214 Therapeutics. Pharmacology RM1-950
spellingShingle	human islet transplantation etanercept inflammation hypoxia cytokines Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Brandhorst D Brandhorst H Acreman S Abraham A Johnson PRV High Concentrations of Etanercept Reduce Human Islet Function and Integrity
description	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 daniel.brandhorst@nds.ox.ac.ukBackground: 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
format	article
author	Brandhorst D Brandhorst H Acreman S Abraham A Johnson PRV
author_facet	Brandhorst D Brandhorst H Acreman S Abraham A Johnson PRV
author_sort	Brandhorst D
title	High Concentrations of Etanercept Reduce Human Islet Function and Integrity
title_short	High Concentrations of Etanercept Reduce Human Islet Function and Integrity
title_full	High Concentrations of Etanercept Reduce Human Islet Function and Integrity
title_fullStr	High Concentrations of Etanercept Reduce Human Islet Function and Integrity
title_full_unstemmed	High Concentrations of Etanercept Reduce Human Islet Function and Integrity
title_sort	high concentrations of etanercept reduce human islet function and integrity
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/2a3c25709d1143d5b7625030a604adde
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High Concentrations of Etanercept Reduce Human Islet Function and Integrity

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