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Treatment with Tacrolimus and Sirolimus Reveals No Additional Adverse Effects on Human Islets In Vitro Compared to Each Drug Alone but They Are Reduced by Adding Glucocorticoids
Oslo Univ Hosp, Dept Transplant Med, POB 4950, N-0424 Oslo, Norway.;Oslo Univ Hosp, Inst Surg Res, POB 4950, N-0424 Oslo, Norway.;Univ Oslo, Inst Clin Med, POB 1171, N-0318 Oslo, Norway..
Oslo Univ Hosp, Dept Transplant Med, POB 4950, N-0424 Oslo, Norway.;Oslo Univ Hosp, Inst Surg Res, POB 4950, N-0424 Oslo, Norway.;Univ Oslo, Inst Clin Med, POB 1171, N-0318 Oslo, Norway..
Oslo Univ Hosp, Dept Pharmacol, POB 4950, N-0424 Oslo, Norway..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2016 (English)In: Journal of Diabetes Research, ISSN 2314-6745, E-ISSN 2314-6753, 4196460Article in journal (Refereed) Published
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Abstract [en]

Tacrolimus and sirolimus are important immunosuppressive drugs used in human islet transplantation; however, they are linked to detrimental effects on islets and reduction of long-term graft function. Few studies investigate the direct effects of these drugs combined in parallel with single drug exposure. Human islets were treated with or without tacrolimus (30 mu g/L), sirolimus (30 mu g/L), or a combination thereof for 24 hrs. Islet function as well as apoptosis was assessed by glucose-stimulated insulin secretion (GSIS) and Cell Death ELISA. Proinflammatory cytokines were analysed by qRT-PCR and Bio-Plex. Islets exposed to the combination of sirolimus and tacrolimus were treated with or without methylprednisolone (1000 mu g/L) and the expression of the proinflammatory cytokines was investigated. We found the following: (i) No additive reduction in function and viability in islets existed when tacrolimus and sirolimus were combined compared to the single drug. (ii) Increased expression of proinflammatory cytokines mRNA and protein levels in islets took place. (iii) Methylprednisolone significantly decreased the proinflammatory response in islets induced by the drug combination. Although human islets are prone to direct toxic effect of tacrolimus and sirolimus, we found no additive effects of the drug combination. Short-term exposure of glucocorticoids could effectively reduce the proinflammatory response in human islets induced by the combination of tacrolimus and sirolimus.

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2016. 4196460
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Endocrinology and Diabetes
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URN: urn:nbn:se:uu:diva-294603DOI: 10.1155/2016/4196460ISI: 000372990500001OAI: oai:DiVA.org:uu-294603DiVA: diva2:931065
Available from: 2016-05-26 Created: 2016-05-25 Last updated: 2017-11-30Bibliographically approved

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