title: 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.
abstract: 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 μg/L), sirolimus (30 μg/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 μg/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.
authors.affiliation: Department of Transplant Medicine, Oslo University Hospital, P.O. Box 4950, 0424 Oslo, Norway; Institute for Surgical Research, Oslo University Hospital, P.O. Box 4950, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, P.O. Box 1171, Blindern, 0318 Oslo, Norway.
authors.forename: Kristine
authors.initials: K
authors.lastname: Kloster-Jensen
authors.affiliation: Department of Transplant Medicine, Oslo University Hospital, P.O. Box 4950, 0424 Oslo, Norway; Institute for Surgical Research, Oslo University Hospital, P.O. Box 4950, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, P.O. Box 1171, Blindern, 0318 Oslo, Norway.
authors.forename: Afaf
authors.initials: A
authors.lastname: Sahraoui
authors.affiliation: Department of Pharmacology, Oslo University Hospital, P.O. Box 4950, 0424 Oslo, Norway.
authors.forename: Nils Tore
authors.initials: NT
authors.lastname: Vethe
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Box 815, 75108 Uppsala, Sweden; Department of Clinical Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University Hospital, 75185 Uppsala, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Korsgren
authors.affiliation: Department of Pharmacology, Oslo University Hospital, P.O. Box 4950, 0424 Oslo, Norway; School of Pharmacy, University of Oslo, P.O. Box 1171, Blindern, 0318 Oslo, Norway.
authors.forename: Stein
authors.initials: S
authors.lastname: Bergan
authors.affiliation: Department of Transplant Medicine, Oslo University Hospital, P.O. Box 4950, 0424 Oslo, Norway; Institute for Surgical Research, Oslo University Hospital, P.O. Box 4950, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, P.O. Box 1171, Blindern, 0318 Oslo, Norway.
authors.forename: Aksel
authors.initials: A
authors.lastname: Foss
authors.affiliation: Department of Transplant Medicine, Oslo University Hospital, P.O. Box 4950, 0424 Oslo, Norway; Institute for Surgical Research, Oslo University Hospital, P.O. Box 4950, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, P.O. Box 1171, Blindern, 0318 Oslo, Norway.
authors.forename: Hanne
authors.initials: H
authors.lastname: Scholz
mesh_terms: D000328:Adult; D017209:Apoptosis; D015992:Body Mass Index; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage*; D005947:Glucose / Q000737:chemistry; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007249:Inflammation; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects*; D016381:Islets of Langerhans Transplantation; D008297:Male; D008775:Methylprednisolone / Q000737:chemistry; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage* / Q000009:adverse effects*; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects*
chemical_list: D016207:Cytokines; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D007328:Insulin; D012333:RNA, Messenger; D005947:Glucose; D020123:Sirolimus; D016559:Tacrolimus; D008775:Methylprednisolone