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AEB071 (sotrastaurin) does not exhibit toxic effects on human islets in vitro, nor after transplantation into immunodeficient mice

Merani, Shaheed
McCall, Michael
Pawlick, Rena L
Edgar, Ryan L
Davis, Joy
Emamaullee, Juliet A
Kin, Tatsuya
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Published in Islets. 2011, vol. 3, no. 6, p. 338-43
Abstract AEB071 (AEB, sotrastaurin), a specific inhibitor of protein kinase C, reduces T-lymphocyte activation and cytokine release. AEB delays islet allograft rejection in rats and prevents rejection when combined with cyclosporine. Since many immunosuppressive agents have toxic effects on the function of transplanted islets, we investigated whether this was also the case with AEB. Human islets were transplanted into Rag-knockout mice randomly assigned to vehicle control, AEB or sirolimus treatment groups. Non-fasting blood glucose levels, body weight and glucose tolerance was measured in recipients. In a separate experiment, human islets were cultured in the presence of AEB and assayed for glucose dependent insulin secretion and level of β-cell apoptosis. Eighty-six percent of the AEB-treated recipients achieved normoglycemia following transplant (compared with none in sirolimus-treated group, p < 0.05). AEB-treated recipients exhibited similar glucose homeostasis as vehicle-treated controls, which was better than in sirolimus-treated recipients. Human islets cultured with AEB showed similar rates of β-cell apoptosis (p = 0.98 by one-way ANOVA) and glucose stimulated insulin secretion (p = 0.15) as those cultured with vehicle. These results suggest that AEB is not associated with toxic effects on islet engraftment or function. AEB appears to be an appropriate immunosuppressive candidate for clinical trials in islet transplantation.
Keywords AnimalsApoptosis/drug effectsBlood Glucose/metabolismBody Weight/drug effectsFemaleGlucose Tolerance TestHumansImmunohistochemistryIn Situ Nick-End LabelingInsulin/secretionIslets of Langerhans/drug effectsIslets of Langerhans Transplantation/methodsKaplan-Meier EstimateMiceMice, Inbred C57BLMice, KnockoutProtein Kinase Inhibitors/pharmacology/toxicityPyrroles/pharmacology/toxicityQuinazolines/pharmacology/toxicityRandom Allocation
PMID: 21934354
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Research group Transplantation et hépatologie (905)
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MERANI, Shaheed et al. AEB071 (sotrastaurin) does not exhibit toxic effects on human islets in vitro, nor after transplantation into immunodeficient mice. In: Islets, 2011 , vol. 3, n° 6, p. 338-43. doi: 10.4161/isl.3.6.17766 https://archive-ouverte.unige.ch/unige:25032

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Deposited on : 2013-01-07

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