Protein Kinase C Inhibitor, AEB-071, Acts Complementarily With Cyclosporine to Prevent Islet Rejection in Rats

Abstract

AEB-071 (AEB) is a specific inhibitor of protein kinase C, which prevents T-lymphocyte activation. The present study investigated the effect of AEB on rat islet allotransplantation alone or in combination with CTLA4-Ig, mycophenolate mofetil, or cyclosporine A (CsA). A rodent allogeneic islet transplant model (Lewis to Wistar Furth) was used to investigate the efficacy of AEB as an immunosuppressive agent. Furthermore, the Lewis rat was used to screen for any AEB associated toxicities on glucose homeostasis in vivo. AEB alone (30 mg/kg per os [p.o.] two times per day [bid]) delayed rejection to a median survival time of 22 days (vs. 7 days in control vehicle-treated animals, P<0.05). When combined with CsA (5 mg/kg p.o. bid), AEB prolonged survival from 12 (CsA alone) to over 100 days in 80% of animals (P<0.05). No delay in allograft rejection (above that resulting from AEB alone) was observed when AEB was combined with a sub-therapeutic dose of CTLA4-Ig or mycophenolate mofetil, nor low dose of CsA. The frequency of allospecific interferon-gamma-secreting splenocytes, assessed ex vivo by enzyme-linked immunosorbent spot (ELISPOT) assay, was lower in AEB-treated recipients compared with controls (P<0.05). AEB treatment did not alter the intraperitoneal glucose tolerance, the glucose-dependent insulin release, or the insulin content of the native pancreas. These data suggest that AEB is an appropriate immunosuppressive agent for islet transplantation, as it can prolong islet graft survival alone or in combination with CsA, without toxicity on glucose metabolism.