Activated Protein C Preserves Functional Islet Mass After Intraportal Transplantation

Abstract

Clinical studies indicate that significant loss of functional islet mass occurs in the peritransplant period. Islets are injured as a result of detrimental effects of brain death, pancreas preservation, islet isolation, hypoxia, hyperglycemia, and immune-mediated events. In addition, recent studies demonstrated that islets are injured as a result of their exposure to blood and of activation of intrahepatic endothelial and Kupffer cells, resulting in inflammation and thrombosis. Activated protein C (APC) is an anticoagulant enzyme that also exerts anti-inflammatory and antiapoptotic activities by acting directly on cells. Here, we report that exogenous administration of recombinant murine APC (mAPC) significantly reduced loss of functional islet mass after intraportal transplantation in diabetic mice. Animals given mAPC exhibited better glucose control, higher glucose disposal rates, and higher arginine-stimulated acute insulin release. These effects were associated with reduced plasma proinsulin, intrahepatic fibrin deposition, and islet apoptosis early after the transplant. In vitro and in vivo data demonstrated that mAPC treatment was associated with a significant reduction of proinflammatory cytokine release after exposure of hepatic endothelial cells to islets. mAPC treatment also prevented endothelial cell activation and dysfunction elicited by intrahepatic embolization of isolated islets inherent to pancreatic islet transplantation (PIT). This study demonstrates multiple remarkable beneficial effects of mAPC for PIT and suggests that APC therapy may enhance the therapeutic efficacy of PIT in diabetic patients.

Bilirubin protects grafts against nonspecific inflammation-induced injury in syngeneic intraportal islet transplantation

“…Therefore, inhibiting the nonspecific inflammatory response may protect transplanted islets and increase the success rate of IPIT. There have been several approaches already to improve the survival of transplanted islets by inhibiting the ensuing nonspecific inflammation (Arita et al, 1998;Ozmen et al, 2002;Tran et al, 2002;Moberg et al, 2003;Contreras et al, 2004;Goto et al, 2004;Yang et al, 2005;Jung et al, 2009).…”

Anti-Inflammatory Actions of the Anticoagulant, Activated Protein C

“…APC treatment is also associated with a significant reduction of proinflammatory cytokine release and prevents endothelial cell activation and dysfunction. This study suggests that APC therapy will improve the take-rate of the transplanted islet cells and thus decrease the number of the cells required for human pancreatic islet transplantation (Contreras, 2004). Interestingly, plasma levels of protein C/APC are reduced in humans with T1D (Gruden, 1997;Vukovich & Schernthaner, 1986).…”

“…Exogenous administration of APC significantly reduces loss of functional islet mass after intraportal transplantation in diabetic mice (Contreras, 2004). Animals given APC exhibit better glucose control, higher glucose disposal rates and higher arginine-stimulated acute insulin release (Contreras, 2004). These effects are associated with a reduction in plasma proinsulin, intrahepatic fibrin deposition, and islet apoptosis early after the transplant.…”

“…APC's strong anti-inflammatory and antiapoptotic properties appear to be beneficial in preventing destruction of islet cells. Exogenous administration of APC significantly reduces loss of functional islet mass after intraportal transplantation in diabetic mice (Contreras, 2004). Animals given APC exhibit better glucose control, higher glucose disposal rates and higher arginine-stimulated acute insulin release (Contreras, 2004).…”

Withaferin A inhibits pro-inflammatory cytokine-induced damage to islets in culture and following transplantation

“…The blood-mediated nonspecific immune response is characterised by coagulation, complement activation, platelet aggregation and cytokine release [2]. Cytokines such as TNF-α, IFN-γ and IL-1β have important pro-inflammatory and proapoptotic roles in type 1 diabetes and islet transplantation [3][4][5]. Although immunosuppressants are administered after transplantation of islets, effective control of cytokinemediated damage to islets is still not achieved.…”