Macrophage overgrowth affects neighboring nonovergrown encapsulated islets

Encapsulation significantly prolongs islet graft survival in the absence of immunosuppression. However, encapsulated islet graft survival is limited to periods of several months. Part of the encapsulated islet graft is affected by a nonprogressive pericapsular overgrowth. To investigate whether macrophages on overgrown capsules affect neighboring nonovergrown encapsulated islets, encapsulated islets were studied during coculture. Encapsulated islet function, islet vitality, and islet cell replication were assessed, as well as the mRNA expression of Bcl-2, Bax, inducible nitric oxide synthase, and monocyte chemoattractant protein-1 in encapsulated islets after 48 h of culture together with microcapsules with macrophage overgrowth. Overgrown capsules were retrieved from the rat peritoneum, three weeks after implantation of an encapsulated islet graft. Coculture was associated with inhibition of the stimulated insulin secretion, with decreased cell replication, and with increased cell necrosis, but not with apoptosis of encapsulated islet cells. mRNA expression levels in encapsulated islets after coculture were not different from controls, except for a decrease in Bax mRNA. We found a high level of nitrite, as an indicator of nitric oxide production, but not an increase in inducible nitric oxide synthase mRNA in islets. This, in combination with the absence of increase in monocyte chemoattractant protein-1 mRNA and the lack of apoptosis, indicates that neither interleukin-1beta nor tumor necrosis factor-alpha was responsible for the deleterious effects of coculture on encapsulated islets. Nonovergrown encapsulated islets are affected by the overgrowth on encapsulated islets in their close proximity. This overgrowth contains macrophages that produce nitric oxide which, rather than cytokines, may be held responsible for the deleterious effect on the neighboring encapsulated islets.