CYCLOSPORINE-A BLOCKADE OF THE INDUCTION OF ORNITHINE DECARBOXYLASE ACTIVITY AS A CAUSE OF FAILURE OF ISLET-CELL PROLIFERATION AND DIFFERENTIATION

Maintenance of islet cell mass may be one factor that contributes to l ong-term islet allograft viability. It is important, therefore, to det ermine whether transplant-related events, such as immunosuppression, i nterfere with the regenerative capacity of the hormone-producing cellu lar elements of the islet. To investigate this possibility, we utilize d a well-characterized model of islet cell growth in which partial obs truction of the hamster pancreatic duct leads to the induction of duct epithelial cell proliferation in association with endocrine cell diff erentiation and new islet formation. These changes appear to be mediat ed by a specific trophic activity (TA) that can be extracted from the pancreas following obstruction. Since the trophic effects of many grow th factors are mediated through the polyamine pathway, we postulated t hat the trophic effect of TA is associated with the induction of ornit hine decarboxylase (ODC) activity, the rate-limiting step in polyamine biosynthesis. The effect of TA on pancreatic ODC activity was studied atone, and after pretreatment with cyclosporine A (CsA), an immunosup pressive agent that is known to inhibit ODC activity. Eight h followin g the administration of TA, pancreatic ODC activity increased approxim ately 6-fold. Pretreatment with CsA for 7 d at a daily dose of 20 mg/k g prevented the induction of pancreatic ODC activity. We conclude that , in this model, CsA can block islet cell proliferation, and that this may be mediated by inhibition of TA-stimulated ODC activity.