Cyclosporine and Islet Mass—Implications for Islet Transplantation

Cyclosporine (CsA) is an inhibitor of ornithine decarboxylase (ODC), a key enzymatic step in cell proliferation. The purpose of this study was to determine the effect of CsA on islet cell mass. Partial obstruction (PDO) of the hamster pancreas is an established model of islet cell differentiation and proliferation in which regeneration is mediated by the induction of trophic activity (TA) that can be extracted from the pancreas. In Part 1 of these studies, hamsters were randomized to (i) Control ( n = 5); (ii) PDO alone ( n = 5); (iii) PDO + CsA (20 mg/kg ip daily) ( n = 5); (iv) CsA alone ( n = 5). On Day 21, 1 hr prior to sacrifice, animals received tritiated thymidine, 2 μCi/g body wt ip. Pancreata were excised for analysis of islet cell mass (No. islets/mm 2) by morphometry and of cell proliferation (islet cell labeling index) by autoradiography. In Part 2 of these studies, hamsters were randomized to receive CsA ( n = 34), as in Part 1, or saline ( n = 30). After 7 days, animals received 1 ml of TA ip and were sacrificed after 0, 6, 8, and 10 hr. The pancreata were excised and determinations made of organ weight, DNA content, and ODC bioactivity (pmole/CO 2/hr/mg DNA). Data (mean ± SEM) were analyzed by ANOVA. In Part 1, the number of islets/mm 2 in the PDO group was increased two-fold compared to control animals, those receiving CsA, and those undergoing PDO with CsA (2.4 ± 0.1 vs 1.1 ± 0.0, 1.4 ± 0.2, 1.2 ± 0.1, P < 0.01). An increase of similar magnitude was also noted in the islet cell labeling index (0.50 ± 0.06 vs 0.22 ± 0.07, 0.17 ± 0.05, 0.24 ± 0.01, P < 0.01). In Part 2 of the study, TA induced a significant eightfold increase in ODC bioactivity which was completely abrogated by prior treatment with CsA. We conclude that, in this model, CsA blocks islet cell proliferation and differentiation by inhibition of TA-stimulated ODC activity. If ongoing islet cell proliferation is necessary for maintenance of islet allograft survival, then the use of CsA in islet transplantation may need to be reassessed.