IMMUNOSUPPRESSIVE EFFECT OF 2'-DEOXYCOFORMYCIN (PENTOSTATIN(R)) FOR RAT ISLET ALLOTRANSPLANTATION

Adenosine deaminase (ADA) is an important enzyme for proper function o f lymphocytes and congenital absence of ADA results in a form of sever e combined immunodeficiency syndrome. 2'-Deoxycoformycin (Pentostatin( R), DCF) irreversibly inhibits ADA and therefore has been suggested as an immunosuppressive drug. The present study evaluated the immunosupp ressive effect of DCF for islet allotransplantation in rats, Isolated islets (1,500 islets) from Lewis rats were transplanted into the kidne y subcapsular space of streptozotocin-induced diabetic Wistar-Furth ra ts. DCF was administered IP either as a single injection at 1 mg/kg/wk , 1 mg/kg twice weekly, 5 mg/kg/twice weekly or 1 mg/kg/day, or as a c ontinuous infusion at 0.8 or 1 mg/kg/day. Daily administration of DCF at 0.8 mg/kg in both methods, single daily injection or continuous inf usion, resulted in a lymphopenia and a decrease in concanavalin A stim ulation of splenic lymphocytes. However, DCF (in all doses) was not ef fective in preventing islet allograft rejection as evaluated by measur ing the duration of normoglycemia following islet transplantation and by microscopic examination of the islet grafts. In fact, the duration of normoglycemia following islet transplantation was 7.5 +/- 0.9 and 9 .0 +/- 1.0 days in rats receiving DCF in single daily injection or con tinuous infusion, respectively. This was not significantly different f rom control nontreated transplanted rats (8.5 +/- 0.7 days). Increasin g the dose of DCF to 1 mg/kg, administered by continuous infusion, res ulted in 100% mortality. For comparison, cyclosporine A (20 mg/kg, IP daily injection for 14 days) prolonged islet allograft survival to 27. 3 +/- 1.5 days (p < 0.001). It is concluded that inhibition of ADA by DCF, despite its marked lymphotoxic effect, does not prevent rejection of islet allograft.