Immunosuppressive Effect of 2′-Deoxycoformycin (Pentostatin®) for Rat Islet Allotransplantation

Abstract

Adenosine deaminase (ADA) is an important enzyme for proper function of lymphocytes and congenital absence of ADA results in a form of severe combined immunodeficiency syndrome. 2′-Deoxycoformycin (Pentostatin®, DCF) irreversibly inhibits ADA and therefore has been suggested as an immunosuppressive drug. The present study evaluated the immunosuppressive effect of DCF for islet allotransplantation in rats. Isolated islets (1,500 islets) from Lewis rats were transplanted into the kidney subcapsular space of streptozotocin-induced diabetic Wistar-Furth rats. 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 continuous 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 infusion, resulted in a lymphopenia and a decrease in concanavalin A stimulation of splenic lymphocytes. However, DCF (in all doses) was not effective in preventing islet allograft rejection as evaluated by measuring 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 continuous infusion, respectively. This was not significantly different from control nontreated transplanted rats (8.5 ± 0.7 days). Increasing the dose of DCF to 1 mg/kg, administered by continuous infusion, resulted 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.