TY - JOUR
T1 - Immunosuppressive effect of 2′-deoxycoformycin (pentostatin®) for rat islet allotransplantation
AU - Ar'Rajab, Aamer
AU - Harris, Richard B.
AU - Khair-El-Din, Tarik A.
AU - Sentementes, James T.
AU - Lu, Christopher
AU - Dawidson, Ingemar J A
PY - 1995
Y1 - 1995
N2 - 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.
AB - 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.
KW - 2′-Deoxycoformycin (Pentostaün®)
KW - Diabetes
KW - Islet
KW - Kidney subcapsule
KW - Streptozotocin
KW - Transplantation
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U2 - 10.1016/0963-6897(95)00002-F
DO - 10.1016/0963-6897(95)00002-F
M3 - Article
C2 - 7640871
AN - SCOPUS:0029003417
SN - 0963-6897
VL - 4
SP - 315
EP - 321
JO - Cell Transplantation
JF - Cell Transplantation
IS - 3
ER -