Complete suppression of skin allograft rejection in rats treated with continuous infusion of 2'deoxycoformycin

Congenital deficiency of the enzyme adenosine deaminase (ADA) results in severe combined immunodeficiency. 2'deoxycoformycin (2'dcf) is a tightly binding inhibitor of ADA, and the drug makes it possible to mimic a state of ADA deficiency. In this study we tested the immunosuppressive effect of 2'dcf in a rat skin transplantation model. Rats treated with continuous infusion of 2'dcf at doses of 0.3 mg/kg, 0.5 mg/kg and 0.7 mg/kg body wt/day showed significant prolongation of graft survival. 2'dcf given by bolus injections did not prolong graft survival. In rats treated with continuous infusion of 2'dcf at a dose of 0.7 mg/kg body wt/day mean graft survival time (MST) after withdrawal of treatment was equal to MST in untreated animals, suggesting that during 2'dcf treatment allograft rejection was completely suppressed. In vitro, lymphocytes isolated from animals treated with continuous infusion of 2'dcf showed marked suppression of mitogen response. The 2'dcf preferentially effects lymphocytes, but neutrophils seem resistant to the effect of the drug. The lymphocytotoxic effect of the drug is extreme; during therapy splenic weight decreased by almost 50% and the differential lymphocyte count in blood decreased from 85% to 17%. Immunofluorescence studies showed that, within the spleen, the amount of T cells and B cells decreased markedly. Both T cell subsets were affected--OX8+ cells (suppressor/cytotoxic T cells) and W3/25+ (helper T cells). However OX8+ cells were more resistant to the drug than W3/25+ cells. Skin-grafted rats treated with 2'dcf showed a strong decrease in the W3/25: OX8 ratio. In contrast, untreated rats showed a slight increase in the ratio after skin transplantation. It is concluded that 2'dcf is a strong immunosuppressive drug in rats if given by continuous infusion.