554 EVIDENCE FOR THE ROLE OF RIBONUCLEOTIDE REDUCTASE INHIBITION IN ADENOSINE DEAMINASE DEFICIENCY

Abstract

Adenosine deaminase (ADA) deficiency is associated with a form of severe combined immunodeficiency disease (SCID). Enzyme replacement therapy has restored immunologic competence in some ADA-SCID patients (Polmar et al. N Engl J Med 295:1337, 1976). Their lymphocytes, however, remain ADA deficient. Enzyme therapy also reduces the high levels of deoxyATP (dATP) present in these patients prior to therapy. The effects of adenosine and deoxyadenosine upon proliferation of ADA deficient lymphocytes were studied using ³H-leucine incorporation as a measure of cell proliferation. Studies were carried out upon lymphocytes from one ADA-SCID patient and three normal individuals whose lymphocytes were made ADA deficient with the ADA inhibitor EHNA.

ADA deficient lymphocytes were 100-1000 times more sensitive to inhibition by deoxyadenosine than by adenosine. Inhibition could be partially reversed (up to 78%) by low concentrations (1-10 uM) of deoxycytidine and to a lesser extent by thymidine, but not by other ribo- or deoxyribonucleosides. Addition of both deoxycytidine and thymidine completely reversed inhibition.

Deoxyadenosine's inhibitory effects appear to be mediated through dATP, a potent inhibitor of ribonucleotide reductase. Deoxycytidine and thymidine can bypass this block and supply these cells with deoxypyrimidine nucleosides for DNA synthesis. These data suggest that deoxycytidine and thymidine supplementation may be clinically useful in the therapy of ADA-SCID patients.

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