Selective toxicity of purine deoxynucleosides for human lymphocyte growth and function

Abstract

A role for the enzymes adenosine deaminase [ADA] (adenosine aminohydrolase, EC 3.5.4.4) and purine-nucleoside phosphorylase (purine-nucleoside:orthophosphate ribosyltransferase, EC 2.4.2.1) in the functional maturation of lymphoid cells was revealed by the association of inherited deficiencies of these enzymes and profound immune deficiency. The selective toxicity for lymphocytes may be mediated by the accumulation of toxic deoxynucleoside metabolites, likely through the action of specific kinases enriched in lymphoid cells. To study possible mechanisms whereby lymphocyte function may be impaired in these disorders, the effect of nucleosides and their deoxy analogs on T [thymus-derived] and B [bone marrow-derived] lymphocyte growth and function was studied. In the presence of deoxyguanosine, there was marked inhibition of T lymphoblast growth, phytohemagglutinin-induced cell proliferation and T suppressor cell activity. T helper cell activity and the differentiation of B cells to an antibody-secreting stage were unaffected. Deoxyadenosine was much less inhibitory, but in the presence of an inhibitor of ADA, its effects on lymphocyte growth and function were markedly potentiated. The addition of deoxycytidine prevented deoxyadenosine toxicity in all assays, whereas it only interfered with deoxyguanosine effects on T lymphoblast growth. These studies provide some initial understanding for the selective loss of specific lymphocyte functions in individuals with inborn errors of purine metabolism.