THE INHIBITORY EFFECT OF DEOXYADENOSINE AND DEOXY GUANOSINE ON IN VITRO LYMPHOCYTE FUNCTION ARE EXPRESSED AT DIFFERENT STAGES OF LYMPHOCYTE ACTIVATION: 182

In earlier studies we showed that deoxyguanosine(dGuo) which confers immunodeficiency in purine nucleoside phosphorylase (PNP) deficient patients, inhibits the in vitro proliferation of normal human T and B lymphocytes. Deoxyadenosine (dAdo) being the toxic metabolite in adenosine deaminase (ADA) deficiency, also inhibits the in vitro proliferation of normal human T lymphocytes under conditions where ADA activity is inhibited. We analyzed the kinetics of the inhibition of T cell proliferation by dAdo and dGuo respectively and found significant differences. Whereas dAdo has to be present from the initiation of the culture onwards, dGuo can be added as late as 48 hrs. after the initiation of the culture to exert its toxic effect. This finding points towards an interference of dAdo with early lymphocyte activation events which preceed the onset of DNA synthesis. Subsequently, the effect of dAdo and dGuo on a number of events associated with lymphocyte activation was investigated like e.g. on mitogen-induced Ca-influx, on Ca-ionofoor-mediated expression of the receptor for Interleukin 2 (IL-2) and on the IL-2 dependent proliferation of receptor carrying T lymphocytes. The results provide evidence for different mechanisms underlying the toxic effects of dAdo and dGuo for lymphocytes.