Inhibition of K and NK lymphocyte cytotoxicity by an inhibitor of adenosine deaminase and deoxyadenosine.

A deficiency of adenosine deaminase is associated with severe combined immunodeficiency disease. Intracellular accumulation of deoxyadenosine triphosphate (dATP) or S-adenosylhomocysteine has been proposed to result in impairment of immune effector cells. Pharmacologic inhibitors of the enzyme are under investigation for utility as cancer chemotherapeutic and immunosuppressive agents. Although lymphocyte proliferation requires functional adenosine deaminase, little attention has been given to the importance of this enzyme in nonproliferative cell function. We investigated the effect of inhibition of this enzyme by 2'deoxycoformycin (dCF) on human lymphocyte antibody-dependent cytotoxicity (ADCC) and nonantibody-dependent cytotoxicity (non-ADCC). Human lymphocytes were incubated in vitro for 72 hr under the following conditions in complete RPMI and 10% fetal calf serum: a) medium alone; b) supplemented with dCF 10–6 M; c) supplemented with 2'deoxyadenosine (dAdo), 10–6 M; and d) supplemented with both dCF and dAdo. After incubation, the lymphocytes were thoroughly washed and were resuspended in fresh medium before use in the cytotoxicity assays. Lymphocytes exposed to the combination of dCF and dAdo had marked impairment (50%) in both ADCC and non-ADCC (p < 0.01). These functional impairments in both K and NK cell activity did not represent diminished cell viability or decreased frequency of binding of the lymphocytes to the target cells. Substantive changes in the intracellular nucleotide pools were not observed. These data suggest an immunosuppressive effect may be achievable in vivo with low doses of dCF that do not cause massive alteration of the intracellular nucleotide pools.