Locus of selective depression of human natural killer cells by azathioprine

Azathioprine (Aza) was shown to reduce the FcR population and, even more markedly, natural killer (NK) and antibody-dependent cellular cytotoxicity (ADCC)-defined killer (K) cell activities. Patients with multiple sclerosis received Aza, Aza plus prednisone (pred) or methylprednisone (Mpred), or pred alone, or were not treated. A profound deficiency in NK and K activity measured by 51Cr release was produced in patients treated with Aza alone or Aza plus corticosteroid (ster). In contrast to the decrease in FcR + cells, T cells were not reduced by Aza. Pred alone had no effect. Monocyte removal did not correct the Aza-induced impairment, indicating that NK deficiency reflects a property of nonphagocytic and, presumably, lymphocytic cells. Single-cell NK assays showed a decrease in target-binding cells as well as a reduction in target-killing lymphocytes. Furthermore, exposure of lymphocytes from Aza-treated multiple sclerosis subjects to in vitro interferon did not result in the normal augmentation of NK activity. Thus, the loss of NK activity with Aza treatment is attributable to reductions of active NK cells and interferon-activatable pre-NK cells. A primary target cell for Aza at clinically used dosages is postulated to be a precursor of pre-NK cells.