Inhibition of Immune Responses by Glutamine Antagonism: Effect of Azotomycin on Lymphocyte Blastogenesis

The effects of the glutamine antagonist azotomycin on the immune response in vitro was studied by measuring the effect of the drug on the blastogenic responses of human lymphocytes to mitogens. Doses of 1.0 μg/ml or greater completely inhibited responses to phytohemagglutinin, streptolysin 0, and allogenic leukocytes. Both thymidine-³ H incorporation and morphological manifestations of blastogenesis were inhibited. Inhibition could be achieved without cytotoxicity, as demonstrated by stable viable cell counts and restoration of responses by washing the drug from the cultures. Specificity of action was proved by complete reversal of inhibition by L-glutamine. Addition of a wide range of L-asparaginase doses markedly increased the inhibition produced by azotomycin. Certain dosage combinations were synergistic. This study suggests that, depending upon pharmacological factors, azotomycin, either alone or in combination with L-asparaginase, may produce potent immunosuppression in vivo.