DRUG-INDUCED AGRANULOCYTOSIS - INVITRO EVIDENCE FOR IMMUNE SUPPRESSION OF GRANULOPOIESIS AND A CROSS-REACTING LYMPHOCYTE ANTIBODY

Abstract

Two patients with agranulocytosis associated with diphenylhydantoin (DPH) therapy and clinical data suggesting suppression of granulopoiesis were investigated using in vitro culture techniques for committed granulocyte/macrophage precursors. Addition of DPH to cultures containing the patients'' sera resulted in significant suppression of colony growth. Extensive studies on the acute serum from 1 patient revealed the drug-dependent inhibitory activity to be nondialyzable, resistant to chloroform extraction, heat stable, active in the presence of heat-inactivated fetal bovine serum, active against autologous as well as allogeneic cells and absent from convalescent sera. Drug-dependent bone marrow colony-suppressing activity was removed by absorption on an antiimmunoglobulin[anti-Ig]-Sepharose column but not by IgG-Sepharose. The serum showed non-drug dependent suppression of O2 consumption by normal polymorphonuclear leukocytes [PMN] engaged in phagocytosis and also showed evidence of ability to opsonize these cells. When the serum was incubated with mitogen-stimulated lymphocytes, suppression of 3H-thymidine uptake by autologous but not allogeneic cells was noted. Similarly, the serum suppressed short-term 3H-thymidine uptake by autologous but not allogeneic bone marrow. Absorption of the patients'' sera with allogeneic PMN, autologous PMN or autologous lymphocytes removed the drug-dependent inhibitory activity, but absorption with allogeneic lymphocytes did not. These data are most consistent with the presence of a noncomplement dependent antibody capable of suppressing granulopoiesis, mediating peripheral destruction of PMN, and cross-reacting with a lymphocyte antigen of limited population distribution.