The inhibition of polymorphonuclear leukocyte cytotoxicity by dapsone. A possible mechanism in the treatment of dermatitis herpetiformis.
The effect of the sulfone compound 4,4'-diaminodiphenyl sulfone (dapsone) on normal human polymorphonuclear leukocytes (PMNL) has been investigated in vitro. The drug has a dramatically beneficial effect in dermatitis herpetiformis in which the PMNL and immune complexes has been stressed to be of importance for the development of the skin lesions. Pruritus disappears and the inflammatory eruptions clear within a few days of starting therapy. The effect of dapsone has been evaluated on the different stages of phagocytosis. Using dapsone concentrations (1-30 mug/ml) comparable with those found after therapeutic doses, we have found that the drug interferes primarily with the myeloperoxidase (MPO)-H(2)O(2)-halide-mediated cytotoxic system in the PMNL. No effect was observed on random locomotion, chemotaxis, phagocytic ingestion, oxidative metabolism, or the release of lysosomal enzymes. Kinetic studies in a cell-free system with purified MPO revealed a competitive type of inhibition using varying concentrations of NaI. Furthermore, the inhibition resulted in reduced candidicidal activity during phagocytosis of Candida albicans, and reduced cytotoxicity to adjacent mammalian cells measured as the (51)Cr release from virus-induced lymphoma cells. Because the MPO-H(2)O(2)-halide system not only fulfills the antimicrobial activity but is suggested to be a modulator of the inflammatory reaction as well, the action of dapsone in dermatitis herpetiformis may in part be explained by its effect on this system.
D000293:Adolescent; D000328:Adult; D001770:Blood Bactericidal Activity / Q000187:drug effects; D002176:Candida albicans; D002465:Cell Movement / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D003622:Dapsone / Q000494:pharmacology*; D003874:Dermatitis Herpetiformis / Q000188:drug therapy*; D006801:Humans; D006861:Hydrogen Peroxide / Q000097:blood; D066298:In Vitro Techniques; D007454:Iodides / Q000097:blood; D008247:Lysosomes / Q000201:enzymology; D009504:Neutrophils / Q000276:immunology* / Q000502:physiology; D009195:Peroxidase / Q000097:blood; D010587:Phagocytosis / Q000187:drug effects; D013481:Superoxides / Q000097:blood
D007454:Iodides; D013481:Superoxides; D003622:Dapsone; D006861:Hydrogen Peroxide; D009195:Peroxidase