title: Sulfamethoxazole and its metabolite nitroso sulfamethoxazole stimulate dendritic cell costimulatory signaling.
abstract: Different signals in addition to the antigenic signal are required to initiate an immunological reaction. In the context of sulfamethoxazole allergy, the Ag is thought to be derived from its toxic nitroso metabolite, but little is known about the costimulatory signals, including those associated with dendritic cell maturation. In this study, we demonstrate increased CD40 expression, but not CD80, CD83, or CD86, with dendritic cell surfaces exposed to sulfamethoxazole (250-500 microM) and the protein-reactive metabolite nitroso sulfamethoxazole (1-10 microM). Increased CD40 expression was not associated with apoptosis or necrosis, or glutathione depletion. Covalently modified intracellular proteins were detected when sulfamethoxazole was incubated with dendritic cells. Importantly, the enzyme inhibitor 1-aminobenzotriazole prevented the increase in CD40 expression with sulfamethoxazole, but not with nitroso sulfamethoxazole or LPS. The enzymes CYP2C9, CYP2C8, and myeloperoxidase catalyzed the conversion of sulfamethoxazole to sulfamethoxazole hydroxylamine. Myeloperoxidase was expressed at high levels in dendritic cells. Nitroso sulfamethoxazole immunogenicity was inhibited in mice with a blocking anti-CD40L Ab. In addition, when a primary nitroso sulfamethoxazole-specific T cell response using drug-naive human cells was generated, the magnitude of the response was enhanced when cultures were exposed to a stimulatory anti-CD40 Ab. Finally, increased CD40 expression was 5-fold higher on nitroso sulfamethoxazole-treated dendritic cells from an HIV-positive allergic patient compared with volunteers. These data provide evidence of a link between localized metabolism, dendritic cell activation, and drug immunogenicity.
authors: Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom.
authors: Joseph P
authors: JP
authors: Sanderson
authors: Dean J
authors: DJ
authors: Naisbitt
authors: John
authors: J
authors: Farrell
authors: Charlotte A
authors: CA
authors: Ashby
authors: M Jane
authors: MJ
authors: Tucker
authors: Michael J
authors: MJ
authors: Rieder
authors: Munir
authors: M
authors: Pirmohamed
authors: Stephen E
authors: SE
authors: Clarke
authors: B Kevin
authors: BK
authors: Park
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D019013:CD40 Antigens / Q000032:analysis / Q000378:metabolism; D023201:CD40 Ligand / Q000037:antagonists & inhibitors; D065633:Cytochrome P-450 CYP1B1; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D004342:Drug Hypersensitivity / Q000276:immunology*; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins; D013420:Sulfamethoxazole / Q000031:analogs & derivatives* / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D000890:Anti-Infective Agents; D019013:CD40 Antigens; D007377:Interleukin-3; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C404145:myelopoietin; C072956:4-nitrososulfamethoxazole; D016179:Granulocyte Colony-Stimulating Factor; D023201:CD40 Ligand; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C450259:CYP2C8 protein, human; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1; D065727:Cytochrome P-450 CYP2C8; D013420:Sulfamethoxazole