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Sulfamethoxazole and Its Metabolite Nitroso Sulfamethoxazole Stimulate Dendritic Cell Costimulatory Signaling¹

Joseph P. Sanderson^*, Dean J. Naisbitt^*, John Farrell^*, Charlotte A. Ashby, M. Jane Tucker, Michael J. Rieder, Munir Pirmohamed^*, Stephen E. Clarke and B. Kevin Park^2,*

^* Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom; GlaxoSmithKline, Drug Metabolism and Pharmacokinetics, Ware, Hertfordshire, United Kingdom; and Department of Medicine, University of Western Ontario, London, Ontario, Canada

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 µM) and the protein-reactive metabolite nitroso sulfamethoxazole (1–10 µM). 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ J.P.S. is a Ph.D. student funded by GlaxoSmithKline Pharmaceuticals.

² Address correspondence and reprint requests to Prof. B. Kevin Park, Department of Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, L69 3GE, U.K. E-mail address: bkpark{at}liverpool.ac.uk

³ Abbreviations used in this paper: SMX, sulfamethoxazole; SMX-NHOH, sulfamethoxazole hydroxylamine; SMX-NO, nitroso sulfamethoxazole; MPO, myeloperoxidase; ABT, 1-aminobenzotriazole; rh, recombinant human; GSH, reduced glutathione; SI, stimulation index; COX-2, cyclooxygenase-2.

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