Dapsone and Nitroso Dapsone Activation of Naı̈ve T-Cells from Healthy Donors
| Autor: | James L. Maggs, Arun Tailor, Catherine J. Betts, Abdulaziz Alzahrani, John Farrell, J. C. Waddington, Xioali Meng, B. Kevin Park, Dean J. Naisbitt, Monday O. Ogese |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
T-Lymphocytes Metabolite Priming (immunology) Pharmacology Dapsone Lymphocyte Activation Toxicology medicine.disease_cause Cross-reactivity Peripheral blood mononuclear cell Mass Spectrometry Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Animals Humans Cells Cultured Chromatography High Pressure Liquid Serum Albumin Cell Proliferation MHC class II Molecular Structure biology Immunogenicity General Medicine Healthy Volunteers Hypersensitivity reaction 030104 developmental biology chemistry Immunology biology.protein Spleen Nitroso Compounds 030215 immunology medicine.drug |
| Zdroj: | Chemical Research in Toxicology. 30:2174-2186 |
| ISSN: | 1520-5010 0893-228X |
| DOI: | 10.1021/acs.chemrestox.7b00263 |
| Popis: | Dapsone (DDS) causes hypersensitivity reactions in 0.5-3.6% of patients. Although clinical diagnosis is indicative of a hypersensitivity reaction, studies have not been performed to define whether dapsone or a metabolite activates specific T-cells. Thus, the aims of this study were to explore the immunogenicity DDS and nitroso DDS (DDS-NO) using peripheral blood mononuclear cells from healthy donors and splenocytes from mice and generate human T-cell clones to characterize mechanisms of T-cell activation. DDS-NO was synthesized from DDS-hydroxylamine and shown to bind to the thiol group of glutathione and human and mouse albumin through sulfonamide and N-hydroxyl sulphonamide adducts. Naïve T-cell priming to DDS and DDS-NO was successful in three human donors. DDS-specific CD4+ T-cell clones were stimulated to proliferate in response to drug via a MHC class II restricted direct binding interaction. Cross reactivity with DDS-NO, DDS-analogues, and sulfonamides was not observed. DDS-NO clones were CD4+ and CD8+, MHC class II and I restricted, respectively, and activated via a pathway dependent on covalent binding and antigen processing. DDS and DDS-NO-specific clones secreted a mixture of Th1 and Th2 cytokines, but not granzyme-B. Splenocytes from mice immunized with DDS-NO were stimulated to proliferate in vitro with the nitroso metabolite, but not DDS. In contrast, immunization with DDS did not activate T-cells. These data show that DDS- and DDS-NO-specific T-cell responses are readily detectable. |
| Databáze: | OpenAIRE |
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