Exposure of mice to the nitroso metabolite of sulfamethoxazole stimulates interleukin 5 production by CD4+ T-cells.
Sulfamethoxazole hypersensitivity may be caused by production of the protein-reactive metabolite nitroso sulfamethoxazole (SMX-NO) and interaction of SMX-NO with T-cells. We have characterised the nature of the immune response induced by administration of sulfamethoxazole, sulfamethoxazole metabolites and nitrosobenzene to BALB/c mice. Drugs were administered over a 13-day period to induce polarised cytokine secretion profiles. Proliferation was measured by [(3)H] thymidine incorporation. Cytokine secretion was monitored by ELISA. Results were compared with those provoked by exposure to type 1 and type 2 chemical allergens, 2,4-dinitrochlorobenzene (DNCB) and trimellitic anhydride (TMA). CD4(+) or CD8(+) T-cells were depleted ex vivo to identify the primary source of cytokines. Lymph node activation was observed following treatment with DNCB, TMA, nitrosobenzene and SMX-NO, but not with sulfamethoxazole or sulfamethoxazole hydroxylamine (SMX-NHOH). DNCB and TMA induced type 1 and type 2 cytokine profiles, respectively. SMX-NO treatment stimulated the production of high levels of IL-5, variable amounts of IFN-gamma, and relatively low levels of IL-10 and IL-4. Nitrosobenzene-activated lymph node cells secreted only low levels of IFN-gamma and IL-5. Depletion of CD4(+) or CD8(+) T-cells from SMX-NO stimulated lymph node cells revealed that CD4(+) T-cells were the major source of IL-5. In conclusion, the data presented indicates that subcutaneous administration to mice of SMX-NO, but not the parent drug, stimulated the secretion of high levels of IL-5 from activated CD4(+) T-cells, which is consistent with the clinical profile of the drug.
Hopkins
Josephine E
JE
Department of Pharmacology and Therapeutics, The University of Liverpool, Sherrington Building, Ashton Street, P.O. Box 147, Liverpool L69 3BX, UK.
Naisbitt
Dean J
DJ
Humphreys
Neil
N
Dearman
Rebecca J
RJ
Kimber
Ian
I
Park
B Kevin
BK
D000818:Animals; D000890:Anti-Infective Agents / Q000276:immunology* / Q000493:pharmacokinetics; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004137:Dinitrochlorobenzene / Q000276:immunology; D004342:Drug Hypersensitivity / Q000209:etiology* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015848:Interleukin-5 / Q000096:biosynthesis* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009603:Nitroso Compounds / Q000276:immunology / Q000493:pharmacokinetics / Q000633:toxicity*; D010796:Phthalic Anhydrides / Q000276:immunology; D013420:Sulfamethoxazole / Q000031:analogs & derivatives* / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D000890:Anti-Infective Agents; D016207:Cytokines; D004137:Dinitrochlorobenzene; D015848:Interleukin-5; D009603:Nitroso Compounds; D010796:Phthalic Anhydrides; C059873:sulfamethoxazole hydroxylamine; C015559:trimellitic anhydride; D013420:Sulfamethoxazole