title: T-cell-mediated cytotoxicity against keratinocytes in sulfamethoxazol-induced skin reaction.
abstract: BACKGROUND
  The incidence of skin rashes or erythema multiforme to sulfamethoxazole in exposed patients is about 3%. Among patients with acquired immunodeficiency syndrome the risk is approximately 10 times higher. The pathogenesis of these reactions and the reason for the increased frequency in HIV infections are not understood.
  
  
  OBJECTIVE
  To investigate drug specific T-cell-mediated cytotoxicity in sulfamethoxazole- induced skin reactions.
  
  
  METHODS
  Specific T-cell lines and T-cell clones generated from a donor who developed a skin rash to sulfamethoxazole were assessed with a standard 4 h 51Cr cytotoxicity assay in the presence or absence of soluble sulfamethoxazole. B lymphoblasts and keratinocytes with and without interferon gamma pretreatment were used as target cells. Selective blockers of FasL/Fas and perforin-mediated killing and immunostaining for perforin were used to evaluate the involvement of the different cytolytic pathways.
  
  
  RESULTS
  CD4+ and CD8+ sulfamethoxazole specific T-cell clones showed a drug-specific and MHC-restricted cytotoxicity against autologous B lymphoblasts in the presence of soluble sulfamethoxazole. Keratinocytes, if pretreated with interferon gamma, were specifically killed predominantly by CD4+ T-cell clones. Specific T-cell clones of both CD4+ and CD8+ phenotype showed a strong immunoreactivity for perforin and the cytotoxicity was blocked by concanamycin A which suggests a perforin-mediated killing.
  
  
  CONCLUSIONS
  Perforin-mediated killing of autologous keratinocytes in the presence of soluble sulfamethoxazole by drug-specific CD4+ lymphocytes may be a pathway for generalized drug-induced delayed skin reactions. The requirement of interferon gamma pretreatment of keratinocytes for efficient specific killing might explain the increased frequency of drug allergies in generalized viral infections like HIV, when interferon gamma levels are elevated.
authors.affiliation: Institute of Immunology and Allergology, Inselspital, Bern, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Schnyder
authors.forename: K
authors.initials: K
authors.lastname: Frutig
authors.forename: D
authors.initials: D
authors.lastname: Mauri-Hellweg
authors.forename: A
authors.initials: A
authors.lastname: Limat
authors.forename: N
authors.initials: N
authors.lastname: Yawalkar
authors.forename: W J
authors.initials: WJ
authors.lastname: Pichler
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic; D015235:HLA-B Antigens / Q000276:immunology; D059948:HLA-B44 Antigen; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000502:physiology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012882:Skin Tests; D013420:Sulfamethoxazole / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology
chemical_list: D015235:HLA-B Antigens; D059948:HLA-B44 Antigen; D006684:HLA-DR Antigens; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D007371:Interferon-gamma; D013420:Sulfamethoxazole