title: Drug specific cytotoxic T-cells in the skin lesions of a patient with toxic epidermal necrolysis.
abstract: Toxic epidermal necrolysis is an extremely severe drug reaction, manifesting itself by widespread apoptosis of keratinocytes, generally considered to result from Fas/CD95-FasLigand interaction, but of unknown primary mechanism. We looked at the role of cells present in the skin blisters as probable effectors of this immune reaction. In a patient suffering from cotrimoxazole-induced toxic epidermal necrolysis, blister fluid cells were phenotyped by FACS and tested without prior restimulation for cytotoxicity on autologous and allogeneic cells in the presence of the drug. Blister fluid lymphocytes were predominantly CD8+, DR+, CLA+, CD56+ T lymphocytes, perforin positive and expressing preferentially two Vbeta chains of the T cell receptor repertoire. These lymphocytes were cytotoxic only in the presence of the drug towards autologous EBV transformed lymphocytes and towards allogeneic cells sharing HLA-Cw4. Cytotoxicity occurred in the presence of either cotrimoxazole, sulfamethoxazole, or the nitroso metabolite of sulfamethoxazole, but not with the hydroxylamine metabolite of sulfamethoxazole. The lysis was blocked by an anti-MHC class I monoclonal antibody. It was abolished by EGTA and CMA, but neither by anti-fas, brefeldin A, nor by anti-TRAIL receptor monoclonal antibodies, strongly suggesting perforin/granzyme-mediated cytotoxicity, without implication of Fas or TRAIL at this stage. This is direct evidence that T lymphocytes present within the lesions of toxic epidermal necrolysis may exhibit, without any re-stimulation, a drug-specific cytotoxicity against autologous cells. Harboring the markers of classical CTL and MHC class I restriction these lymphocytes reacted against the parent drug and one of its reactive metabolites. These results challenge several current concepts and could support new therapeutic approaches.
authors.affiliation: INSERM U 448 Department of Dermatology, Hôpital H Mondor, Université Paris XII, Créteil, France.
authors.forename: Amal
authors.initials: A
authors.lastname: Nassif
authors.forename: Armand
authors.initials: A
authors.lastname: Bensussan
authors.forename: Guillaume
authors.initials: G
authors.lastname: Dorothée
authors.forename: Fathia
authors.initials: F
authors.lastname: Mami-Chouaib
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bachot
authors.forename: Martine
authors.initials: M
authors.lastname: Bagot
authors.forename: Laurence
authors.initials: L
authors.lastname: Boumsell
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Roujeau
mesh_terms: D000890:Anti-Infective Agents / Q000009:adverse effects; D001768:Blister / Q000276:immunology / Q000473:pathology; D016827:CD8 Antigens / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D013262:Stevens-Johnson Syndrome / Q000276:immunology* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000009:adverse effects
chemical_list: D000890:Anti-Infective Agents; D016827:CD8 Antigens; D015395:Histocompatibility Antigens Class I; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015662:Trimethoprim, Sulfamethoxazole Drug Combination