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. 2004 Nov;114(5):1209-15.
doi: 10.1016/j.jaci.2004.07.047.

Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells

Amal Nassif  1 , Armand Bensussan, Laurence Boumsell, Aurelien Deniaud, Homayoun Moslehi, Pierre Wolkenstein, Martine Bagot, Jean-Claude Roujeau
Affiliations

Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells

Amal Nassif et al. J Allergy Clin Immunol. 2004 Nov.

Abstract

Background: Toxic epidermal necrolysis (TEN) is a very rare but extremely severe drug reaction characterized by widespread apoptosis of epidermis with extensive blisters. We previously found drug-specific cytotoxic CD8 T lymphocytes in the blisters of a single patient.

Objective: To confirm the role of drug specific cytotoxic lymphocytes in a larger series, to test the cytotoxicity on keratinocytes, and to look for cross-reactivity between chemically related drugs.

Methods: The phenotype of lymphocytes present in the blister fluids of 6 patients with TEN was analyzed by flow cytometry. Cytotoxic functions were tested by chromium release assay on a variety of target cells (autologous or MHC class I-matched EBV-transformed lymphocytes, autologous keratinocytes) after nonspecific (CD3 monoclonal antibody) or specific (suspected and potentially cross-reactive drugs) activation.

Results: Blister lymphocytes were CD8 + HLA-DR + CLA + CD56 + . In all 6 cases, they were cytotoxic after nonspecific activation. A drug-specific cytotoxicity was observed in 4 cases (3 related to cotrimoxazole and 1 to carbamazepine) toward lymphocytes. Blister cells also killed IFN-gamma-activated autologous keratinocytes in the presence of drug in the 2 patients tested. Blister cells showed a strong immunoreactivity for granzyme B, and cytotoxicity was abolished by EGTA, but not by anti-Fas/CD95, suggesting perforin/granzyme-mediated killing. By using several sulfonamides for testing the specificity of the drug T-cell receptor interaction, we observed cross-reactivity only between 4 structurally closely related medications.

Conclusion: These results strongly suggest that drug-specific, MHC class I-restricted, perforin/granzyme-mediated cytotoxicity probably has a primary role in TEN.

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Comment in

  • Drug presentation to T cells.
    Naisbitt DJ, Pirmohamed M, Park BK. Naisbitt DJ, et al. J Allergy Clin Immunol. 2005 Apr;115(4):876-7; author reply 877-8. doi: 10.1016/j.jaci.2005.01.011. J Allergy Clin Immunol. 2005. PMID: 15806015 No abstract available.
  • Drug-induced epidermal necrolysis: Important new piece to end the puzzle.
    Roujeau JC, Bricard G, Nicolas JF. Roujeau JC, et al. J Allergy Clin Immunol. 2011 Dec;128(6):1277-8. doi: 10.1016/j.jaci.2011.10.015. J Allergy Clin Immunol. 2011. PMID: 22133320 No abstract available.

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