T-cell-mediated cytotoxicity against keratinocytes in sulfamethoxazol-induced skin reaction

Background The incidence of skin rashes or erythema multiforme to sulfameth oxazole in exposed patients is about 3%, Among patients with acquired immun odeficiency syndrome the risk is approximate to 10 times higher. The pathog enesis 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 sulf amethoxazole-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 Cr-51 cytotoxicity assay in the presence or absence of soluble sulfamethox azole. B lymphoblasts and keratinocytes with and without interferon gamma p retreatment were used as target cells. Selective blockers of FasL/Fas and p erforin-mediated killing and immunostaining for perforin were used to evalu ate 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 lymphobl asts in the presence of soluble sulfamethoxazole. Keratinocytes, if pretrea ted 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 bloc ked by concanamycin A which suggests a perforin-mediated killing. Conclusion Perforin-mediated killing of autologous keratinocytes in the pre sence of soluble sulfamethoxazole by drug-specific CD4(+) lymphocytes may b e a pathway for generalized drug-induced delayed skin reactions. The requir ement of interferon gamma pretreatment of keratinocytes for efficient speci fic killing might explain the increased frequency of drug allergies in gene ralized viral infections like HIV, when interferon gamma levels are elevate d.