The involvement of specific t cells in the pathogenesis of metamizole‐induced agranulocytosis

Background Non-chemotherapy related, drug-induced agranulocytosis is a rare idiosyncratic reaction, which may be fatal. Along with betalactames, the analgesic metamizole is reported to occasionally cause agranulocytosis. The disease results in a severe reduction of granulocytes rendering affected patients susceptible to bacterial and fungal infections. The pathogenesis of drug-induced agranulocytosis is complex as non-immune (mainly toxic) and immune mechanisms might be involved. Aim The identification and characterization of metamizolespecific T cells in patients with drug-induced agranulocytosis by generating metamizole-specific T cell lines. Methods PBMCs from metamizole-allergic and metamizole-tolerant subjects were induced with 100ug/ml metamizole. Cultures were supplemented with IL-2 and were restimulated every 14 days. Drug-specific cell activation was determined by flow cytometry after a 6h restimulation phase. Results After two restimulation rounds, metamizole-specific T cells were identified in a metamizole-allergic and in a metamizole-tolerant individual. In both cases, CD8+ T cells but no CD4+ cells reacted to the drug. Reactive cells secreted IFN and upregulated CD107a upon drug exposure. Interestingly, T cells were activated exclusively by metamizole in solution. Autologous antigen presenting cells incubated overnight in 100ug/ml metamizole prior to restimulation failed to activate CD8+ T cells. Furthermore, metamizole-specific T cells from both donors, allergic and tolerant, were self-reactive, i.e. reacted to the drug even in the absence of antigen presenting cells. Conclusion