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  • Open Access

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

  • Jacqueline Adam1,
  • Antonia Bünter2,
  • Werner J Pichler1 and
  • Thomas Wendland3
Clinical and Translational Allergy20144(Suppl 3):P107

https://doi.org/10.1186/2045-7022-4-S3-P107

Published: 18 July 2014

Keywords

Antigen Present CellHypersensitivity ReactionDrug ExposureAgranulocytosisAbacavir

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 metamizole-specific 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

The observed CD8+ T cell reactivity which was exclusively restricted to metamizole in solution supports a T cell activation according to the p-i concept (pharmacological interactions with immune receptors). Other hypersensitivity reactions underlying this concept revealed the crucial role of particular HLA class I molecules (e.g. HLA-B*57:01 in abacavir hypersensitivity). We therefore plan to type the study participants for their HLA class I expression in order to identify HLA molecules potentially involved in metamizole-induced agranulocytosis. This screening process will be supported by in silico modeling of metamizole binding to a panel of common HLA class I molecules. Furthermore, we plan to characterize metamizole-specific T cells in regards to their cytotoxic potential, i.e their expression of Granzyme B, Granulysin, perforin and FasL upon drug exposure.

Authors’ Affiliations

(1)
Clinic for Rheumatology and clin. Immunology/Allergology, University Hospital of Bern, Switzerland
(2)
Adverse Drug Reactions – Analysis and Consulting GmbH, ADR-AC GmbH, Switzerland
(3)
Clinic for internal medicine, University Hospital of Bern, Switzerland

Copyright

© Adam et al; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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