title: HLA haplotype determines hapten or p-i T cell reactivity to flucloxacillin.
abstract: Drug-induced liver injury (DILI) is a main cause of drug withdrawal. A particularly interesting example is flucloxacillin (FLUX)-DILI, which is associated with the HLA-B*57:01 allele. At present, the mechanism of FLUX-DILI is not understood, but the HLA association suggests a role for activated T cells in the pathomechanism of liver damage. To understand the interaction among FLUX, HLA molecules, and T cells, we generated FLUX-reacting T cells from FLUX-naive HLA-B*57:01(+) and HLA-B*57:01(-) healthy donors and investigated the mechanism of T cell stimulation. We found that FLUX stimulates CD8(+) T cells in two distinct manners. On one hand, FLUX was stably presented on various HLA molecules, resistant to extensive washing and dependent on proteasomal processing, suggesting a hapten mechanism. On the other hand, in HLA-B*57:01(+) individuals, we observed a pharmacological interaction with immune receptors (p-i)-based T cell reactivity. FLUX was presented in a labile manner that was further characterized by independence of proteasomal processing and immediate T cell clone activation upon stimulation with FLUX in solution. This p-i-based T cell stimulation was restricted to the HLA-B*57:01 allele. We conclude that the presence of HLA-B*57:01 drives CD8(+) T cell responses to the penicillin-derivative FLUX toward nonhapten mechanism.
authors.affiliation: Clinic for Rheumatology and Clinical Immunology/Allergology, University Hospital of Bern, 3010 Bern, Switzerland.
authors.forename: Natascha
authors.initials: N
authors.lastname: Wuillemin
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Adam
authors.forename: Stefano
authors.initials: S
authors.lastname: Fontana
authors.forename: Stephan
authors.initials: S
authors.lastname: Krähenbühl
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Pichler
authors.forename: Daniel
authors.initials: D
authors.lastname: Yerly
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D005436:Floxacillin / Q000494:pharmacology*; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology*; D006239:Haplotypes; D006241:Haptens; D006801:Humans; D008099:Liver / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology
chemical_list: D015235:HLA-B Antigens; C484830:HLA-B*57:01 antigen; D006241:Haptens; D005436:Floxacillin