title: Multiple drug hypersensitivity: normal Treg cell function but enhanced in vivo activation of drug-specific T cells.
abstract: BACKGROUND
  Up to 10% of patients with severe immune-mediated drug hypersensitivity reactions have tendencies to develop multiple drug hypersensitivities (MDH). The reason why certain individuals develop MDH and the underlying pathomechanism are unclear. We investigated different T cell subpopulations in MDH patients and compared them with patients allergic to a single drug and with healthy controls (HC).
  
  
  METHODS
  We analyzed the in vitro reactivity of peripheral blood mononuclear cells from MDH patients (n=7), patients with hypersensitivity to a single drug (monoallergic, n=6), and healthy controls (HD) (n=6) to various drugs (mainly antibiotics and antiepileptics). By depleting and selectively re-adding CD4(+)  CD25(bright) T cells (T regulatory cells, Treg), their effect on drug-specific T cell reactivity was analyzed. The phenotype of reacting T cells was determined ex vivo by staining for markers of activation (CD38) and cell exhaustion (PD-1).
  
  
  RESULTS
  No functional deficiency of Treg cells was observed in all drug-allergic patients. Drug-reactive T cells from MDH patients were found in the CD4(+) CD25(dim) T cell fraction and showed enhanced CD38 and PD-1 expression, while those from monoallergic patients reside in the resting CD4(+)  CD25(neg) T cell fraction.
  
  
  CONCLUSIONS
  In patients with MDH, the drug-reactive T cells are contained in an in vivo pre-activated T cell fraction. Therefore, they may show a lower threshold for activation by drugs. The reason for this in vivo T cell pre-activation needs further investigations.
authors.affiliation: Adverse Drug Reactions-Analysis and Consulting (ADR-AC) GmbH, Bern, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Daubner
authors.forename: M
authors.initials: M
authors.lastname: Groux-Keller
authors.forename: O V
authors.initials: OV
authors.lastname: Hausmann
authors.forename: T
authors.initials: T
authors.lastname: Kawabata
authors.forename: D J
authors.initials: DJ
authors.lastname: Naisbitt
authors.forename: B K
authors.initials: BK
authors.lastname: Park
authors.forename: T
authors.initials: T
authors.lastname: Wendland
authors.forename: M
authors.initials: M
authors.lastname: Lerch
authors.forename: W J
authors.initials: WJ
authors.lastname: Pichler
mesh_terms: D002469:Cell Separation; D002478:Cells, Cultured; D004342:Drug Hypersensitivity / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D018189:Immunomagnetic Separation; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*