title: HLA-DQ allele-restricted activation of nitroso sulfamethoxazole-specific CD4-positive T lymphocytes from patients with cystic fibrosis.
abstract: BACKGROUND
  For certain HLA allele-associated drug hypersensitivity reactions, the parent drug has been shown to associate directly with the risk allele. In other forms of hypersensitivity, HLA risk alleles have not been identified and T cells are activated in an allele unrestricted manner. Chemically reactive drug metabolites bind to multiple proteins; thus, it is assumed that the derived peptide antigens interact with a number of HLA molecules to activate T cells; however, HLA restriction of the drug metabolite-specific T-cell response has not been studied.
  
  
  OBJECTIVE
  To utilize T cells from sulfamethoxazole (SMX) hypersensitive patients with cystic fibrosis to examine the HLA molecules that interact with nitroso SMX (SMX-NO)-derived antigens.
  
  
  METHODS
  T-cell clones were generated from 4 hypersensitive patients. Drug-specific proliferative responses and cytokine secretion were measured. Anti-human class I and class II antibodies were used to analyse HLA restriction. Antigen-presenting cells expressing different HLA molecules were used to determine the alleles involved in the presentation of SMX-NO-derived antigens to T cells.
  
  
  RESULTS
  A total of 976 clones were tested for SMX-NO reactivity. Thirty-nine CD4+ clones were activated with SMX-NO and found to proliferate and secrete cytokines. The SMX-NO-specific response was blocked with an antibody against HLA-DQ. SMX-NO-specific responses were detected with antigen-presenting cells expressing HLA-DQB1*05:01 (patient 1) and HLA-DQB1*02:01 (patient 2), but not other HLA-DQB1 alleles.
  
  
  CONCLUSIONS
  HLA-DQ plays an important role in the activation of SMX-NO-specific CD4+ T cells. Detection of HLA-DQ allele-restricted responses suggests that T cells are activated by a limited repertoire of SMX-NO-modified peptides.
authors: Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.
authors: M O
authors: MO
authors: Ogese
authors: Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.
authors: K
authors: K
authors: Saide
authors: Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.
authors: L
authors: L
authors: Faulkner
authors: Regional Adult Cystic Fibrosis Unit, St James's Hospital, Leeds, UK.
authors: P
authors: P
authors: Whitaker
authors: Regional Adult Cystic Fibrosis Unit, St James's Hospital, Leeds, UK.
authors: D
authors: D
authors: Peckham
authors: Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.
authors: A
authors: A
authors: Alfirevic
authors: La Jolla Institute for Allergy and Immunology, La Jolla, San Diego, CA, USA.
authors: D M
authors: DM
authors: Baker
authors: La Jolla Institute for Allergy and Immunology, La Jolla, San Diego, CA, USA.
authors: A
authors: A
authors: Sette
authors: Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.
authors: M
authors: M
authors: Pirmohamed
authors: Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.
authors: B K
authors: BK
authors: Park
authors: Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.
authors: D J
authors: DJ
authors: Naisbitt
mesh_terms: D000483:Alleles; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D003550:Cystic Fibrosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004342:Drug Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D059866:HLA-DQ beta-Chains / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000235:genetics; D008297:Male; D013420:Sulfamethoxazole / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; C072956:4-nitrososulfamethoxazole; D013420:Sulfamethoxazole
keywords: HLA-DQ; T-cells; drug hypersensitivity; sulfamethoxazole