HLA-DQ allele-restricted activation of nitroso sulfamethoxazole-specific CD4-positive T lymphocytes from patients with cystic fibrosis

Clin Exp Allergy. 2015 Aug;45(8):1305-16. doi: 10.1111/cea.12546.

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.

Conclusion and clinical relevance: 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.

Keywords: HLA-DQ; T-cells; drug hypersensitivity; sulfamethoxazole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / pathology
  • Cell Proliferation / drug effects*
  • Cell Proliferation / genetics
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / immunology*
  • Cystic Fibrosis / pathology
  • Drug Hypersensitivity / genetics
  • Drug Hypersensitivity / immunology*
  • Drug Hypersensitivity / pathology
  • Female
  • HLA-DQ beta-Chains / genetics
  • HLA-DQ beta-Chains / immunology*
  • Humans
  • Lymphocyte Activation / drug effects*
  • Lymphocyte Activation / genetics
  • Male
  • Sulfamethoxazole / adverse effects
  • Sulfamethoxazole / analogs & derivatives*
  • Sulfamethoxazole / pharmacology

Substances

  • HLA-DQ beta-Chains
  • HLA-DQB1 antigen
  • 4-nitrososulfamethoxazole
  • Sulfamethoxazole