title: Human leukocyte antigen and idiosyncratic adverse drug reactions.
abstract: A clinical association between a specific human leukocyte antigen (HLA) allele and idiosyncratic adverse drug reactions (IADRs) is a strong indication that IADRs are mediated by the adaptive immune system. For example, it is well-established that HLA-B*15:02 and HLA-B*57:01 are associated with carbamazepine-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and abacavir-induced hypersensitivity/flucloxacillin-induced liver injury, respectively. Drug-specific T-cells whose response is restricted by specific HLA risk alleles have been detected from IADR patients, also suggesting an adaptive immune pathogenesis. T-cells from carbamazepine SJS/TEN patients are activated by direct pharmacological interaction between carbamazepine and HLA-B*15:02 expressed on antigen presenting cells (APCs). Abacavir-specific, HLA-B*57:01-restricted T-cells are activated by APCs presenting peptides which are only displayed by the HLA molecule when abacavir is bound during peptide loading. Finally, HLA-B*57:01-restricted activation of T-cells from patients with flucloxacillin-induced liver injury is dependent on processing of drug protein adducts. Based on these observations, it is now possible to utilize blood from healthy drug-naïve volunteers to study the priming of naïve T-cells to drugs. Future development of these methodologies may lead to the development of assays that predict intrinsic immunogenicity of drugs and chemicals at the preclinical stage of drug development.
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Usui
authors.affiliation: MRC Centre for Drug Safety Science, Department of Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool L69 3GE, England, UK. Electronic address: dnes@liverpool.ac.uk.
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Naisbitt
mesh_terms: D000483:Alleles; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics / Q000276:immunology*; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D004364:Pharmaceutical Preparations
chemical_list: D006680:HLA Antigens; D004364:Pharmaceutical Preparations
keywords: Altered peptide repertory concept; Drug-induced liver injury; Hapten concept; Hepersensitivity; Human leukocyte antigen; Reactive metabolites; Severe cutaneous adverse reactions; p-i concept