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Human leukocyte antigen and idiosyncratic adverse drug reactions.

Authors
  • Usui, Toru1
  • Naisbitt, Dean J2
  • 1 Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan. , (Japan)
  • 2 MRC Centre for Drug Safety Science, Department of Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool L69 3GE, England, UK. Electronic address: [email protected]
Type
Published Article
Journal
Drug metabolism and pharmacokinetics
Publication Date
Feb 01, 2017
Volume
32
Issue
1
Pages
21–30
Identifiers
DOI: 10.1016/j.dmpk.2016.11.003
PMID: 28017537
Source
Medline
Keywords
License
Unknown

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.

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