PMID- 34175955
OWN - NLM
STAT- MEDLINE
DCOM- 20210929
LR  - 20220112
IS  - 1096-0929 (Electronic)
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 183
IP  - 1
DP  - 2021 Aug 30
TI  - Deciphering Adverse Drug Reactions: In Vitro Priming and Characterization of 
      Vancomycin-Specific T Cells From Healthy Donors Expressing HLA-A*32:01.
PG  - 139-153
LID - 10.1093/toxsci/kfab084 [doi]
AB  - Drug rash with eosinophilia with systemic symptoms (DRESS) is a serious adverse 
      event associated with use of the glycopeptide antibiotic vancomycin. 
      Vancomycin-induced drug rash with eosinophilia with systemic symptoms is 
      associated with the expression of human leukocyte antigen (HLA)-A*32:01, 
      suggesting that the drug interacts with this HLA to activate CD8+ T cells. The 
      purpose of this study was to utilize peripheral blood mononuclear cell from 
      healthy donors to: (1) investigate whether expression of HLA-A*32:01 is critical 
      for the priming naive of T cells with vancomycin and (2) generate T-cell clones 
      (TCC) to determine whether vancomycin exclusively activates CD8+ T cells and to 
      define cellular phenotype, pathways of drug presentation and cross-reactivity. 
      Dendritic cells were cultured with naive T cells and vancomycin for 2 weeks. On 
      day 14, cells were restimulated with vancomycin and T-cell proliferation was 
      assessed by [3H]-thymidine incorporation. Vancomycin-specific TCC were generated 
      by serial dilution and repetitive mitogen stimulation. Naive T cells from 
      HLA-A*02:01 positive and negative donors were activated with vancomycin; however 
      the strength of the induced response was significantly stronger in donors 
      expressing HLA-A*32:01. Vancomycin-responsive CD4+ and CD8+ TCC from HLA-A*32:01+ 
      donors expressed high levels of CXCR3 and CCR4, and secreted IFN-gamma, IL-13, and 
      cytolytic molecules. Activation of CD8+ TCC was HLA class I-restricted and 
      dependent on a direct vancomycin HLA binding interaction with no requirement for 
      processing. Several TCC displayed cross-reactivity with teicoplanin and 
      daptomycin. To conclude, this study provides evidence that vancomycin primes 
      naive T cells from healthy donors expressing HLA-A*32:01 through a direct 
      pharmacological binding interaction. Cross-reactivity of CD8+ TCC with 
      teicoplanin provides an explanation for the teicoplanin reactions observed in 
      vancomycin hypersensitive patients.
CI  - (c) The Author(s) 2021. Published by Oxford University Press on behalf of the 
      Society of Toxicology.
FAU - Ogese, Monday O
AU  - Ogese MO
AUID- ORCID: 0000-0002-1873-4032
AD  - Department of Molecular & Clinical Pharmacology, MRC Centre for Drug Safety 
      Science, University of Liverpool, Liverpool L69 3GE, UK.
FAU - Lister, Adam
AU  - Lister A
AD  - Department of Molecular & Clinical Pharmacology, MRC Centre for Drug Safety 
      Science, University of Liverpool, Liverpool L69 3GE, UK.
FAU - Gardner, Joshua
AU  - Gardner J
AD  - Department of Molecular & Clinical Pharmacology, MRC Centre for Drug Safety 
      Science, University of Liverpool, Liverpool L69 3GE, UK.
FAU - Meng, Xiaoli
AU  - Meng X
AD  - Department of Molecular & Clinical Pharmacology, MRC Centre for Drug Safety 
      Science, University of Liverpool, Liverpool L69 3GE, UK.
FAU - Alfirevic, Ana
AU  - Alfirevic A
AD  - Department of Molecular & Clinical Pharmacology, MRC Centre for Drug Safety 
      Science, University of Liverpool, Liverpool L69 3GE, UK.
FAU - Pirmohamed, Munir
AU  - Pirmohamed M
AD  - Department of Molecular & Clinical Pharmacology, MRC Centre for Drug Safety 
      Science, University of Liverpool, Liverpool L69 3GE, UK.
FAU - Park, B Kevin
AU  - Park BK
AD  - Department of Molecular & Clinical Pharmacology, MRC Centre for Drug Safety 
      Science, University of Liverpool, Liverpool L69 3GE, UK.
FAU - Naisbitt, Dean J
AU  - Naisbitt DJ
AUID- ORCID: 0000-0003-4107-7832
AD  - Department of Molecular & Clinical Pharmacology, MRC Centre for Drug Safety 
      Science, University of Liverpool, Liverpool L69 3GE, UK.
LA  - eng
GR  - MR/L006758/1/MRC_/Medical Research Council/United Kingdom
GR  - G0700654/MRC_/Medical Research Council/United Kingdom
GR  - BB/R008108/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (HLA-A Antigens)
RN  - 0 (Interleukin-13)
RN  - 0 (Pharmaceutical Preparations)
RN  - 6Q205EH1VU (Vancomycin)
SB  - IM
MH  - CD8-Positive T-Lymphocytes
MH  - HLA-A Antigens
MH  - Humans
MH  - Interleukin-13
MH  - Leukocytes, Mononuclear
MH  - *Pharmaceutical Preparations
MH  - *Vancomycin/toxicity
PMC - PMC8404995
OTO - NOTNLM
OT  - HLA
OT  - T cells
OT  - drug hypersensitivity
OT  - vancomycin
EDAT- 2021/06/28 06:00
MHDA- 2021/09/30 06:00
PMCR- 2021/06/27
CRDT- 2021/06/27 21:04
PHST- 2021/06/28 06:00 [pubmed]
PHST- 2021/09/30 06:00 [medline]
PHST- 2021/06/27 21:04 [entrez]
PHST- 2021/06/27 00:00 [pmc-release]
AID - 6310194 [pii]
AID - kfab084 [pii]
AID - 10.1093/toxsci/kfab084 [doi]
PST - ppublish
SO  - Toxicol Sci. 2021 Aug 30;183(1):139-153. doi: 10.1093/toxsci/kfab084.