PMID- 37284777
OWN - NLM
STAT- MEDLINE
DCOM- 20230712
LR  - 20230826
IS  - 1473-6322 (Electronic)
IS  - 1528-4050 (Print)
IS  - 1473-6322 (Linking)
VI  - 23
IP  - 4
DP  - 2023 Aug 1
TI  - Transgenic murine models for the study of drug hypersensitivity reactions linked 
      to HLA-I molecules.
PG  - 279-286
LID - 10.1097/ACI.0000000000000913 [doi]
AB  - PURPOSE OF REVIEW: Immune-mediated drug hypersensitivity reactions (DHRs) can be 
      life-threatening and an impediment to drug development. Mechanism of disease 
      studies are difficult to perform in humans. Here we review human leukocyte 
      antigens class I (HLA-I) transgenic murine models and highlight how these systems 
      have helped to elucidate drug-specific and host immune factors that initiate, 
      propagate and control severe drug toxicities to skin and liver. RECENT FINDINGS: 
      HLA transgenic mice have been developed and used to study immune-mediated drug 
      reactions in vitro and in vivo . CD8+ T cells from HLA-B *57:01-expressing mice 
      respond strongly to abacavir (ABC) in vitro but have self-limited responses to 
      drug exposure in vivo . Immune tolerance can be overcome by depleting regulatory 
      T cells (Treg) allowing antigen-presenting dendritic cells to express CD80/86 
      costimulatory molecules and signal through CD28 on the CD8+ T cell. Depletion of 
      Treg also removes competition for interleukin 2 (IL-2) to allow T cell expansion 
      and differentiation. Fine tuning of responses depends on inhibitory checkpoint 
      molecules such as PD-1. Improved mouse models express only HLA in the absence of 
      PD-1. These models show enhanced liver injury to flucloxacillin (FLX) which 
      depends on drug priming, CD4+ T cell depletion, and lack of PD-1 expression. 
      Drug-specific HLA-restricted cytotoxic CD8+ T cells can infiltrate the liver but 
      are suppressed by Kupffer and liver sinusoidal endothelial cells. SUMMARY: HLA-I 
      transgenic mouse models are now available to study ABC, FLX and 
      carbamazepine-induced adverse reactions. In vivo studies range from 
      characterizing drug-antigen presentation, T cell activation, immune-regulatory 
      molecules and cell-cell interaction pathways that are specifically involved in 
      causing or controlling unwanted DHRs.
FAU - Puig, Montserrat
AU  - Puig M
AD  - Laboratory of Immunology, Office of Biotechnology Products, Center for Drug 
      Evaluation and Research, Food and Drug Administration. Silver Spring, Maryland 
      20993, USA.
FAU - Norcross, Michael A
AU  - Norcross MA
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20230605
PL  - United States
TA  - Curr Opin Allergy Clin Immunol
JT  - Current opinion in allergy and clinical immunology
JID - 100936359
RN  - 0 (Programmed Cell Death 1 Receptor)
SB  - IM
MH  - Mice
MH  - Humans
MH  - Animals
MH  - Disease Models, Animal
MH  - Programmed Cell Death 1 Receptor
MH  - Endothelial Cells
MH  - *Drug Hypersensitivity/genetics
MH  - Mice, Transgenic
MH  - CD8-Positive T-Lymphocytes
MH  - *Drug-Related Side Effects and Adverse Reactions
PMC - PMC10317295
COIS- There are no conflicts of interest.
EDAT- 2023/06/07 13:10
MHDA- 2023/07/12 06:42
PMCR- 2023/07/03
CRDT- 2023/06/07 10:12
PHST- 2023/07/12 06:42 [medline]
PHST- 2023/06/07 13:10 [pubmed]
PHST- 2023/06/07 10:12 [entrez]
PHST- 2023/07/03 00:00 [pmc-release]
AID - 00130832-202308000-00004 [pii]
AID - ACI230411 [pii]
AID - 10.1097/ACI.0000000000000913 [doi]
PST - ppublish
SO  - Curr Opin Allergy Clin Immunol. 2023 Aug 1;23(4):279-286. doi: 
      10.1097/ACI.0000000000000913. Epub 2023 Jun 5.