PMID- 34606953
OWN - NLM
STAT- MEDLINE
DCOM- 20211228
LR  - 20211228
IS  - 1879-3185 (Electronic)
IS  - 0300-483X (Linking)
VI  - 463
DP  - 2021 Nov
TI  - The PD1 inhibitory pathway and mature dendritic cells contribute to abacavir 
      hypersensitivity in human leukocyte antigen transgenic PD1 knockout mice.
PG  - 152971
LID - S0300-483X(21)00293-6 [pii]
LID - 10.1016/j.tox.2021.152971 [doi]
AB  - Based on recent genome-wide association studies, abacavir-induced 
      hypersensitivity is highly associated with human leukocyte antigen (HLA)-B*57:01 
      allele. However, the underlying mechanism of this occurrence is unclear. To 
      investigate the underlying mechanism, we developed HLA-B*57:01 transgenic mice 
      and found that application of abacavir could cause CD8 T cell activation with 
      elevation in PD1 expression; however, severe skin hypersensitivity was not 
      observed. To eliminate the immunosuppressive effect of PD1, HLA-B*57:01 
      transgenic/PD1 knockout (01Tg/PD1) mice were generated by mating HLA-B*57:01 
      transgenic mice and PD1 knockout mice. Thereafter, 01Tg/PD1 mice were treated 
      with abacavir. Similar to the above results, severe skin hypersensitivity was not 
      observed. Therefore, we treated 01Tg/PD1 mice with an anti-CD4 antibody to 
      deplete CD4 T cells, followed by abacavir topically and orally. Severe 
      abacavir-induced skin hypersensitivity was observed in 01Tg/PD1 mice after 
      depletion of CD4 T cells, in addition to significant CD8 T cell activation and 
      dendritic cell maturation. Taken together, we succeeded in reproducing severe 
      skin hypersensitivity in a mouse model. And we found that through the combined 
      depletion of PD1 and CD4 T cells, CD8 T cells could be activated and could 
      proceed to clonal proliferation, which is promoted by mature dendritic cells, 
      thereby eventually inducing severe skin hypersensitivity.
CI  - Copyright (c) 2021 Elsevier B.V. All rights reserved.
FAU - Song, Binbin
AU  - Song B
AD  - Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba 
      University, Chiba, Japan; Key Laboratory of Ethnomedicine (Minzu University of 
      China), Ministry of Education, School of Pharmacy, Minzu University of China, 
      Beijing, China.
FAU - Aoki, Shigeki
AU  - Aoki S
AD  - Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba 
      University, Chiba, Japan.
FAU - Liu, Cong
AU  - Liu C
AD  - Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba 
      University, Chiba, Japan.
FAU - Susukida, Takeshi
AU  - Susukida T
AD  - Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba 
      University, Chiba, Japan; Laboratory of Cancer Biology and Immunology, Section of 
      Host Defences, Institute of Natural Medicine, University of Toyama, Toyama, 
      Japan.
FAU - Kuwahara, Saki
AU  - Kuwahara S
AD  - Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba 
      University, Chiba, Japan.
FAU - Ito, Kousei
AU  - Ito K
AD  - Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba 
      University, Chiba, Japan. Electronic address: itokousei@chiba-u.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211001
PL  - Ireland
TA  - Toxicology
JT  - Toxicology
JID - 0361055
RN  - 0 (Anti-HIV Agents)
RN  - 0 (Dideoxynucleosides)
RN  - 0 (HLA-B Antigens)
RN  - 0 (Pdcd1 protein, mouse)
RN  - 0 (Programmed Cell Death 1 Receptor)
RN  - WR2TIP26VS (abacavir)
SB  - IM
MH  - Animals
MH  - Anti-HIV Agents/administration & dosage/immunology/toxicity
MH  - CD8-Positive T-Lymphocytes/immunology
MH  - Dendritic Cells/immunology
MH  - Dideoxynucleosides/administration & dosage/immunology/*toxicity
MH  - Disease Models, Animal
MH  - Drug Eruptions/*immunology
MH  - Drug Hypersensitivity/*immunology
MH  - HLA-B Antigens/immunology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Programmed Cell Death 1 Receptor/*genetics
OTO - NOTNLM
OT  - CD4 T cell depletion
OT  - Humanized mice
OT  - Idiosyncratic adverse drug reactions
OT  - Immune suppression
OT  - Skin damage
OT  - T cell reactivity
EDAT- 2021/10/05 06:00
MHDA- 2021/12/29 06:00
CRDT- 2021/10/04 20:15
PHST- 2021/09/03 00:00 [received]
PHST- 2021/09/24 00:00 [revised]
PHST- 2021/09/29 00:00 [accepted]
PHST- 2021/10/05 06:00 [pubmed]
PHST- 2021/12/29 06:00 [medline]
PHST- 2021/10/04 20:15 [entrez]
AID - S0300-483X(21)00293-6 [pii]
AID - 10.1016/j.tox.2021.152971 [doi]
PST - ppublish
SO  - Toxicology. 2021 Nov;463:152971. doi: 10.1016/j.tox.2021.152971. Epub 2021 Oct 1.