PMID- 35963284
OWN - NLM
STAT- MEDLINE
DCOM- 20220928
LR  - 20221031
IS  - 1879-0542 (Electronic)
IS  - 0165-2478 (Linking)
VI  - 249
DP  - 2022 Sep
TI  - Conjugation of human serum albumin and flucloxacillin provokes specific immune 
      response in HLA-B*57:01 transgenic mice.
PG  - 5-11
LID - S0165-2478(22)00113-4 [pii]
LID - 10.1016/j.imlet.2022.08.002 [doi]
AB  - Flucloxacillin (FLX) induces adverse liver reactions, which has been reported to 
      be related to human leukocyte antigen (HLA)-B*57:01. In a previous study, 
      abacavir-induced hypersensitivity was induced in HLA-B*57:01-transgenic mice 
      (B*57:01-Tg), originally constructed by our group (Susukida et al., 2021). In 
      this study, B*57:01-Tg mice were used to reproduce FLX-induced liver injury. 
      However, treatment of B*57:01-Tg mice with FLX alone did not increase serum ALT 
      levels. Immune-deficient B*57:01-Tg/PD-1(-/-)mice were produced by mating 
      B*57:01-Tg with PD-1(-/-) mice. The immune response of B*57:01-Tg/PD-1(-/-) mice 
      was further modulated by co-administration of CpG-oligodeoxynucleotides and 
      anti-CD4 mAb. Nevertheless, immune regulation in B*57:01-Tg mice did not 
      contribute to the onset of FLX-induced liver injury or immune activation. 
      Moreover, we generated an FLX-human serum albumin (HSA) conjugate and showed that 
      FLX covalently bound to HSA in a time-dependent manner. The FLX-HSA conjugate was 
      administered to the B*57:01-Tg mice. The immune response was investigated using 
      flow cytometry, revealing the phenotype of CD44(high)CD62L(low) in CD8(+) T cells 
      (T(EM) cells). Administration of the FLX-HSA conjugate resulted in an HLA-B*57:01 
      restricted immune response as shown by the stimulation of T(EM) cells in the 
      draining lymph nodes. In conclusion, administration of FLX alone to B*57:01-Tg 
      mice did not induce liver injury or immune activation. Immune system sensitivity 
      does not play a decisive role in this process. The conjugation of FLX and HSA 
      results in specific T(EM) cell stimulation, which suggests that HLA-B*57:01 
      drives a stronger interaction with CD8(+) T cells. These results suggest that 
      patients carrying HLA-B*57:01 could be more susceptible to a conjugate of FLX and 
      albumin and drive CD8(+) T cell activation, which may be a vital risk factor for 
      FLX-induced liver injury. In addition, the application of the FLX-HSA adduct may 
      be an effective method for the construction of FLX-induced idiosyncratic liver 
      injury in mice.
CI  - Copyright (c) 2022 European Federation of Immunological Societies. Published by 
      Elsevier B.V. All rights reserved.
FAU - Gao, Yuying
AU  - Gao Y
AD  - Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba 
      University, Japan.
FAU - Song, Binbin
AU  - Song B
AD  - Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba 
      University, 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, Japan.
FAU - Ito, Kousei
AU  - Ito K
AD  - Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba 
      University, Japan. Electronic address: itokousei@chiba-u.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220810
PL  - Netherlands
TA  - Immunol Lett
JT  - Immunology letters
JID - 7910006
RN  - 0 (HLA-B Antigens)
RN  - 0 (HLA-B57 antigen)
RN  - 0 (Oligodeoxyribonucleotides)
RN  - 0 (Programmed Cell Death 1 Receptor)
RN  - 43B2M34G2V (Floxacillin)
RN  - ZIF514RVZR (Serum Albumin, Human)
SB  - IM
MH  - Animals
MH  - CD8-Positive T-Lymphocytes
MH  - *Chemical and Drug Induced Liver Injury, Chronic
MH  - *Floxacillin/pharmacology
MH  - HLA-B Antigens/genetics
MH  - Humans
MH  - Lymphocyte Activation
MH  - Mice
MH  - Mice, Transgenic
MH  - Oligodeoxyribonucleotides/pharmacology
MH  - Programmed Cell Death 1 Receptor
MH  - Serum Albumin, Human/pharmacology
OTO - NOTNLM
OT  - Adaptive immune response
OT  - Conjugation
OT  - Flucloxacillin
OT  - HLA-B*57:01 transgenic mouse
OT  - Human serum albumin
COIS- Declaration of Competing Interest None
EDAT- 2022/08/14 06:00
MHDA- 2022/09/28 06:00
CRDT- 2022/08/13 19:22
PHST- 2022/03/15 00:00 [received]
PHST- 2022/07/19 00:00 [revised]
PHST- 2022/08/09 00:00 [accepted]
PHST- 2022/08/14 06:00 [pubmed]
PHST- 2022/09/28 06:00 [medline]
PHST- 2022/08/13 19:22 [entrez]
AID - S0165-2478(22)00113-4 [pii]
AID - 10.1016/j.imlet.2022.08.002 [doi]
PST - ppublish
SO  - Immunol Lett. 2022 Sep;249:5-11. doi: 10.1016/j.imlet.2022.08.002. Epub 2022 Aug 
      10.