RRC ID 72389
Author Gao Y, Song B, Aoki S, Ito K.
Title Conjugation of human serum albumin and flucloxacillin provokes specific immune response in HLA-B*57:01 transgenic mice.
Journal Immunol Lett
Abstract 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 adverse liver reactions. 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 CD44highCD62Llow in CD8+ T cells (TEM cells). Administration of the FLX-HSA conjugate resulted in an HLA-B*57:01 restricted immune response as shown by the stimulation of TEM 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 TEM 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.
Volume 249
Pages 5-11
Published 2022-9-1
DOI 10.1016/j.imlet.2022.08.002
PII S0165-2478(22)00113-4
PMID 35963284
MeSH Animals CD8-Positive T-Lymphocytes Chemical and Drug Induced Liver Injury, Chronic* Floxacillin* / pharmacology HLA-B Antigens / genetics Humans Lymphocyte Activation Mice Mice, Transgenic Oligodeoxyribonucleotides / pharmacology Programmed Cell Death 1 Receptor Serum Albumin, Human / pharmacology
IF 3.276
Mice RBRC02142