| First Author | Gao Y | Year | 2022 |
| Journal | Immunol Lett | Volume | 249 |
| Pages | 5-11 | PubMed ID | 35963284 |
| Mgi Jnum | J:336078 | Mgi Id | MGI:7461990 |
| Doi | 10.1016/j.imlet.2022.08.002 | Citation | Gao Y, et al. (2022) Conjugation of human serum albumin and flucloxacillin provokes specific immune response in HLA-B*57:01 transgenic mice. Immunol Lett 249:5-11 |
| abstractText | 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. |
