Abstract
Recent studies have highlighted the strong relationship between specific human leukocyte antigen (HLA) alleles and the onset of idiosyncratic drug toxicities. For example, HLA-B*57:01 is a potential risk factor of abacavir-induced hypersensitivity. However, the precise mechanism of the onset has been still unrevealed, and we are attempting to elucidate it using HLA transgenic mice (HLA-Tg).
In order to reproduce the HLA-dependent immune reactions, a mouse-human chimeric HLA gene was transduced to mice. The resulting HLA-B*57:01-Tg exhibited proliferation and activation of lymphocytes including CD8+ T cells by exposure to abacavir. However, we could not observe strong toxic symptoms in the mice. We identified one of the main reasons was upregulated immunosuppressive factors, thus knockout of PD-1 gene and depletion of CD4+ T cells in HLA-B*57:01-Tg strongly induced immunotoxicity.
HLA-mediated drug toxicities are frequently observed in several specific tissues including skin. Our study indicated that exposure to abacavir induced endoplasmic reticulum (ER) stress in HLA-B*57:01-Tg. Especially, HLA-B*57:01-expressing keratinocytes evoked ER stress by abacavir. The relief of the ER stress by a chemical chaperon in HLA-B*57:01-Tg attenuated abacavir-induced toxicity, implying that ER stress played a crucial role in the onset of HLA-mediated drug toxicities.
Today, I would like to introduce the mechanism underlying HLA-mediated immunotoxicities from in vivo studies using HLA-Tg to in vitro analyses of HLA molecular characteristics.
