Fulminant liver failure triggered by therapeutic antibody treatment in a mouse model

Abstract

Monoclonal antibodies are finding ever increasing therapeutic applications. However, lethal liver damage has been reported following monoclonal antibody (mAb) treatment in combination with subtoxic doses of cytotoxic drugs. In this study, mice were intravenously injected with 200 μg/mouse of anti-CD8 (anti-Lyt-2.2), anti-CD4 (GK1.5) or anti-B220 (RA3-6B2) mAb. Subsequently, mice were administered 15 mg azoxymethane (AOM) per kg body weight by subcutaneous injection. Unexpectedly, all mice pretreated with mAb died within 72 h of a single injection of AOM. The injection of mAb-coated spleen cells accelerated the induction and the severity of liver disease. We found that mAb treatment activates Kupffer cells to produce inflammatory cytokines such as TNF-α and IL-12, and induces the expression of FasL on Kupffer and NKT cells. The concomitant upregulation of Fas on hepatocytes increases the susceptibility of the liver to apoptotic signals, and subsequent treatment with AOM causing mitochondrial injury synergistically induces lethal liver damage. Consistently, the lethal liver damage was abrogated in mice which were deficient for Kupffer cells, NKT cells or Fas-antigen. In conclusion, we have demonstrated a potential risk of lethal fulminant liver damage in the concomitant use of therapeutic antibodies and cytotoxic drugs. A possible side effect of antibody therapy is mediated through activation of the immune system, the very mechanism of action on which this treatment depends. In this context, the risk of combining therapeutic antibodies with other agents, particularly cytotoxic drugs, requires careful consideration.