Inhibition of the Adaptive Immune Response following Drug‐Induced Liver Injury

Abstract

Current evidence suggests that drug-induced liver injury is often caused by an allergic response (drug-induced allergic hepatitis, DIAH) induced by hepatic drug-protein adducts. The relatively low incidence of these reactions has led us to hypothesize that tolerogenic mechanisms prevent DIAH from occurring in most people. Here we present evidence for the existence of one of these regulatory pathways. Following a hepatotoxic dose of APAP (300 mg/kg), widespread lymphocytolysis was noted in the spleen, thymus, and draining lymph nodes of the liver, which appeared to be due, at least in part, to apoptosis in both the T- and B-cell populations of these organs. There was no observable lymphocytolysis in the absence of hepatotoxicity, as noted in mice treated with non-hepatotoxic doses of 80 mg/kg. In fact, a correlation was observed between the degree of liver injury and the extent of lymphocytolysis. Acetaminophen-induced liver injury also led to a functional suppression of the immune system as determined by inhibition of a delayed-type hypersensitivity response to dinitrochlorobenzene. Further studies suggested that corticosterone may have a role in initiating acetaminophen-induced lymphocytolysis and immunosuppression because a correlation was found between serum levels of this hormone and the magnitude of lymphocytolysis. These findings suggest that drug-induced liver injury may cause widespread lymphocytolysis and immunosuppression thus preventing occurrences of not only DIAH, but also other forms of drug allergies. This research was supported in part by the Intramural Research Program of the NIH, NHLBI and by a Cooperative Research and Development Agreement (CRADA) with GSK.