Evidence for prostaglandin-producing suppressor cells in drug-induced liver injury and implications in the diagnosis of drug sensitization

Abstract

SUMMARY Lymphocyte reactivity to drugs is present in a majority of cases of drug-induced liver injury when in vitro proliferation assays to the suspected drugs are used. One possible explanation to this could be that adherent suppressor cells mediating their action through the production of prostaglandin E2 would suppress the lymphocyte proliferation to drugs in vitro. We studied 42 patients with a clinical diagnosis of drug-induced liver injury by comparing lymphocyte proliferation observed in cultures with five different concentrations of the suspected drug with the lymphocyte proliferation observed in cultures with drug and a prostaglandin inhibitor (indomethacin). Forty-four healthy subjects and 15 individuals with a recent exposure to the suspected drug without development of adverse drug reactions were also studied as controls. In nine (21%) out of 42 patients with drug-induced liver injury a significant lymphocyte reactivity to drugs was detected. When a prostaglandin inhibitor was added to the cultures, the detection of lymphocyte reactivity increased from 21% lo 57%. No cases of lymphocyte reactivity to drugs or drugs with prostaglandin inhibitor were found in the control groups. The phenomenon of increase of lymphocyte proliferation with the addition of a prostaglandin inhibitor was more frequent in patients whose hepatitis was cured in less than 2 months, was more frequently found in certain pharmacological groups and was significantly associated to a latency period to development of hepatitis of less than 8 days. In conclusion, the in vitro phenomenon described here may be used to improve the ability to demonstrate lymphocyte sensitization in drug-induced liver injury and the clinical correlations found are consistent with the possibility of its relevance in vivo.