The Effects of Immune Modulators on Amodiaquine-Induced Liver Injury

If idiosyncratic drug-induced liver injury (IDILI) is immune mediated, then it is logical that immune modulators may be able to affect liver injury caused by a drug. We have previously shown that modulating the immune system by impairing programmed cell death protein (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) signaling, both receptors involved in immune tolerance, was capable of producing an animal model of amodiaquine (AQ) IDILI with characteristics very similar to IDILI in humans. Other immune modulators may also increase liver injury caused by drugs that cause IDILI in humans. In this study, myeloid derived suppressor cells (MDSCs), transforming growth factor beta (TGF-β), and lymphocyte-activation gene 3 (LAG3) were targeted with antibodies, with and without PD-1 and CTLA-4 impairment. We found that anti-Gr1 antibodies used to deplete MDSCs led to a significant increase in AQ-induced liver injury in wild-type mice; however, the injury was actually less in PD-1^-/- mice, with or without anti-CTLA-4, and it was less than we have previously observed in PD-1^-/- mice combined with anti-CTLA-4 without anti-Gr1. Addition of anti-LAG3 or anti-TGF-β antibodies produced a small increase ALT in AQ-treated wild-type mice. There was a significant increase in ALT in PD-1^-/- mice co-treated with anti-LAG3 or anti-TGF-β relative to AQ-treated wild-type mice. In the case of TGF-β, this was further increased by the addition of anti-CTLA-4, but if anything, there appeared to be a paradoxical decrease when anti-CTLA-4 was combined with anti-LAG3. Overall, the results from this study were not always as expected, and they highlight the complexity of the immune response, in particular immune tolerance, which appears to be the dominant immune response to drugs that cause IDILI.