Idiosyncratic drug
reactions are unpredictable adverse reactions.
Although most such adverse reactions appear to be immune mediated,
their exact mechanism(s) remain elusive. The idiosyncratic drug reaction
most associated with serious consequences is idiosyncratic drug-induced
liver injury (IDILI). We have developed a mouse model of amodiaquine
(AQ)-induced liver injury that reflects the clinical characteristics
of IDILI in humans. This was accomplished by impairing immune tolerance
by using PD-1–/– mice and an antibody against
CTLA-4. PD-1 and CTLA-4 are known negative regulators of lymphocyte
activation, which promote immune tolerance. Immune checkpoint inhibitors
have become important tools for the treatment of cancer. However,
as in our model, immune checkpoint inhibitors increase the risk of
IDILI with drugs that have an incidence of causing liver injury. Agents
such as 1-methyl-d-tryptophan (D-1-MT), an inhibitor of the
immunosuppressive indoleamine 2,3-dioxygenase (IDO) enzyme, have also
been proposed as anti-cancer treatments. Another possible risk factor
for the induction of an immune response is the release of danger-associated
molecular patterns (DAMPs). Acetaminophen (APAP) is known to cause
acute liver injury, and it is likely to cause the release of DAMPs.
Therefore, either of these agents could increase the risk of IDILI,
although through different mechanisms. If true, then this would have
clinical implications. We found that co-treatment with D-1-MT paradoxically
decreased liver injury in our model, and although APAP appeared to
slightly increase AQ-induced liver injury, the difference was not
significant. Such results highlight the complexity of the immune response,
which makes potential interactions difficult to predict.
