Immune mechanisms of idiosyncratic drug-induced liver injury

Abstract

Idiosyncratic drug reactions (IDRs) continue to be an important issue. Specifically, idiosyncratic drug-induced liver injury (IDILI) is the most likely IDR to lead to drug withdrawal, and it accounts for a significant portion of all cases of acute liver failure. In addition, IDRs are unpredictable and their mechanisms are not well understood. There is increasing clinical evidence that most IDILI is immune mediated. Several immune mediated mechanistic hypotheses exist such as the hapten and danger hypothesis; however, they do not completely explain the idiosyncratic nature of these reactions. Extensive mechanistic studies are needed to better understand these reactions; however, it is impossible to do controlled experiments in humans, and previous animal models did not properly model IDILI. If IDILI is immune mediated and the major factor preventing liver injury in patients is immune tolerance, then a plausible method to develop an animal model of IDILI would be to impair immune tolerance. This hypothesis has shown promise in developing valid animal models of IDILI as demonstrated by a halothane induced liver injury mouse model developed by depleting myeloid derived suppressor cells (MDSCs), as well as an amodiaquine-, isoniazid-and nevirapine-induced liver injury mouse model developed by impairing immune tolerance by blocking PD-1 and CTLA-4, two immune checkpoint inhibitors. Further characterization and validation of these models is required; however, it is likely that they will make it possible to perform mechanistic studies that have been impossible in the past. Relevance for patients: Idiosyncratic drug-induced liver injury can be serious leading to liver transplantation or death. Their idiosyncratic nature makes mechanistic studies very difficult. However, with the development of the first animal model that is similar to the liver injury that occurs in humans, it will be possible to study the mechanisms involved. With a better mechanistic understanding it should be possible to test drug candidates and produce safer drugs. In addition, it should be possible to design better treatments when drug-induced liver injury does occur.

Keywords: idiosyncratic drug reactions; idiosyncratic drug-induced liver injury; immune mediated; immune tolerance.

Figure 1.. Pharmacology, genetics, and the environment may all play roles in determining who will develop an IDR, in this case liver injury. In general there is a delay in the onset of injury, and depending on the individual, a patient may have no clinically evident liver injury, develop mild liver injury that resolves despite continued treatment, or develop liver failure. The characteristics such as time to onset are similar in the mild and serious injury

Figure 2.. Hypotheses of immune mediated IDRs. A) The Hapten hypothesis: a reactive drug or reactive metabolite acting as a hapten binds to endogenous proteins, creating drug-modified proteins and generating Signal 1 of the immune response. B) The Danger hypothesis: reactive species damage cells, resulting in the release of danger signals and leading to Signal 2 of the immune response. Immune cells such as CD8 T cells that have received Signal 1 and 2 can then cause cell death. C) Molecular mimicry and heterologous immunity: previous exposure to pathogens can prime the immune system, create memory immune cells that recognize subsequent drug-modified proteins, and lead to a strong immune response and cell death.

Figure 3.. Inflammasome activation. Drugs have the potential to activate the inflammasome, leading to release of IL-1ß and IL-18, which can further stimulate an immune response.

Figure 4.. There are multiple immune tolerance pathways including CTLA-4 and PD-1 signalling from regulatory immune cells such as Treg cells or MDSCs. Therefore immune tolerance can be impaired by (A) interfering with signalling pathways by using PD-1-/-mice lacking the PD-1 receptor or using anti-CTLA-4 antibodies, or (B) depleting MDSCs using anti-Gr-1 antibodies.