Drug-induced immunotoxicity

Immune-related drug responses are one of the most common sources of idiosyncratic toxicity. A number of organs may be the target of such reactions; however, this review concentrates mostly on the liver. Drug-induced hepatitis is generally divided into two categories: acute hepatitis in which the drug or a metabolite destroys a vital target in the cell; immunoallergic hepatitis in which the drug triggers an adverse immune response directed against the liver. Their clinical features are: a) low frequency; b) dose independence: c) typical immune system manifestations such as fever, eosinophilia; d) delay between the initiation of treatment and onset of the disease; e) a shortened delay upon rechallenge; and f) occasional presence of autoantibodies in the serum of patients. Such signs have been found in cases of hepatitis triggered by drugs such as halothane, tienilic acid, dihydralazine and anticonvulsants. They will be taken as examples to demonstrate the recent progress made in determining the mechanisms responsible for the disease. The following mechanisms have been postulated: I) the drug is first metabolized into a reactive metabolite which binds to the enzyme that generated it; 2) this produces a neoantigen which, once presented to the immune system, might trigger an immune response characterized by 3) the production of antibodies recognizing both the native and/or the modified protein; 4) rechallenge leads to increased neoantigen production, a situation in which the presence of antibodies may induce cytolysis. Toxicity is related to the nature and amount of neoantigen and also to other factors such as the individual immune system. An effort should be made to better understand the precise mechanisms underlying this kind of disease and thereby identify the drugs at risk; and also the neoantigen processes necessary for their introduction into the immune system. An animal model would be useful in this regard.