Drug-induced immunotoxicity

Immune-related drug responses are one of the most common sources of idiosyn cratic toxicity. A number of organs may be the target of such reactions; ho wever, this review concentrates mostly on the liver. Drug-induced hepatitis is generally divided into two categories: acute hepatitis in which the dru g or a metabolite destroys a vital target in the cell; immunoallergic hepat itis in which the drug triggers an adverse immune response directed against the liver. Their clinical features are: a) low frequency; b) dose independ ence: 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 autoantibo dies in the serum of patients. Such signs have been found in cases of hepat itis 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. Th e following mechanisms have been postulated: I) the drug is first metaboliz ed into a reactive metabolite which binds to the enzyme that generated it; 2) this produces a neoantigen which, once presented to the immune system, m ight trigger an immune response characterized by 3) the production of antib odies recognizing both the native and/or the modified protein; 4) rechallen ge leads to increased neoantigen production, a situation in which the prese nce of antibodies may induce cytolysis. Toxicity is related to the nature a nd amount of neoantigen and also to other factors such as the individual im mune system. An effort should be made to better understand the precise mech anisms underlying this kind of disease and thereby identify the drugs at ri sk; and also the neoantigen processes necessary for their introduction into the immune system. An animal model would be useful in this regard.