PubMed · 7749965
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M S Blaiss. 1995. Why outcomes?. https://pubmed.ncbi.nlm.nih.gov/7749965/
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Idiosyncratic adverse drug reactions have characteristics that suggest involvement of the immune system. In particular, drug-induced lupus which is an autoimmune syndrome, must be immune-mediated. A major working hypothesis for the first step in the mechanism of drug-induced autoimmunity is that the drug, or more commonly a reactive metabolite of the drug, must irreversibly bind to some structure. In view of the reactive nature of these metabolites, in most cases it is likely that the metabolite must be formed in the organ where toxicity occurs. The liver is the major site of drug metabolism and it is a common target for idiosyncratic drug reactions. In the case of immune reactions directly involving leukocytes, the enzyme system most likely responsible for the formation of reactive metabolites is the NADPH oxidase/myeloperoxidase system found in neutrophils and monocytes. In some cases, the reactive metabolite results in the production of antibodies or T-cells directed against the altered structure. However, in many other cases, the mechanism appears to be more complex than this. In some cases, true auto-antibodies are produced that do not require the presence of the drug, and furthermore, the antibodies produced often are the same as those induced by other stimuli, such as viruses. This suggests either molecular mimicry or a common alteration in the processing and presentation of antigens such that cryptic antigens are presented. Another possibility is that the reactive metabolite directly alters the class II MHC molecule leading to a graft-vs-host reaction.
An overview is given in simple terms of the techniques behind transgenic, knock-out and knock-in mice. The principles for the creation and use in toxicology of genetically engineered animals are outlined, and some examples are given from areas related to immunotoxicology. Genetically engineered animals have so far been used only to a very limited extent in immunotoxicology. Practical aspects of work with transgenic animals are discussed, and sources of information and services related to transgenic animals are listed.
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