Ingested drugs can act as haptens, which combine with normal tissue proteins forming immunogenic complexes that are recognized by T cells. Although drugs tend not to be highly chemically reactive molecules, their metabolites may well be. An example is penicillin, which can be associated with autoimmune hemolytic anemia. Although not likely to conjugate proteins itself, in solution penicillin spontaneously forms penicillenic acids with a highly reactive oxazolone group (22) that modifies proteins in the membranes of erythrocytes.
A frequently studied example of drug-induced autoimmunity is drug-induced hepatitis that can be associated with the commonly used antihistamine, chlorpheniramine (23). Peripheral blood lymphocytes (PBLs), and several CD4+ clones derived from them, proliferated upon stimulation with a mixture of chlorpheniramine and a liver-derived protein, but not to the drug alone. These results suggested that the T-cell response was directed against the protein that had been modified, in a hapten-like manner, by the drug. In this system there was no detectable T-cell response to liver-derived protein alone, and the hepatitis resolved as soon as administration of the drug was stopped.
There is evidence that the immune response induced by protein-drug conjugates can lead to autoimmunity against the native proteins. Drug-induced (e.g., hydralazine, qui-nidine, or isoniazid) systemic lupus erythematosus is associated with the development of auto-antibodies, particularly antinuclear antibody (24). As a result, the manifestations of the disease can continue even after withdrawal of the offending drug.
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