Originally, the immune stimulation by drugs were exclusively explained by the hapten concept, which was investigated in the early 1930s: In these early studies it was found that drugs were too small to represent an antigen inherently. Only if they or their metabolites are haptens, thereby forming larger and stable drug-protein complexes, were they seen as new antigens. Such a formation of a complete antigen (drug-protein complexes, so-called adducts) were considered a necessary step to stimulate an immune response, since the drug alone remained unnoticed by the immune cells.
One classical clinical model for a hapten reaction is contact dermatitis. This is a skin disease based on a localized immune reaction in the skin to a chemically reactive, topical applied compound, which binds by covalent bonds to a carrier protein; many of the contact sensitizers also have a toxic effect, which may be important for the costimulation of the immune system. Extensive in vitro and in vivo data support the hapten concept in contact dermatitis.
It was tempting to use the hapten model to explain generalized DH as well: The drug class most often involved in generalized DHR are penicillins. When applied to the skin, they elicit contact dermatitis. Penicillins are classical haptens and penicillin modified proteins like albumin have been repeatedly found in patients after therapy. Thus it was assumed that the generalized DHR upon parenteral or oral application after penicillins is also due to the hapten-feature of this drug class.
The “hapten-concept” was soon extended to explain all immune mediated (adverse drug reactions): Only if the drug or a metabolite could act as hapten and bind covalently to proteins, then was the drug considered to be able to elicit immune reactions including generalized exanthema, drug induced hepatitis, DRESS, SJS/TEN etc. Consequently, during preclinical risk assessment of a new drug, the potential drug candidate may be screened carefully for hapten-features, and if the candidate drugs caused some adverse immune mediated reaction, it was linked to their hapten feature or, if the parent compound lacked hapten characteristics, a hapten feature of a drug metabolite as cause for the DHR was postulated. Importantly, the hapten theory as explanation for all generalized immune reactions was often disputed and hard to reconcile with many experimental or clinical findings.