Delayed drug hypersensitivity reactions – new concepts

Abstract

Immune reactions to small molecular compounds such as drugs can cause a variety of diseases mainly involving skin, but also liver, kidney, lungs and other organs. In addition to the well-known immediate, IgE-mediated reactions to drugs, many drug-induced hypersensitivity reactions appear delayed. Recent data have shown that in these delayed reactions drug-specific CD4(+) and CD8(+) T cells recognize drugs through their T cell receptors (TCR) in an MHC-dependent way. Immunohistochemical and functional studies of drug-reactive T cells in patients with distinct forms of exanthems revealed that distinct T cell functions lead to different clinical phenotypes. Taken together, these data allow delayed hypersensitivity reactions (type IV) to be further subclassified into T cell reactions, which by releasing certain cytokines and chemokines preferentially activate and recruit monocytes (type IVa), eosinophils (type IVb), or neutrophils (type IVd). Moreover, cytotoxic functions by either CD4(+) or CD8(+) T cells (type IVc) seem to participate in all type IV reactions. Drugs are not only immunogenic because of their chemical reactivity, but also because they may bind in a labile way to available TCRs and possibly MHC-molecules. This seems to be sufficient to stimulate certain, probably preactivated T cells. The drug seems to bind first to the fitting TCR, which already exerts some activation. For full activation, an additional interaction of the TCR with the MHC molecules is needed. The drug binding to the receptor structures is reminiscent of a pharmacological interaction between a drug and its (immune) receptor and was thus termed the p-i concept. In some patients with drug hypersensitivity, such a response occurs within hours even upon the first exposure to the drug. The T cell reaction to the drug might thus not be due to a classical, primary response, but is due to peptide-specific T cells which happen to be stimulated by a drug. This new concept has major implications for understanding clinical and immunological features of drug hypersensitivity and a model to explain the frequent skin symptoms in drug hypersensitivity is proposed.

Management of allergy to penicillins and other beta‐lactams

“…The high occurrence of morbilliform eruptions with aminopenicillins results from hyperstimulation of T cells caused by specific virus exposure [64].…”

A study of 300 cases of allergic contact dermatitis

“…1 It is a delayed type of induced sensitivity (allergy) resulting from cutaneous contact with a specific allergen to which the patient has developed a specific sensitivity. 2 In other words allergic contact dermatitis is caused by the body's reaction to something that directly contacts the skin. Many different substances can cause allergic contact dermatitis, which are called 'allergens' like fragrances, small molecule preservatives, etc.…”

A importância das provas epicutâneas de contacto no diagnóstico diferencial de reações a medicamentos

“…6.7 According to the latest knowledge about the function of T cells, Type IV reactions were subclassified as IVa-IVd, with the reactions associated with type IVc: maculopapular, bullous and neutrophilic skin reactions (with a prevalence of SJS and TEN), in which the role of cytotoxic T cells predominates through cytotoxicity mediated by CD8+ T cells, with the destruction of keratinocytes. 7 In some cases, both agents (drugs and infection) can be identified as potentially precipitating EEM. 3 Viral infections have been associated with increased risk of allergic reactions and, although the exact mechanism is not yet fully known, a breakdown Reading done 72 hours after patch tests for amoxicillin and ampicillin of tolerance or an enhanced immune reaction to drugs after a viral infection have been suggested.…”