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REVIEW

Delayed Drug Hypersensitivity Reactions

Werner J. Pichler, MD

21 October 2003 | Volume 139 Issue 8 | Pages 683-693

Immune reactions to small molecular compounds, such as drugs, can cause a variety of diseases involving the skin, liver, kidney, and lungs. In many drug hypersensitivity reactions, drug-specific CD4⁺ and CD8⁺ T cells recognize drugs through their ß T-cell receptors in an MHC-dependent way. Drugs stimulate T cells if they act as haptens and bind covalently to peptides or if they have structural features that allow them to interact with certain T-cell receptors directly. Immunohistochemical and functional studies of drug-reactive T cells in patients with distinct forms of exanthema reveal that distinct T-cell functions lead to different clinical phenotypes. In maculopapular exanthema, perforin-positive and granzyme B–positive CD4⁺ T cells kill activated keratinocytes, while a large number of cytotoxic CD8⁺ T cells in the epidermis is associated with formation of vesicles and bullae. Drug-specific T cells also orchestrate inflammatory skin reactions through the release of various cytokines (for example, interleukin-5, interferon) and chemokines (such as interleukin-8). Activation of T cells with a particular function seems to lead to a specific clinical picture (for example, bullous or pustular exanthema). Taken together, these data allow delayed hypersensitivity reactions (type IV) to be further subclassified into T-cell reactions, which through the release of 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.

Author and Article Information

From University of Bern, Bern, Switzerland.

Grant Support: By grant 31-61452.00 of the Swiss National Science Foundation, grant 97.0431 from the Swiss Federal Office of Education and Science (BIOMED program of the European Union), and a grant from Amersham Health.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Werner J. Pichler, MD, Division of Allergology, Clinic for Rheumatology and Clinical Immunology/Allergology, Inselspital, University of Bern, CH-3010 Bern, Switzerland; e-mail, werner.pichler{at}insel.ch.

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