Volume 73 Number 5 September 2006	back to contents

From the Department of Allergy/Immunology, Mount Sinai School of Medicine, Box 1089, One Gustave L. Levy Place, New York, NY.

Address all correspondence to Kirk E. Sperber, M.D., Department of Allergy/Immunology, Mount Sinai School of Medicine, Box 1089, One Gustave L. Levy Place, New York, NY 10029.

Presented to the Department of Medicine, Mount Sinai School of Medicine, New York, NY, June 28, 2005 and updated December 2005.

Abstract

Drug hypersensitivity reactions are a significant cause of iatrogenic-induced illness. (They were originally classified as type IV hypersensitivity, to describe the tuberculin skin reaction.) It now appears that the T-cell directs the entire inflammatory cascade induced by delayed drug allergy. Delayed drug hypersensitivity, usually manifested in the skin, is triggered when drug-specific CD4+ and CD8+ T cells recognize drugs through their T-cell receptors in a process that is dependent on a major histocompatibility complex. Drugs stimulate T-cell receptors by either covalently binding to peptides or using their structural features to interact via a more direct approach. Immunohistochemical and functional analysis of drug-reactive T-cell clones has shown that the phenotypic pattern of delayed drug hypersensitivity depends on the cytokine pattern induced. For example, maculo-papular exanthema may be either TH-1 or TH-2 in nature, depending on whether they are interferon- g /tumor necrosis factor- a or interleukin-4, 5 and 13 driven. Bullous reactions to drugs (i.e., Stevens-Johnson syndrome or toxic epidermal necrolysis) are characterized by widespread keratinocyte apoptosis, a consequence of high CD8+ T-cell involvement and the molecular cytotoxicity of Fas, perforin and granzyme B. Pustular exanthema reactions to medications are stimulated via the T-cell release of IL-8 and granulocyte-monocyte colony-stimulating factor (GM-CSF). With better understanding of these unique inflammatory cascades, delayed type IV hypersensitivity reactions have been re-classified into four main subtypes: IVa (TH-1/monocyte directed), IVb (TH-2/eosinophil directed), IVc (CD8+/ Fas/perforin/Granzyme B directed) and IVd (IL-8/GM-CSF/neutrophil directed). Clinically, delayed hypersensitivity eruptions are often an overlap of cytokine pathways, with one preferential reaction dominating the final picture.

Key Words

Drug hypersensitivity, allergy, T-cell, type IV reaction.

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