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Delayed Drug Hypersensitivity Reactions

Werner J. Pichler, MD
[+] Article, Author, and Disclosure 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@insel.ch.

Ann Intern Med. 2003;139(8):683-693. doi:10.7326/0003-4819-139-8-200310210-00012
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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 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 Bpositive 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.


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Figure 1.
The hapten and prohapten concept and the noncovalent drug presentation to T cells.APC(29)NO(30-33)TCR(24)

Hapten-like drugs (penicillins) can bind covalently to both soluble or cell-bound molecules. They can even bind directly to the immunogenic MHC–peptide complex on antigen-presenting cells ( ), either the embedded peptide or the MHC molecule itself . Thus, the chemical reactivity of haptens leads to the formation of many distinct antigenic epitopes, which can elicit both humoral and cellular immune responses. Other drugs are prohaptens, which require metabolism to become haptens (that is, chemically reactive). The metabolism occurs mainly inside cells (for example, from sulfamethoxazole to the chemically reactive form, sulfamethoxazole-nitroso [ ]). Metabolism may lead to modification of cell-bound or soluble proteins by the chemically reactive metabolite . A third, nonhapten pathway (pharmacologic interaction with immune receptors, also known as the “p–i concept”) does not require covalent association of the drug with the MHC molecule. The chemically inert drug seems to bind directly to the T-cell receptor ( ). Full T-cell stimulation requires an interaction with the MHC molecule. This type of drug stimulation is restricted to certain drugs that fit into TCRs and results in an exclusive T-cell stimulation (see text) .

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Figure 2.
Typical changes of maculopapular drug eruptions and depiction of the killing of keratinocytes by drug-specific, perforin-positive and granzyme B–positive T cells.Left.Right.ICAM-1LFA-1TCR

Histologic features of maculopapular exanthema: hydropic degeneration of keratinocytes, necrosis of keratinocytes, and lymphocyte and eosinophil infiltrations into dermis and epidermis. (Hematoxylin–eosin; original magnification, ×250.) Keratinocytes are stimulated to express MHC class II and intercellular adhesion molecule-1 ( ), a ligand for leukocyte function-related antigen-1 ( ). Infiltrating T cells interact with the drug through their T-cell receptor ( ) for antigen, together with the MHC class II molecules on keratinocytes, and kill them by a mechanism dependent on perforin and granzyme B.

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Figure 3.
Distinct T-cell functions in different forms of exanthemas.ABC+++DE++F(54, 72, 74, 75, 78, 85)

Various drugs can elicit distinct forms of T-cell–mediated drug reactions. For example, amoxicillin causes bullous skin disease ( ), maculopapular exanthema ( ), and acute generalized exanthematous pustulosis ( ). Analysis of skin infiltrates and functional analysis of drug-specific T-cell clones from these different forms of drug allergy revealed distinct contribution of CD4 and CD8 T cells to these disorders, as well as distinct functions of CD4 cells. In maculopapular exanthema, CD4 cells dominate. More CD8 T cells are found in patients with (mild) bullous skin disease, and these cells can kill keratinocytes ( ). CD4 cells secrete high levels of interleukin-5 and substantial amounts of interferon-γ and can kill activated MHC class II–expressing keratinocytes ( ). CD4 and CD8 T cells are found in patients with acute generalized exanthematous pustulosis ( ); both these cells contribute to vesicle formation through their cytotoxic activity. CD4 cells secrete granulocyte-monocyte colony-stimulating factor and interleukin-8, which leads to the recruitment of neutrophils . (Immunostaining by the avidin–biotin complex/alkaline phosphatase method; original magnification, ×250.).

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Summary for Patients

Delayed Drug Hypersensitivity

The summary below is from the full report titled “Delayed Drug Hypersensitivity Reactions.” It is in the 21 October 2003 issue of Annals of Internal Medicine (volume 139, pages 683-693). The author is W.J. Pichler.


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