The increased numbers of perforin and granzyme B containing T cells infiltrating the dermoepidermal junction may contribute to the damage of epidermal cells, which is frequently observed as a typical feature of interface dermatitis in drug-induced exanthem. Our data provide further evidence that cytotoxic T cells play an essential role in cutaneous drug reactions.

In order to investigate the function of T cells in cutaneous adverse drug reactions, skin-derived T cells were analyzed in two patients with a drug-induced exanthem. Skin biopsy specimens were obtained from positive epicutaneous test reactions to amoxicillin and ceftriaxone. Immunohistochemical analysis revealed that the majority of the cell infiltrate in both biopsy specimens was composed of activated T cells, of which some expressed perforin. By limiting dilution 36 amoxicillin-specific and 10 ceftriaxone-specific T cell clones were raised. All of these T cell clones expressed CD4/T cell receptor alphabeta. Cytokine analysis after antigen stimulation of the seven best proliferating T cell clones (four specific for amoxicillin and three for ceftriaxone) revealed that these cells secrete high amounts of interleukin-5 and mostly lower or no amounts of tumor necrosis factor alpha, interleukin-4, and interferon-gamma. A part of these CD4+ T cell clones were cytotoxic, i.e., two selected ceftriaxone-specific T cell clones killed target cells after antigen stimulation. The amoxicillin-specific T cell clones failed to show drug-specific cytotoxicity, but killed target cells in the presence of concanavalin A, indicating a principal ability to be cytolytic. In correlation with the in situ expression of perforin on T cells, the ceftriaxone-specific T cell clones also expressed perforin in vitro. In conclusion, a substantial part of the T cells in drug-induced epicutaneous test reactions are drug specific and are composed of a heterogeneous cell population. Drug-specific T cells producing interleukin-5 may contribute to eosinophilia, whereas cytotoxic CD4+ T cells may account for tissue damage. These data underline the role of T cells in delayed-type cutaneous adverse drug eruptions and drug-induced epicutaneous test reactions.

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Recent reports indicate that cytotoxic T cells are critically involved in contact hypersensitivity reactions in animals. In this study we sought to investigate the in vivo expression of cytotoxic granule proteins in the elicitation phase of allergic contact dermatitis in humans. Skin biopsy specimens were obtained from patients with allergic contact dermatitis (n = 8) and psoriasis (n = 6) and from controls with normal skin (n = 6). Expression of perforin and granzyme B was investigated by in situ hybridization and immunohistochemistry. In contrast to normal skin and psoriasis, a significant enhancement of perforin and granzyme B gene expression and immunoreactivity was observed in the mononuclear cell infiltrate of allergic contact dermatitis. Immunoreactivity for perforin and granzyme B was mainly found in the cytoplasm of lymphocytic cells, which were located in the dense perivascular infiltrate as well as at sites of marked spongiosis in the epidermis. Double immunostaining revealed that both CD4+ and CD8+ T cells are capable of expressing perforin and granzyme B. In conclusion, our data suggest that T-cell-mediated mechanisms involving cytotoxic granule proteins may elicit epidermal cell injury in vivo and thereby strongly contribute to the development of allergic contact dermatitis in humans.

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