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ABSTRACT: Delayed allergic skin reactions to drugs are common iatrogenic diseases mediated by activation of specific T cells in the skin.
To better understand the role of T cells in these diseases, we developed a mouse model of drug allergy induced by skin sensitization to amoxicillin (amox), a penicillin antibiotic frequently involved in delayed drug allergy.
Whereas wild-type mice could not be sensitized to amox, CD4+ T-cell-deficient mice developed an amox-specific allergic skin response, mediated by IFN-gamma-producing CD8+ T cells. Amox-specific CD8+ T cells, induced in lymphoid organs at a high frequency during sensitization, were recruited in the skin upon challenge. CD8+ T cells were effectors of the allergic skin reaction to amox as in vivo treatment with depleting anti-CD8 mAbs abrogated the skin inflammatory reaction and as purified CD8+ T cells could adoptively transfer the allergic response to naive recipients.
CD8+ T cells mediate penicillin skin allergy.
Allergy 08/2010; 65(8):996-1003. · 6.27 Impact Factor
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ABSTRACT: Drug allergic reactions presenting as maculo-papular exanthema (MPE) are mediated by drug-specific T cells. In this study, the frequency of circulating specific T cells was analyzed by interferon-gamma (IFN-gamma) enzyme-linked immunospot assay in 22 patients with an allergic MPE to amoxicillin (amox). Amox-specific circulating T cells were detected in 20/22 patients with frequencies ranging from 1 : 8000 to 1 : 30 000 circulating leucocytes. No reactivity was observed in 46 control patients, including 15 patients with immunoglobulin E-mediated allergy to amoxicillin, 11 patients with a history of drug-induced MPE but tolerant to amoxicillin and 20 healthy individuals. Furthermore, amox-specific T cells were still detectable several years after the occurrence of the allergic reaction even after strict drug avoidance. Finally, analysis of drug-specific T cells in one patient allergic to ticarcillin (a penicillin antibiotic distinct from amox) revealed the presence of IFN-gamma-producing T cells reactive to ticarcillin and several other betalactam antibiotics, suggesting that the IFN-gamma ELISPOT assay is able to detect T cell cross-reactivity against chemically related drugs. These findings confirm that drug-induced MPE is associated with the presence of specific T cells in blood and further suggest that the IFN-gamma ELISPOT is a sensitive assay which could improve the diagnosis of betalactam allergy.
Allergy 02/2009; 64(4):534-42. · 6.27 Impact Factor
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ABSTRACT: Allergic reactions to penicillin/-lactam antibiotics are associated with the presence of circulating drug specific T cells. Diagnosis of delayed drug allergy so far relies on an in vitro assay, the lymphocyte transformation test (LTT), based on the proliferation of PBMC in response to the drug. In the present study, we analyzed the frequency of circulating drug-specific T cells in 22 amoxicillin allergic patients using the highly sensitive IFN-g-ELISPOT assay. Twenty out of 22 patients tested had significant numbers of amoxicillin-specific IFN--producing T cells in blood. Amox-specific IFN--producing T cells were undetectable in 46 control patients including 15 patients with IgE-mediated allergy to amoxicillin, in 11 patients with a history of drug-induced MPE but tolerant to amoxicillin and in 20 normal individuals. Furthermore, analysis of drug-specific T cells in one patient allergic to ticarcillin (a penicillin antibiotic different from amoxicillin) revealed the presence of IFN--producing T cells reactive to ticarcillin and several other -lactam antibiotics, suggesting that the IFN- ELISPOT assay is able to detect T cell cross-reactivity against chemically related drugs. Finally, LTT appeared less sensitive than the ELISPOT assay, both for detection of amoxicillin-specific T cells in allergic patient and for identification of potential cross-reactivities to various -lactams. These findings demonstrate that drug-specific IFN-g ELISPOT assay represents a novel sensitive assay that may serve to improve diagnosis of -lactam allergy and may help to adapt alternative antibiotic treatment.
Revue Française d'Allergologie et d'Immunologie Clinique.
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ABSTRACT: Skin lesions in the allergic form of atopic dermatitis (AD) are induced by allergen-specific T cells which infiltrate the skin at the site of allergen exposure. The pathophysiology of atopic dermatitis is not entirely defined. Although Th2-type CD4+ T cells appear to be crucial in AD pathophysiology, little is known about the contribution of CD8+ T cells in the development of the allergic skin inflammation. In the present study, we have developed a mouse model of allergen-induced AD and we have analyzed the respective roles of CD8+ and CD4+ T cells in the development of AD skin lesions. In sensitized mice, CD8+ T cells are rapidly and transiently recruited to the allergen-exposed site and initiate the inflammatory process, leading to skin infiltration with eosinophils and Th1/Th2 producing cells. CD8+ T cell-depleted mice show no inflammation, demonstrating that these cells are mandatory for the development of AD. In contrast, CD4+ T cell-depleted mice develop a severe form of eczema. Furthermore, adoptive transfer of CD8+ T cells from sensitized mice into naive recipient mice leads to skin inflammation soon after allergen exposure. These data indicate that allergen-primed CD8+ T cells are required for the development of AD-like lesions in mice. Ongoing studies may allow us to confirm these findings in humans.
Revue Française d'Allergologie et d'Immunologie Clinique. 47(3):116-117.
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ABSTRACT: Introduction. – The adverse effects caused by drugs are classified as toxic, pharmacological or allergic. Allergic side effects are hypersensitivity reactions that involve antibodies (immediate hypersensitivity reactions) or T lymphocytes (delayed hypersensitivity). We describe the results of a study evaluating an in vitro method using peripheral blood T lymphocytes for the diagnosis of erythematous drug-induced delayed hypersensitivity reactions.Materials and methods. – Three groups of patients were included: Group A, patients allergic to amoxicillin (N =14); Group B, patients who tolerate amoxicillin without side effects (N =5); and Group C, patients who had developed a non-allergic type of reaction to amoxicillin (N =10). The diagnosis of allergic reactions (Group A) was demonstrated by a positive skin test reaction 48 to 96 hours after applying amoxicillin to the skin. The lymphocyte transformation test (LTT) and the Elispot test for IFN-γ were done simultaneously. Ceftriaxon served as the negative control reagent for both the skin and in vitro tests.Results. – The results observed for the LTT indicated a level of sensitivity of 71% when the stimulation index (SI) was greater than 2.5. Under the conditions used, the results of the IFN-γ assay demonstrated the presence of specific T lymphocytes in Group A with a mean of 70 spots/1 106 cells in the presence of amoxicillin, whereas re-stimulation of the cells with the antibiotic control, ceftriaxone, resulted in no IFN-γ secretion. After stimulation with amoxicilln, 12 out of the 14 patients in Group A had a significantly increased number of spots in comparison with ceftriaxone.Discussion. – These results demonstrate that the Elispot IFN-γ in vitro assay provides a method to estimate the number of amoxicillin-specific T cells in peripheral blood. This test appears to differentiate patients who are allergic to drugs from those who are not. The test is interesting because it is simple to carry out, a large number of drugs can be tested at the same time, and the results are obtained rapidly. If these results can be confirmed with other drug molecules, then the ELISPOT IFN-γ in vitro assay could be included in the battery of in vitro tests for delayed hypersensitivity reactions to drugs.
Revue Française d'Allergologie et d'Immunologie Clinique. 45(3):218-221.
