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Allergic contact dermatitis is the most frequent occupational disease in industrialized countries. It is caused by CD8(+) T cell-mediated contact hypersensitivity (CHS) reactions triggered at the site of contact by a variety of chemicals, also known as weak haptens, present in fragrances, dyes, metals, preservatives, and drugs. Despite the myriad of potentially allergenic substances that can penetrate the skin, sensitization is relatively rare and immune tolerance to the substance is often induced by as yet poorly understood mechanisms. Here we show, using the innocuous chemical 2,4-dinitrothiocyanobenzene (DNTB), that cutaneous immune tolerance in mice critically depends on epidermal Langerhans cells (LCs), which capture DNTB and migrate to lymph nodes for direct presentation to CD8(+) T cells. Depletion and adoptive transfer experiments revealed that LCs conferred protection from development of CHS by a mechanism involving both anergy and deletion of allergen-specific CD8(+) T cells and activation of a population of T cells identified as ICOS(+)CD4(+)Foxp3(+) Tregs. Our findings highlight the critical role of LCs in tolerance induction in mice to the prototype innocuous hapten DNTB and suggest that strategies targeting LCs might be valuable for prevention of cutaneous allergy. [ABSTRACT FROM AUTHOR]

To cite this article: Rozieres A, Vocanson M, Rodet K, Benetiere J, Bienvenu J, Berard F, Hennino A, Nicolas J-F. CD8+ T cells mediate skin allergy to amoxicillin in a mouse model. Allergy 2010; 65: 996–1003. Background: Delayed allergic skin reactions to drugs are common iatrogenic diseases mediated by activation of specific T cells in the skin. Methods: 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. Results: 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-γ-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. Conclusion: CD8+ T cells mediate penicillin skin allergy. [ABSTRACT FROM AUTHOR]

Allergic contact dermatitis (ACD), one of the commonest occupational diseases, is a T-cell-mediated skin inflammation caused by repeated skin exposure to contact allergens, i.e. nonprotein chemicals called haptens. Allergic contact dermatitis, also referred to as contact hypersensitivity, is mediated by CD8+ T cells, which are primed in lymphoid organs during the sensitization phase and are recruited in the skin upon re-exposure to the hapten. Subsets of CD4+ T cells endowed with suppressive activity are responsible for both the down-regulation of eczema in allergic patients and the prevention of priming to haptens in nonallergic individuals. Therefore, ACD should be considered as a breakdown of the skin immune tolerance to haptens. Recent advances in the pathophysiology of ACD have demonstrated the important role of skin innate immunity in the sensitization process and have revisited the dogma that Langerhans cells are mandatory for CD8+ T-cell priming. They have also introduced mast cells as a pivotal actor in the magnitude of the inflammatory reaction. Finally, the most recent studies address the nature, the mode and the site of action of the regulatory T cells that control the skin inflammation with the aim of developing new strategies of tolerance induction in allergic patients. [ABSTRACT FROM AUTHOR]

Abstract: Knowledge of the pathophysiology of Allergic Contact Dermatitis (ACD) derives chiefly from the murine experimental model of Contact Hypersensitivity referred to as the Mouse Ear Swelling Test (MEST). ACD is mediated by activation of CD8+ cytotoxic T cells specific for haptens in contact with the skin, and down-regulated by CD4+ T cells which limit the magnitude of the skin inflammation and participate to its resolution. Although the MEST is a major tool in the fields of immunodermatology and fundamental immunology, it is not sensitive enough to detect the sensitizing properties of common weak allergens and therefore is not used anymore in immunotoxicological studies. The MEST has been replaced by the Local lymph node Assay (LLNA), which brought tangible ethical benefits, but is endowed with low sensitivity and specificity. Recently, we reported that mice deficient in CD4+ T regulatory cells, but not normal mice, could develop a typical ACD reaction to weak haptens involved in human ACD to fragrances (Hexylcinnamaldehyde, Eugenol, Hydroxycitronellal). From this in vivo results, we developed an in vitro assay, referred to as the Weak Hapten Interferon Secreting T LymphocytE test (Whistle), able to detect the sensitizing properties of chemicals in contact with the skin. [Copyright &y& Elsevier]

Background/Aims: Positive patch tests are considered representative of a contact allergy to the tested chemical. However, contaminants and derivatives rather than the suspected chemical itself could be responsible for the allergic skin reactions. Here, we tested the importance of contaminants in the sensitizing and allergenic properties of coumarin in mice and humans. Coumarin, an ingredient in cosmetics and fragrances, was chosen as the reference chemical since conflicting results have been obtained regarding its ability to induce contact allergy. In some chemical preparations, this could be explained by the presence of coumarin derivatives endowed with allergenic properties. Methods: In mice, three different coumarin preparations were tested in the local lymph node assay. In humans, we assessed the irritant and allergenic properties of highly pure coumarin in nonallergic and fragrance-allergic patients. Results: Pure coumarin did not exhibit irritant or sensitizing properties in the local lymph node assay. In contrast, two other commercially available coumarins and three contaminants that were detected in these coumarin preparations were identified as weak and moderate sensitizers, respectively. In humans, pure coumarin was extremely well tolerated since only 1 out of 512 patients exhibited a positive patch test to the chemical. Conclusions: These results indicate that coumarin cannot be considered as a common contact allergen and further emphasize that purity of chemicals is mandatory for the assessment of their allergenicity. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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. [Copyright &y& Elsevier]

T cell-and non T cell-mediated delayed hypersensitivity to dupilumab We hypothesize that Patient 1 was sensitized to T-cell epitopes in the tralokinumab primary sequence with cross-reactivity with dupilumab[6]; (ii) an Arthus-like reaction, that is, an immune complex-mediated reaction produced under conditions of excess antigens, for the second patient. We report the cases of a 52-year-old (Patient 1) and a 56-year-old (Patient 2) female patients, followed for severe AD with multiple previous treatment failures. [Extracted from the article]

Background: Chronic red blood cell exchanges (RBCXs) are frequently used to prevent complications in patients with sickle cell anemia, but the scarcity of matched red blood cell packs (RBCPs) is a serious concern. The main goal of this study was to compare the number of RBCPs used during RBCXs between the Spectra Optia (SO) device (with the automatic depletion step) and the former Cobe Spectra (CSP) device.Study Design and Methods: The performances and safety of 300 SO sessions using the automatic depletion step (SO/DE) in 50 patients with sickle cell anemia under a chronic transfusion program over a 1-year period were prospectively analyzed. The numbers of RBCPs saved using this protocol compared to the SO device without depletion and to the CSP device were determined.Results: The SO/DE protocol appeared to be safe, as only 5% and 17% of the sessions were characterized by a significant decrease in blood pressure and increase in heart rate (grade 2 adverse events), respectively. Postapheresis hematocrit and fraction of cells remaining reached expected values. The SO/DE protocol required 16% fewer RBCPs compared to SO without depletion, allowing a mean saving of 12 RBCPs per patient and per year and 13% fewer compared to CSP device. Interestingly, the saving was more important for patients with high total blood volume and/or high preapheresis hematocrit.Conclusion: The SO/DE protocol is an efficient, safe and cost-effective procedure for patients with sickle cell anemia under a chronic transfusion program. [ABSTRACT FROM AUTHOR]

Background Ivermectin ( IVM) is widely used in both human and veterinary medicine to treat parasitic infections. Recent reports have suggested that IVM could also have anti-inflammatory properties. Methods Here, we investigated the activity of IVM in a murine model of atopic dermatitis ( AD) induced by repeated exposure to the allergen Dermatophagoides farinae, and in standard cellular immunological assays. Results Our results show that topical IVM improved allergic skin inflammation by reducing the priming and activation of allergen-specific T cells, as well as the production of inflammatory cytokines. While IVM had no major impact on the functions of dendritic cells in vivo and in vitro, IVM impaired T-cell activation, proliferation, and cytokine production following polyclonal and antigen-specific stimulation. Conclusion Altogether, our results show that IVM is endowed with topical anti-inflammatory properties that could have important applications for the treatment of T-cell-mediated skin inflammatory diseases. [ABSTRACT FROM AUTHOR]

Abstract: A critical step in the induction of allergic contact dermatitis is the interaction of haptens with immature dendritic cells (iDC) leading to their activation. Therefore iDC appear as suitable targets for the evaluation of the sensitizing properties of haptens with the aim of developing in vitro toxicologic methods. Here, using a low-density cDNA-array, we analyzed the expression of 165 genes related to dendritic cell biology in human iDC following a 24h incubation with four haptens representative of strong (DNBS), moderate (isoeugenol) and weak (eugenol, hydroxycitronellal) contact sensitizers and with one irritant sodium dodecyl sulphate (SDS). Results show that 21/165 iDC genes were significantly modulated by hapten treatment. Some genes were preferentially modulated by a given chemical. Thus, DNBS, isoeugenol, eugenol and hydroxycitronellal consistently modulated CCR5, CCL27, CCL2 and CCR7, respectively, whereas the CXCL10 gene was regulated by SDS. When subjected to principal component analysis, the 21 target genes fell into four groups associated with a particular type of chemical endowed with distinct sensitizing or irritant properties. Thus, gene profiling of iDC using low-density microarray allows, for screening of chemicals, the indentification of weak haptens with potential skin sensitizing properties. These results suggest that gene profiling of iDC using low-density microarrays may be useful to identify chemicals with weak skin sensitizing properties. [Copyright &y& Elsevier]