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Irritant contact dermatitis (ICD) is a frequent inflammatory skin disease induced by skin contact with low molecular weight chemicals such as haptens endowed with proinflammatory properties. Allergic contact dermatitis (ACD) is a frequent complication of ICD and is mediated by hapten-specific T cells primed in lymph nodes by skin emigrating dendritic cells. The aim of this study was to analyze the relationship between ICD and ACD to 2,4-dinitrofluorobenezene (DNFB) in C57BL/6 and BALB/C mice, which develop a severe and a moderate skin inflammation, respectively. Upon a single skin painting with DNFB, C57BL/6 developed within hours a more severe dose-dependent ICD response as compared to BALB/C mice, which was associated with enhanced upregulation of IL-1beta, IL-6, and IL-10. Skin exposure to a low dose of DNFB resulted, in both strains, in a low ICD that resolved in a few hours. Alternatively, skin painting with either an intermediate or a high DNFB concentration induced an ICD that subsequently gave rise to an ACD reaction whose intensity was proportional to the magnitude of the ICD response and was more severe in C57BL/6 mice than in BALB/C mice. In conclusion, the hapten-induced skin contact irritation conditions the development and the severity of ACD.

Skin lesions in the allergic form of atopic dermatitis (AD) are induced by allergen-specific T cells that infiltrate the skin at the site of allergen exposure. 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 analyzed the respective role of CD8+ and CD4+ T cells in the development of AD skin lesions in a mouse model of allergen-induced AD. 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.

Allergic contact dermatitis (ACD) to strong experimental haptens is mediated by specific CD8+ T cells. Here, we show that similar mechanisms occur for weak haptens, which comprise the vast majority of chemicals responsible for human ACD. We used a model of ACD, that is, the contact hypersensitivity reaction, to test for the allergenicity of three weak haptens involved in fragrance allergy. ACD to weak haptens could not be induced in normal mice. In contrast, mice acutely depleted in CD4+ T cells developed a typical ACD reaction to the three weak fragrance allergens that peaked 24 hours after challenge. Priming of CD8+ T cells was observed in draining lymph nodes 5 days after sensitization and development of ACD was associated with the infiltration of activated CD8+ T cells in the challenged skin. CD8+ T cells were effectors of the ACD reaction as in vivo treatment with depleting anti-CD8 mAbs abrogated the ACD responses and as purified CD8+ T cells could adoptively transfer ACD to naive recipients. In conclusion, our data demonstrate a dominant role of CD8+ T cells as initiators of ACD to weak haptens, and suggest that CD8+ T cells may represent potential targets for preventing or treating ACD.

Pathophysiological characteristics of these two types of eczema, both involve antigen specific effector T lymphocytes and down-regulatory CD4+ T cells (Treg). These cells are responsible for the cutaneous inflammatory response through the production of inflammatory cytokines and the destruction of keratinocytes by apoptosis. The main difference between these two types of disease is the nature of the environmental antigen. Indeed, protein allergens are involved in cases of atopic dermatitis whereas non protein chemicals (calles haptens) are responsible for allergic contact dermatitis. The skin lesions of eczema follow the activation of antigen specific T lymphocytes within the skin, leading to the production of inflammatory cytokines and to the destruction of keratinocytes by apoptosis. CD4+ Treg cells are endowed with down-regulatory and tolerogenic functions since they limit the skin inflammation in patients and prevent sensitization and induction of eczema in normal individuals. Eczema should therefore be considered as inflammatory dermatoses caused by the loss of immune tolerance to environmental antigens. Different strategies capable of restoring immune tolerance could avoid eczema outbursts and/or induce prolonged remissions of the disease.

Allergic contact dermatitis (ACD) is a skin inflammatory disease mediated by activation of CD8+ cytotoxic T cells specific for haptens in contact with the skin. CD4+ T cells behave as both regulatory and tolerogenic cells since they down-regulate the skin inflammation in patients with ACD (regulation) and prevent the development of eczema (tolerance) in normal individuals. Thus, ACD corresponds to a breakdown of immune tolerance to haptens in contact with the skin. Several regulatory CD4+ T cell subsets (Treg), especially CD4+CD25+ natural Treg cells, are involved in immunological tolerance and regulation to haptens through the production of the immunosuppressive cytokines IL-10 and TGF-beta. Ongoing strategies to re-induce immune tolerance to haptens in patients with eczema include improvement of existing methods of tolerance induction (oral tolerance, low dose tolerance, allergen-specific immunotherapy, UV-induced tolerance) as well as development of new drugs able to activate IL-10 producing Treg cells in vivo. Ongoing and future progress in this area will open up new avenues for treatment of eczema and more generally autoimmune and allergic diseases resulting from a breakdown of tolerance to autoantigens and allergens, respectively.

Allergic contact dermatitis, also referred to as contact hypersensitivity, is one the most frequent inflammatory skin diseases, and is characterized by redness, papule and vesicles, followed by scaling and dryness. Allergic contact dermatitis is elicited upon skin contact with nonprotein chemicals, haptens, and corresponds to a cutaneous delayed type hypersensitivity reaction, mediated by hapten-specific T-cells. During the sensitization phase, both CD4(+) and CD8(+) T-cell precursors are activated in the draining lymph nodes by presentation of haptenated peptides by skin dendritic cells. Subsequent hapten painting on a remote skin site induces the recruitment and activation of specific T-cells at the site of challenge. This leads to apoptosis of keratinocytes, recruitment of inflammatory cells and development of clinical symptoms. Experimental studies from the last 10 years have demonstrated that, in normal contact hypersensitivity responses to strong haptens, CD8(+) type 1 T-cells are effector cells of contact hypersensitivity through cytotoxicity and interferon-gamma production, while CD4(+) T-cells are endowed with downregulatory functions. The latter may correspond to the recently described CD4(+)CD25(+) regulatory T-cell population. However, in some instances, especially when there is a deficient CD8(+) T-cell pool, CD4(+) T-cells can be effector cells of contact hypersensitivity. Ongoing studies will have to confirm that the pathophysiology of human allergic contact dermatitis is similar to the mouse contact hypersensitivity and that the contact hypersensitivity response to common weak haptens, most frequently involved in human allergic contact dermatitis, is similar to that reported for strong haptens.

Mice deficient in the CD4 molecule (CD4-/-) are widely used to evaluate the requirement for CD4+ T cell help in viral, tumoral, and transplantation immunity. Previous studies, showing that CD4-/- mice develop impaired contact hypersensitivity (CHS) responses, have suggested that CD4+ T cells are required for the optimal induction of this skin inflammatory reaction. other studies have, however, demonstrated that CHS was mediated by CD8+ T cells, without the need for CD4+ T cell help. Here, we show that CD4-/- mice develop a normal delayed-type hypersensitivity response to protein antigen, which is mediated by major histocompatibility molecules class II-restricted CD4-CD8- T cells, but a decreased CHS response to 2,4-dinitro-fluorobenezene. Analysis of the hapten-specific T cell pool demonstrates that priming of CD8+ T cells occurred normally in CD4-/- mice, as assessed by specific proliferative responses and interferon-gamma (IFN-gamma) production of purified CD8+ T cells. Furthermore, CD8+ T cells were able to adoptively transfer a normal CHS reaction. In contrast, total lymph node cells from CD4-/- mice showed decreased IFN-gamma production and diminished specific cytotoxic T lymphocytes (CTL) activity, which could be reversed by in vitro restimulation with hapten-pulsed class II-deficient antigen-presenting cells. These data confirm that class I-restricted CD8+ T cells can fully develop in effectors of CHS in the absence of CD4+ T cell help and suggest that the impaired CHS in CD4-/- mice is because of the presence of a class II-restricted T cell subset, which controls CHS by inhibiting hapten-specific CTL responses.

CD4 regulatory cells have been postulated to prevent autologous graft-vs.-host disease (GVHD). In order to test this hypothesis, we used BALB/c mice, a strain known to be resistant to autologous GVHD, which had received autologous stem cell transplantation (ASCT) and cyclosporine A (CsA). As expected, ASCT/CsA-treated BALB/c mice did not develop any sign of acute or chronic GVHD. However, depletion of CD4 T cells induced a skin disease with clinical and histological features of alopecia areata (AA), a CD8 T-cell-mediated human autoimmune skin disease. The hair loss in mice developing AA was associated with the infiltration of the skin by activated CD8 T cells. Analysis of the T-cell recovery in ASCT- and ASCT/CsA-treated mice showed that CsA induced an increase in the number of CD4+ 25+ T cells, suggesting that the lack of GVHD in ASCT/CsA treated-mice could be related to the expansion of this CD4 T-cell subset. Collectively these data show that CD4 T cells comprise regulatory cells controlling the onset of autologous GVHD and suggest that the naturally occurring CD4+ 25+ subset may be responsible for this effect.

An epidemiological study of neuroblastoma in the Rhône-Alpes area was carried out over a 5 year period. The aim was to set up a background for a screening program in order to increase the number of neuroblastoma diagnosed in children before age 1, and decrease or eliminate advanced stage neuroblastomas.