Dendritic cells require T cells for functional maturation in vivo.
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We examined dendritic cell (DC) status in SCID and RAG2 -/- mice to assess the influence of T cells on DC development and function in vivo. These mice have reduced numbers of DC in the epidermis and lymph nodes draining hapten-sensitized skin. Epidermal DC in these mice were defective in presenting antigen in vivo to adoptively transferred, hapten-sensitized T cells from normal mice. Likewise, draining lymph node DC were deficient in their capacity to stimulate naive T cells in vitro and in vivo. DC numbers as well as the impaired ability to present antigen in vivo, were corrected by reconstituting these animals with normal T lymphocytes, suggesting that T cells are crucial for normal DC maturation and function in vivo. (+info)
Human CD4+ T lymphocytes with remarkable regulatory functions on dendritic cells and nickel-specific Th1 immune responses.
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The contribution of T helper (Th) and T cytotoxic (Tc) type 1 lymphocytes in the expression of allergic contact dermatitis to haptens has been amply documented. Conversely, the existence of T cell-based regulatory mechanisms has been poorly investigated. Here, we examined the properties of a subset of nickel-specific CD4+ T cells displaying the cytokine profile (IL-10 , IL-5 , IFN-gamma+/-, IL-4+/-) of T regulatory cells 1 (Tr1) and with the potential to down-modulate immune responses to nickel. Tr1 clones were isolated from skin challenged with NiSO4 and peripheral blood of nickel-allergic patients, and from the blood of healthy individuals. Tr1 clones expressed CD25, CD28, CD30, CD26, and the IL-12 receptor beta2 chain upon activation, whereas the lymphocyte activation antigen-3 was present on 50% of the clones. Monocytes precultured with Tr1 cells in the presence of nickel, or treated with Tr1-derived supernatant, exhibited a markedly diminished capacity to stimulate nickel-specific Th1 responses. Tr1 supernatants also blocked the differentiation of dendritic cells (DC) from monocytes, as well as DC maturation and IL-12 production induced by lipopolysaccharide. As a consequence, the ability of DC to stimulate nickel-specific Th1 and Tc1 responses was greatly impaired. These inhibitory effects were completely prevented by IL-10, but not IL-5, neutralization. In aggregate, the results indicate that Tr1 cells can potently regulate the expression of Th1-mediated allergic diseases via release of IL-10. (+info)
Different role of IL-4 in the onset of hapten-induced contact hypersensitivity in BALB/c and C57BL/6 mice.
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1. To study the role of interleukin (IL)-4 in the onset of contact hypersensitivity (CH) in mice, the effect of IL-4 gene-depletion and anti-IL-4 monoclonal antibody treatment on dinitrofluorobenzene (DNFB)-induced CH was examined. Simultaneously, to clarify the effect of background gene, DNFB-induced CH in BALB/c and C57BL/6 mice was compared. 2. Five repeated topical applications of DNFB to the ears of mice resulted in CH of the ears in terms of increases in ear thickness and histopathological changes. The magnitude of ear thickness increase in BALB/c mice was almost three times greater than that in C57BL/6 mice. 3. The CH in BALB/c mice was significantly suppressed by IL-4 gene-depletion and anti-IL-4 monoclonal antibody treatment. In contrast, the symptoms of dermatitis in C57BL/6 mice were slightly affected by the same treatment. These changes corresponded well to the production of specific IgE antibody. 4. Total IgE antibody production and the expression of productive Cepsilon mRNA were dramatically suppressed by IL-4 gene-depletion and anti-IL-4 treatment in BALB/c and C57BL/6 mice. Neither total IgG nor IgM levels in either strain of mice was altered by depletion of IL-4. 5. The expression of IFN-gamma in the skin lesion was dramatically suppressed by IL-4 gene-depletion in BALB/c mice, but not in C57BL/6 mice. 6. These findings indicate that IL-4 plays an important role in the onset of DNFB-induced CH in BALB/c mice, but not in C57BL/6 mice. (+info)
Contact allergy in Singapore.
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Contact allergy, viz. allergic contact dermatitis, photo-allergic contact dermatitis and contact urticaria, is a well-studied sub-specialty of dermatology in Singapore. Over the years, numerous studies and anecdotal reports on the subject have been published in both international and local refereed journals. This article reviews the epidemiological data on patch testing and photo-patch testing in Singapore. It also summarizes published clinical reports on important contact allergens that are found in both non-occupational and occupational setting. (+info)
Regulation of inflammation by collagen-binding integrins alpha1beta1 and alpha2beta1 in models of hypersensitivity and arthritis.
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Adhesive interactions play an important role in inflammation by promoting leukocyte attachment and extravasation from the vasculature into the peripheral tissues. However, the importance of adhesion molecules within the extracellular matrix-rich environment of peripheral tissues, in which cells must migrate and be activated, has not been well explored. We investigated the role of the major collagen-binding integrins, alpha1beta1 and alpha2beta1, in several in vivo models of inflammation. mAb's against murine alpha1 and alpha2 were found to significantly inhibit effector phase inflammatory responses in animal models of delayed-type hypersensitivity (DTH), contact hypersensitivity (CHS), and arthritis. Mice that were alpha1-deficient also showed decreased inflammatory responses in the CHS and arthritis models when compared with wild-type mice. Decreased leukocyte infiltration and edema formation accompanied inhibition of antigen-specific models of inflammation, as nonspecific inflammation induced by croton oil was not inhibited. This study demonstrates the importance in vivo of alpha1beta1 and alpha2beta1, the collagen-binding integrins, in inflammatory diseases. The study also extends the role of integrins in inflammation beyond leukocyte attachment and extravasation at the vascular endothelial interface, revealing the extracellular matrix environment of peripheral tissues as a new point of intervention for adhesion-based therapies. (+info)
Allergens and irritants transcriptionally upregulate CD80 gene expression in human keratinocytes.
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The human CD80 costimulatory molecule is an important signal between professional antigen-presenting cells and T helper cells. The immunobiology of CD80 expression by keratinocytes, especially during allergic and irritant contact dermatitis, however, is less well understood. CD80 cell surface expression and gene transcription by keratinocytes was increased when keratinocytes were exposed to certain allergens (chemicals that induce inflammation via hapten-specific T cells) and irritants (chemicals that are toxic to epidermal cells). Therefore, the human CD80 promoter was cloned and luciferase reporter constructs containing various promoter fragments were engineered. Promoter mapping of these CD80 constructs in transiently transfected keratinocytes showed that a construct containing the proximal 231 bp immediately upstream of the transcription start site of the CD80 promoter was most active in keratinocytes and was inducible to a level ranging from 2- to 10-fold higher in keratinocytes treated with certain allergens and irritants, compared with untreated keratinocytes. This pattern of promoter fragment activity in keratinocytes is identical to that found in professional antigen-presenting cells. This is the first demonstration that the CD80 promoter is active in keratinocytes and that this activity is further increased in keratinocytes treated with certain allergens and irritants. These data suggest that allergens and irritants may, in part, break peripheral tolerance by their direct effects on keratinocyte costimulatory molecule expression, thereby facilitating interactions with epidermotropic T helper cells via the CD80-CD28 or CTLA-4 pathways. (+info)
A role for bioactivation and covalent binding within epidermal keratinocytes in sulfonamide-induced cutaneous drug reactions.
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Cutaneous reactions are the most common manifestation of delayed-type hypersensitivity caused by sulfamethoxazole and dapsone. In light of the recognized metabolic and immunologic activity of the skin, we investigated the potential role of normal human epidermal keratinocytes in the development of these reactions. Adult and neonatal normal human epidermal keratinocytes metabolized sulfamethoxazole and dapsone to N-4-hydroxylamine and N-acetyl derivatives in a time-dependent manner. The latter was catalyzed by N-acetyltransferase 1 alone as normal human epidermal keratinocytes did not express mRNA for N-acetyltransferase 2. Investigation of metabolism-dependent toxicity of sulfamethoxazole and dapsone, and subsequent incubation of normal human epidermal keratinocytes with the respective hydroxylamine metabolites, demonstrated that these cells were resistant to the cytotoxic effects of sulfamethoxazole hydroxylamine but not dapsone hydroxylamine. With prior depletion of glutathione, however, normal human epidermal keratinocytes became susceptible to the toxicity of sulfamethoxazole hydroxylamine. Covalent adduct formation by sulfamethoxazole hydroxylamine was detected in normal human epidermal keratinocytes, even in the absence of cell death, and was increased with glutathione depletion. Major protein targets of sulfamethoxazole hydroxylamine were observed in the region of 160, 125, 95, and 57 kDa. Dapsone hydroxylamine also caused covalent adduct formation in normal human epidermal keratinocytes. Together, these observations provide a basis for our hypothesis that normal human epidermal keratinocytes are involved in the initiation and propagation of a cutaneous hypersensitivity response to these drugs. (+info)
Occupational contact dermatitis to Phaseolus vulgaris in a farmer - a case report.
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A case of occupational contact dermatitis in a farmer is described, caused among others by Phaseolus vulgaris. The patient's history of eczematous and vesicular and bullous skin reactions occurring after exposure to Phaseolus was confirmed by skin tests with native leaves of the plant. To the best of our knowledge, this is the first description of occupational contact dermatitis caused by leaves of Phaseolus plant. (+info)