ovalbumin and calcipotriene

Mouse models for atopic dermatitis (AD) are an indispensable preclinical research tool for testing new candidate AD therapeutics and for interrogating AD pathobiology in vivo. In this Viewpoint, we delineate why, unfortunately, none of the currently available so-called "AD" mouse models satisfactorily reflect the clinical complexity of human AD, but imitate more "allergic" or "irriant" contact dermatitis conditions. This limits the predictive value of AD models for clinical outcomes of new tested candidate AD therapeutics and the instructiveness of mouse models for human AD pathophysiology research. Here, we propose to initiate a rational debate on the minimal criteria that a mouse model should meet in order to be considered relevant for human AD. We suggest that valid AD models should at least meet the following criteria: (a) an AD-like epidermal barrier defect with reduced filaggrin expression along with hyperproliferation, hyperplasia; (b) increased epidermal expression of thymic stromal lymphopoietin (TSLP), periostin and/or chemokines such as TARC (CCL17); (c) a characteristic dermal immune cell infiltrate with overexpression of some key cytokines such as IL-4, IL-13, IL-31 and IL-33; (d) distinctive "neurodermatitis" features (sensory skin hyperinnervation, defective beta-adrenergic signalling, neurogenic skin inflammation and triggering or aggravation of AD-like skin lesions by perceived stress); and (e) response of experimentally induced skin lesions to standard AD therapy. Finally, we delineate why humanized AD mouse models (human skin xenotransplants on SCID mice) offer a particularly promising preclinical research alternative to the currently available "AD" mouse models.

Topics: Animals; Biomarkers; Calcitriol; Dermatitis, Atopic; Disease Models, Animal; Haptens; Humans; Mice; Ovalbumin; Skin Physiological Phenomena

To explore whether ozonated oil recovery atopic dermatitis (AD) via immunoregulation.. Mice were repeatedly challenged with the triplex allergens of staphylococcal enterotoxin B, ovalbumin and calcipotriol ointment on the back to develop AD lesions, and were treated with ozonated oil. The lesional skins were scanned by reflectance confocal microscopy to measure the thickness of epidermis. The skin tissues were stained. Th1-type and Th2-type cytokines in serum and in tissues were detected by ELISA and real-time PCR, respectively.. Ozonated oil significantly inhibited inflammation and healed the lesions in 7 d. Ozonated oil inhibited NGF expression as compared to the groups treated with vehicle or PBS (p < .01).The serum proteins and lesional transcripts of Th2 cytokines including IL-4 and IL-31 were lower in the ozonated oil treated group than the groups treated with vehicle or PBS (p < .05). The IL-10 level was increased with treatment of ozonated oil (p < .01). On the other hand, the expressions of Th1 cytokines including IL-2, TNF-α, and IFN-γ in the serum were not regulated by ozonated oil.. Our results showed that ozonated oil could suppress inflammation in an AD murine via decreasing Th2-dominant cytokines response and increasing IL-10 expression. These suggest that ozonated oil may be a potential remedy for AD.

Topics: Allergens; Animals; Calcitriol; Cytokines; Dermatitis, Atopic; Enterotoxins; Interleukin-10; Mice; Mice, Inbred BALB C; Ovalbumin; Ozone; Plant Oils; Skin; Th2 Cells

TSLP is an important trigger and initiator for various atopic diseases mainly atopic dermatitis (AD). Activators of nuclear hormone receptors like bioactive vitamin A and D derivatives are known to induce TSLP up-regulation in the skin. In this study, various combinations of synthetic specific agonists and antagonists of the retinoic acid receptors (RARs), retinoid X receptors (RXRs) and vitamin D receptor (VDR) were topically administered to mice. The aim of the study was to elucidate via which nuclear hormone receptor pathways TSLP is regulated and how this regulation is connected to the development and phenotype of atopic dermatitis. TSLP expression was monitored using QRT-PCR and serum TSLP levels using ELISA. Synthetic agonists of the VDR and RARγ as well as the natural agonist all-trans retinoic acid (ATRA) increased TSLP expression in the skin, while an RXR agonist was not active. Treatments with antagonists of RXRs and RARs in addition to RARα-agonists reduced skin TSLP expression. Strong activation was found after a combination of a VDR and an RXR agonist (ca. 5 times induction) and even stronger by an RARγ and an RXR agonist treatment (ca. 48 times induction). We conclude that besides VDR-mediated signaling mainly RARγ-RXR mediated pathways in the skin are important patho-physiological triggers for increased skin TSLP expression. We conclude that topical synthesized retinoids stimulated by internal or external triggers or topically applied induce TSLP production and are thereby important triggers for atopic dermatitis prevalence.

Topics: Adolescent; Adult; Animals; Calcitriol; Coumaric Acids; Cytokines; Dermatitis, Atopic; Female; Gene Expression Regulation; Humans; Immunization; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Organic Chemicals; Ovalbumin; Receptors, Calcitriol; Receptors, Retinoic Acid; Retinoic Acid Receptor gamma; Retinoid X Receptors; Signal Transduction; Skin; Tetrahydronaphthalenes; Thymic Stromal Lymphopoietin; Tretinoin

Thymic stromal lymphopoietin (TSLP) is a key factor in the development of allergic asthma. Numbers of TH2 memory cells gradually increase in allergic patients with the progression of disease and persist in the lungs during remission, although the mechanism is not clear.. We sought to define the role of TSLP in TH2 memory cell generation and maintenance in vivo.. Adoptive transfer of wild-type and thymic stromal lymphopoietin receptor (TSLPR)-deficient ovalbumin-specific CD4(+) T cells before TH2 sensitization was used to define T cell-specific TSLP effects. Atopic dermatitis and increased serum TSLP concentrations were induced by topical application of the vitamin D3 analog MC903. Memory cells in peripheral blood were monitored weekly with flow cytometry. Memory recall was tested after intranasal ovalbumin challenge.. TSLP signaling in CD4(+) T cells is required for the generation/maintenance of memory cells after in vivo priming. TSLPR-deficient CD4(+) T cells have no defects in proliferation but do not survive 1 week after sensitization, and increased TSLP expression during sensitization significantly increased the frequency of memory cells. Although in vitro-differentiated TSLPR-deficient TH2 cells develop into memory cells with equal efficiency to wild-type cells, the recall response to airway antigen challenge is impaired. Moreover, after antigen challenge of mice with established TH2 memory, TSLP signaling in CD4(+) T cells significantly affects memory cell generation/maintenance from secondary effector cells.. TSLP signaling in CD4(+) T cells is required for not only TH2 memory cell formation in vivo but also the recall response of the memory cells to local antigen challenge.

Topics: Adaptive Immunity; Animals; Antigens, CD; Bronchoalveolar Lavage Fluid; Calcitriol; Cell Differentiation; Cytokines; Dendritic Cells; Dermatitis, Atopic; Female; Gene Expression Regulation; Immunity, Innate; Immunologic Memory; Lung; Mice; Mice, Inbred BALB C; Mice, Transgenic; Ovalbumin; Signal Transduction; Th2 Cells; Thymic Stromal Lymphopoietin

1,25-Dihydroxyvitamin D(3) is immunosuppressive both in vivo and in vitro. Topical vitamin D analogs such as calcipotriol alter keratinocyte function, but their effects on cutaneous immune responses are less well understood. We demonstrate that exposure of the skin to calcipotriol before transcutaneous immunization with OVA protein and CpG adjuvant prevents Ag-specific CD8(+) T cell priming coincident with Langerhans cell depletion in the skin. Immunization through calcipotriol-treated skin induces CD4(+)CD25(+) regulatory T cells (Treg) that prevent subsequent Ag-specific CD8(+) T cell proliferation and IFN-gamma production. Treg induced by calcipotriol are able to inhibit the induction and the elicitation of protein contact hypersensitivity. Topical calcipotriol treatment also induces RANKL (receptor activator of NF-kappaB ligand) expression by keratinocytes, a TNF family member involved in modulation of skin dendritic cells. UV light B induces Ag-specific tolerance when it is applied before transcutaneous immunization. We suggest that UV light B-induced tolerance is induced via a vitamin D receptor-dependent mechanism as vitamin D receptor (VDR) knockout mice fail to increase FoxP3(+) Treg in their peripheral draining lymph node following irradiation. Additionally, keratinocytes of VDR(-/-) mice fail to induce RANKL upon UV irradiation or calcipotriol treatment. The in vivo expansion of Ag-specific Treg with the topical application of the vitamin D analog calcipotriol followed by transcutaneous immunization is a simple method to augment functional Ag-specific CD4(+)CD25(+)Foxp3(+) Treg populations and mimics Ag-specific UV-induced tolerance.

Topics: Administration, Topical; Allergens; Animals; Calcitriol; CD8-Positive T-Lymphocytes; Dermatologic Agents; Flow Cytometry; Immune Tolerance; Immunohistochemistry; Keratinocytes; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; RANK Ligand; Receptors, Calcitriol; Skin; T-Lymphocytes, Regulatory; Ultraviolet Rays; Vitamin D