Effect of Chrysanthemi borealis flos on atopic dermatitis induced by 1-chloro 2,4-dinitrobenzene in NC/Nga mouse

The flower of Chrysanthemum boreale has traditionally been used for treatment of various inflammatory disease including atopic dermatitis (AD). However, its action on AD is unclear. Therefore, we investigated the effect of CB on AD using NC/Nga mice as an AD model. The effect of CB on 1-Chloro-2,4-dinitrobenzene (DNCB) induced NC/Nga mice was evaluated by examining skin symptom severity, itching behavior, ear thickness, levels of serum Immunoglobulin E (IgE), tumor necrosis factor-α (TNF-α), and interleukin-4 (IL-4), skin histology. The CB significantly reduced the total clinical severity score, itching behavior, ear thickness and the level of serum IgE in AD mouse model. CB not only decreased TNF-α but also IL-4. These results suggest that CB may be a potential therapeutic modality for AD.     

Inhibitory effects of Schizandra chinensis extract on atopic dermatitis in NC/Nga mice

Context: Schizandra chinensis Baillon (SC) is traditionally used as a medicinal plant in the Orient. Recently, SC has become recognized as an adaptogen by the mainstream medical community. Phytoadaptogens influence respiratory, cardiovascular, uterus myotonic, and immune activities. Atopic dermatitis (AD) is an allergic inflammatory skin disease caused by aberrant and over-reactive immune responses.

Objective: This study assessed the suppressive effect of SC extract (SCE) on 1-chloro-2,4-dinitrobenzene (DNCB)-induced AD in a NC/Nga mouse model.

Materials and methods: AD was induced by topically applying 0.2% DNCB to the hairless-back of NC/Nga mice for 4 weeks. Treated mice received SCE or dexamethasone after AD induction.

Results: SCE markedly suppressed DNCB-induced dermatitis, as determined by a count of scratching frequency; measurement of IgE, IgM, and histamine levels in serum; and histological observation of epidermal hyperplasia and mast-cell infiltration. Additionally, SCE lessened DNCB-induced histamine receptor mRNA expression in skin tissue and the splenic expressions of interleukin (IL)-4, IL-5, and high-affinity IgE receptor B protein.

Conclusion: SCE appears useful for suppression of AD, even though the active pathway(s) remain unknown.     

Physiological effects of brominated flame retardants on NC/Nga mice

Purpose: Brominated flame retardants (BFRs) are used as an additive or reactive components in various materials. Regarding their health concerns, their immunotoxicity have not been clarified yet.

Materials and methods: In the current study, we examined the effects of systemic exposure to two types of BFRs, DE71 and DE79, on pathophysiologic traits of murine atopic dermatitis (AD). Male NC/Nga mice were repeatedly injected intraperitoneally with DE71 and DE79 and/or mite allergen (Dermatophagoides pteronyssinus: Dp) into their right ears. Thereafter, clinical scores, macroscopic findings of inflammatory foci, and Ig values in serum were examined.

Results: Both DEs significantly aggravated clinical scores induced by mite allergen including skin dryness and edema. Total IgE titer was significantly greater in the Dp?+?DE79 group than in the Dp group.

Conclusions: Taken together, exposure to BFRs can exacerbate AD-like skin lesions related to mite allergen in mice. The accentuating effects may be mediated, at least in part, through hyperproduction of IgE.     

Transforming growth factor‐bβ1 suppresses atopic dermatitis‐like skin lesions in NC/Nga mice

BACKGROUND: Atopic dermatitis is a chronic, relapsing inflammatory disorder characterized by pruritic and eczematous skin lesions. Transforming growth factor (TGF)-beta1 has been implicated in the suppression of inflammatory responses. OBJECTIVE: The purpose of this study is to determine whether TGF-beta1 suppresses skin lesions in a mouse model of atopic dermatitis. METHODS: We used the NC/Nga strain of mice as an in vivo model of atopic dermatitis. The effects of exogenous TGF-beta1 on atopic dermatitis-like skin lesions in NC/Nga mice were evaluated clinically, histologically and immunologically. RESULTS: Subcutaneous injection of recombinant TGF-beta1 macroscopically suppressed eczematous skin lesions in NC/Nga mice associated with reduced serum immunoglobulin E (IgE) levels. Histological analysis showed that TGF-beta1 significantly inhibited the infiltration of inflammatory cells such as mast cells and eosinophils into the skin of NC/Nga mice. Spontaneous interferon (IFN)-gamma production from splenocytes of NC/Nga mice was down-regulated by the treatment with TGF-beta1 and neutralizing antibody against IFN-gamma inhibited skin lesions in NC/Nga mice. The inhibitory effect of TGF-beta1 on the skin lesions lasted at least 1 week after cessation of the treatment. CONCLUSION: These findings indicate that TGF-beta1 suppressed atopic dermatitis-like skin lesions in NC/Nga mice at least in part through down-regulation of IFN-gamma. These results suggest that TGF-beta1 may have a therapeutic potential for atopic dermatitis.     

Sclareol attenuates the development of atopic dermatitis induced by 2,4-dinitrochlorobenzene in mice

Context: Atopic dermatitis is a common chronic inflammatory skin disease affecting up to 20% of children and 1% of adults worldwide. Treatment of atopic dermatitis include corticosteroids and immunosuppressants, such as calcineurin inhibitors and methotrexate. However, these treatments often bring about adverse effects including skin atrophy, osteoporosis, skin cancer, and metabolic syndrome.

Objective: In this study, we evaluated the therapeutic effects and mechanisms of sclareol, a natural diterpene, on atopic dermatitis (AD)-like skin lesions induced by 2,4-dinitrochlorobenzene (DNCB) in mice.

Materials and methods: To evaluate the effect of sclareol in vivo model, BALB/c mice were repeatedly injected intraperitoneally with sclareol (50 and 100?mg/kg) in 2,4-dinitrochlorobenzene (DNCB)-induced AD-like murine model. Major assays were enzyme-linked immunosorbent assay, histological analysis, flow cytometry, western blot analysis.

Results: Intraperitoneal administration of sclareol (50 and 100?mg/kg) significantly attenuated AD-like symptoms, such as serum IgE levels, epidermal/dermal hyperplasia, and the numbers of infiltrated mast cells. In addition, systemic sclareol treatments reduced local pro-inflammatory cytokine concentrations, including IL-6, IL-1b, TNF-a, IL-4, IFN-g, and IL-17A, on AD-like lesions. Furthermore, we demonstrated that sclareol also suppressed T cell activation and the capability of cytokine productions (IFN-g, IL-4 and IL-17A) in response to DNCB stimulation. By examining the skin homogenate, we found that sclareol inhibited the AD-like severity likely through suppressions of both NF-kB translocation and phosphorylation of the MAP kinase pathway.

Discussion and conclusions: Cumulatively, our results indicate that sclareol induced anti-inflammatory effects against the atopic dermatitis elicited by DNCB. Thus, sclareol is worth of being further evaluated for its potential therapeutic benefits for the clinical treatment of AD.     

Ingestion of heat-treated Lactobacillus rhamnosus GG prevents development of atopic dermatitis in NC/Nga mice

Background Continuous oral administration of live Lactobacillus rhamnosus GG (L. GG) to pregnant subjects with atopic dermatitis and their children, suppressed the frequency of atopic dermatitis. The details of mechanisms and immune systems involved in this suppressive effect, however, remain speculative. Objective We sought to clarify suppressive mechanisms of L. GG on atopic dermatitis by using NC/Nga mice, a model of human atopic dermatitis. Methods Maternal mice and infant mice were fed with food containing or not containing heat‐treated L. GG during pregnancy and breastfeeding, and after weaning. Results Control NC/Nga mice raised under an air‐uncontrolled condition spontaneously manifested typical skin lesions very similar to those in patients with atopic dermatitis. On the other hand, administration of food containing heat‐treated L. GG inhibited the onset and development of atopic skin lesions, accompanied by smaller numbers of mast cells and eosinophils in the affected skin sites. Mice fed with L. GG showed a significant increase in plasma IL‐10 levels compared with control mice, while there was no significant difference in the proportion of splenic CD4⁺CD25⁺ regulatory T cells between mice fed with L. GG and control mice. The IL‐10 mRNA expression was enhanced in both Peyer's patches and mesenteric lymph nodes in mice fed with L. GG. Conclusion These findings suggest that some components of heat‐treated L. GG may have an ability to delay the onset and suppress the development of atopic dermatitis, probably through a strong induction of IL‐10 in intestinal lymphoid organs and systemic levels.     

Serum and monoclonal immunoglobulin E antibodies from NC/Nga mice with severe atopic-like dermatitis recognize an auto-antigen, histone H3

Background NC/Nga mice are known to show a spontaneous outbreak of atopic‐like dermatitis accompanied by a marked elevation in serum IgE levels when reared in a conventional environment. The specific effects of such a strong serum IgE response on the development of the dermatitis and specific antigens recognized by the IgE antibodies are still uncertain. Objective and methods To characterize the IgE of NC/Nga mice, we established IgE‐secreting hybridoma clones from spleen cells of NC/Nga mice spontaneously developing dermatitis and identified variable‐region genes and specific antigens of the IgE monoclonal antibodies (mAbs). Serum polyclonal IgE, as well as IgG1 and IgG2a, specific for the identified antigen were also analysed. Results Four IgE‐producing hybridoma clones were established. Variable‐region nucleotide sequences of the IgE mAbs showed that these clones did not necessarily share common germline gene segments (V, D or J) for each variable region, and several somatic mutations had occured in the V gene segments. Through antigen screening, histone H3 was identified to be an auto‐antigen recognized by three of the four IgE mAbs. Serum IgE as well as IgG1 specific for histone H3 were almost undetectable in 6‐week‐old mice, but rapidly increased by 10–12 weeks of age. This age‐dependent increase in the serum anti‐histone H3 IgE was roughly in parallel with the onset of dermatitis, and slightly preceding total IgE elevation. The serum‐specific IgE level correlated well with a dermatitis‐severity score of each mouse at 12–16 weeks of age, and weakly with the severity of ear erosion of each mouse over 28 weeks of age. Furthermore, immunologically detectable histone‐H3 antigens were observed in skin tissue sections from the dermatitis sites. Conclusion In NC/Nga mice, anti‐histone H3 auto‐antibodies may contribute, at least in part, to the considerably elevated serum IgE and might play some roles in the development and exacerbation of dermatitis.     

Role of immunoglobulin E sensitization in eczema,previously referred to as atopic dermatitis

This review aims to clarify existing knowledge on the relationship between eczema and immunoglobulin (Ig)E sensitization. Over the years this debate has been complicated by unclear definitions of what constitutes an atopic individual. The new, uniform allergy nomenclature introduced by the European Academy of Allergology and Clinical Immunology and the World Allergy Organization uses the term eczema to denote what was previously known as ‘atopic dermatitis’ or ‘atopic eczema’. Despite detailed knowledge of localized IgE–allergen interactions at the level of the skin, the exact role of IgE and IgE antibody sensitization in the disease process remains widely debated. The association between IgE sensitization and eczema has been clearly demonstrated in population-based studies. There is, however, variation in the strength of the association between IgE sensitization and eczema in hospital versus community studies. While IgE sensitization is not a useful disease discriminator, once other factors have been taken into account, knowledge of atopic status appears to have prognostic value in children with eczema, since IgE sensitization is associated with an increased risk of developing allergic respiratory disease later in life. These children may also experience a more persistent and severe disease.     

Upregulation of IgE synthesis by staphylococcal toxic shock syndrome toxin-1 in peripheral blood mononuclear cells from patients with atopic dermatitis

Background Atopic dermatitis (AD) is a chronic skin disease associated with increased IgE synthesis and colonization with Staphyiococcus aureus secreting exotoxins, such as Toxic Shock Syndrome Toxin-1 (TSST-1). Objectives In this study, we were interested in determining the in vitro effects of TSST-1 on IgE synthesis in peripheral blood mononuclear cells from patients with AD. Methods We stimulated peripheral blood mononuclear cells (PBMC) from AD patients with a wide range of TSST-1 concentrations and measured IgE synthesis by enzyme-linked immunosorbent assay (ELISA) after 14 days. Results We show herein that TSST-1 produced antagonistic effects on IgE synthesis by PBMC from AD patients, depending on the concentration used: IgE synthesis was inhibited at 1000 pg/mL (P<0.05) and enhanced at 0.01 pg/mL (P<0.01) of toxin. TSST-1 was found to induce the production of much higher amounts of interferon-gamma (IFNγ) at 1000 pg/mL than at 0.01pg/mL of toxin (P= 0.0001). More importantly, immunoglobulin E (IgE) synthesis was enhanced by TSST-1 at 1 pg/mL in the presence of antibodies blocking IFN-γ activity. The other immunoglobulin (Ig) isotypes were also increased after TSST-1 stimulation suggesting that the enhanced IgE synthesis was secondary to a polyclonal B cell activation rather than an isotype switch. TSST-1-stimulated IgE synthesis was T cell-dependent because purified tonsil B cells were only able to synthesize increased amounts of IgE when small numbers of T cells were added to the cultures. Anti-HLA-DR and anti-LFA-1 monoclonal antibodies (MoAb) inhibited TSST-1-enhanced IgE synthesis, suggesting that the bridging of the T cell receptor (TCR) and major histocompalibilily complex (MHC) class II on B cells was necessary for activation of B cell differentiation. Conclusion These data indicate that staphylococcal superantigens are able, at concentrations inducing low amounts of IFNγ, to stimulate IgE synthesis by PBMC from AD patients, and suggest that staphylococcal toxins may contribute to elevated IgE synthesis in AD.     

Randomized, placebo-controlled trial of Lactobacillus rhamnosus GG as treatment of atopic dermatitis in infancy

BACKGROUND: Some studies have suggested that supplementation of food with lactobacilli may prevent or improve atopic dermatitis in children. This study was designed to investigate the therapeutic effect of Lactobacillus rhamnosus GG (LGG) as a food supplement in infants suffering from atopic dermatitis. METHODS: Infants aged 3-12 months suffering from mild-to-moderate atopic dermatitis (severity scoring of atopic dermatitis or SCORAD index of 15-40) without current antiinflammatory treatment were randomized to receive LGG (5 x 10(9) colony forming units b.i.d.) or placebo as a food supplement for 12 weeks. Severity scoring of atopic dermatitis index and use of hydrocortisone 1% ointment as rescue medication (2 points per application) were recorded at 4, 8, and 12 weeks of treatment and combined as symptom load (SL). RESULTS: Fifty-four infants (LGG group, mean +/- SD SCORAD index 24.6 +/- 8.8) and 48 infants (placebo group, SCORAD index 23.6 +/- 7.8) were randomized and completed the treatment period (intention-to-treat analysis). Symptom load generally improved over time at 4 weeks (LGG vs placebo, 23.8 +/- 12.4 vs 20.6 +/- 9.9), 8 weeks (22.5 +/- 14.6 vs 17.9 +/- 13.1), and 12 weeks (19.6 +/- 15.4 vs 15.1 +/- 12.1), without statistically significant group differences. When stratified for age, eczema severity or use of rescue medication, no statistically significant group differences, in improvement, were found. No significant group differences were found for the use of rescue medication (0.8 +/- 45.0 g vs 3.5 +/- 29.8 g), increase in mean logarithmic total serum IgE (0.17 +/- 0.30 kU/l vs 0.26 +/- 0.45 kU/l), and newly developed allergic sensitization against hen's egg or cow's milk (18.8%vs 10.0%). CONCLUSION: This placebo-controlled trial showed no therapeutic effect of LGG against mild-to-moderate atopic dermatitis in infancy.     

Increased levels of urinary leukotriene E4 in children with severe atopic eczema/dermatitis syndrome

BACKGROUND: Leukotrienes are thought to play a role in the pathogenesis of atopic eczema/dermatitis syndrome (AEDS). Urinary leukotriene E4 (U-LTE4) is a marker of whole-body cysteinyl-leukotriene production. AIMS OF THE STUDY: To evaluate the role of leukotrienes in children with AEDS by measuring levels of U-LTE4, and to evaluate whether levels of U-LTE4 may reflect disease activity and allergic sensitization in AEDS. METHODS: U-LTE4 was measured by enzyme-linked immunosorbent assay in 87 children with mild (n=32), moderate (n=34) and severe (n=21) AEDS, as well as in 72 nonatopic healthy controls. Fifty-eight of the children with AEDS were sensitized to common allergens, and 29 were not. RESULTS: Levels of U-LTE4 were higher in children with severe AEDS (140; 66-166 microg/mmol creatinine, median; quartiles) than in controls (52; 30-90, P <0.05), whereas levels of U-LTE4 in moderate and mild disease were similar to controls. U-LTE4 levels were similar in children with or without sensitization to common allergens, but severe AEDS children with sensitization had higher levels of U-LTE4 than those without sensitization. CONCLUSION: The results suggest a role for leukotrienes in the pathogenesis of severe AEDS, and may support a role for leukotriene-antagonists in the treatment of this disorder. Levels of U-LTE4 may reflect the disease severity and sensitization to allergens in AEDS.     

The effect of matured date palm tree (Phoenix dactylifera L.) fruit extract on mite-induced allergic symptoms in NC/Nga mice

The effect of a hot water extract of matured date palm tree fruit on allergic responses was investigated in NC/Nga mice. The allergic score was significantly reduced in the mice fed a date palm tree fruit extract-added diet than the fruit extract-free diet. The levels of serum antigen-specific immunoglobulin E and spleen interleukin (IL)-4⁺CD4⁺ cells were significantly lowered in the mice fed the fruit extract-added diet. Bruton's tyrosine kinase (Btk) and IL-2-inducible T cell kinase (Itk) mRNA expressions in spleen cells were significantly lowered in the mice fed the fruit extract-added diet. Moreover, chlorogenic acid and pelargonin decreased these mRNA expressions in C3H/HeN mouse spleen cell cultures. These results suggest that the date palm tree fruit extract may reduce allergic symptoms in mice via a decrease in the number of type 2 helper T (Th2) cells, and a suppression of the expression of kinases involved in mast cell degranulation and Th2 cell differentiation.     

Detection of respiratory allergies caused by environmental chemical allergen via measures of hyper-activation and degranulation of mast cells in lungs of NC/Nga mice

Respiratory allergy triggered by exposure to environmental chemical allergen is a serious problem in many Asian countries and has the potential to cause severe health problems. Here, we aimed to elucidate the pathogenic mechanisms of this disease and develop an in vivo detection method for respiratory allergy induced by environmental chemical allergen. Both BALB/c and NC/Nga mice were sensitized topically for 3 weeks and were then subjected to inhalation challenge with pulverized trimellitic anhydride into particles measuring 2-μm in diameter. On the day after the final challenge, all mice were sacrificed, and IgE levels, immunocyte counts, and cytokine levels in the serum, hilar lymph nodes, and bronchoalveolar lavage fluid were measured. We also monitored the expression of genes encoding pro-inflammatory cytokines in the lung. We found that all endpoints were significantly increased in mice of both strains subjected to trimellitic anhydride inhalation as compared with the respective control groups. However, worsening of respiratory status was noted only in NC/Nga mice. Interestingly, type 2 helper T-cell reactions were significantly increased in BALB/c mice compared with that in NC/Nga mice. In contrast, the number of mast cells, levels of mast cell-related cytokine/chemokines, and production of histamine in NC/Nga mice were significantly higher than those in BALB/c mice. Thus, environmental chemical allergen induced respiratory allergy in NC/Nga mice in terms of functional and inflammatory symptoms. Furthermore, mast cells may be involved in the aggravation of airway allergic symptoms induced by environmental chemical allergens.