Atopic dermatitis-like symptoms in hypomagnesaemic hairless rats are prevented and inhibited by systemic or topical SDZ ASM 981

Magnesium deficiency in hairless rats results in a transient erythematous rash within several days, the pathogenetic mechanisms of which are not yet well defined. However, the extremely pruritic rash closely mimics the acute clinical features of atopic dermatitis. Owing to the similarity of clinical signs between hypomagnesaemic rats and patients with atopic dermatitis, this rodent skin condition holds promise as a model for the in vivo evaluation of new treatment modalities against pruritic inflammatory skin conditions. The efficacy of the new ascomycin macrolactam derivative SDZ ASM 981 was tested in hypomagnesaemic rats by systemic or topical administration using prophylactic or therapeutic treatment regimens. Oral treatment of diseased rats with SDZ ASM 981 (12.5 mg kg-1 daily) inhibited the erythematous pruritic rash within 1 day after the start of treatment. This was associated with a clear reduction in histaminaemia, leucocytosis, eosinophilia and serum nitric oxide levels. The same daily oral dose of SDZ ASM 981 administered before the onset of the rash proved to be an efficacious prophylactic treatment regimen to prevent signs. Topical treatment of the ears with 0.4% SDZ ASM 981 locally inhibited and prevented inflammatory changes in a therapeutic and prophylactic treatment regimen, respectively. The histo- and immunopathological skin changes, as well as the numbers of degranulated mast cells in the dermis, were reversed towards normal after oral and topical administration. The pharmacological activity of SDZ ASM 981 reported here corresponds well to its anti-inflammatory and antipruritic activity observed in atopic dermatitis patients, confirming the usefulness of this rat model in drug evaluations.     

A novel anti-inflammatory drug, SDZ ASM 981, for the topical and oral treatment of skin diseases: in vivo pharmacology

There is a need for safe and effective therapies for inflammatory skin diseases. Current topical and systemic treatment of psoriasis is effective but suffers from side-effects or is inconvenient. The therapeutic armamentarium for atopic dermatitis is very limited and far from satisfactory. In vivo preclinical data are presented for SDZ ASM 981, a novel ascomycin macrolactam derivative with high anti-inflammatory activity. Anti-inflammatory activity was observed in mouse, rat and pig models of allergic contact dermatitis. In the pig model, topical SDZ ASM 981 was as effective as the ultrapotent corticosteroid clobetasol-17-propionate, and when compared with a series of commercial topical corticosteroid preparations, 0·1% SDZ ASM 981 had equivalent efficacy to clobetasol-17-propionate (0·05%), the most potent product on the market. Unlike the corticosteroid, however, SDZ ASM 981 did not cause skin atrophy in pigs. SDZ ASM 981 potently inhibited allergic contact dermatitis in mice and rats when given systemically, and oral treatment was more effective than cyclosporin A in rats. Furthermore, SDZ ASM 981 has a low potential for affecting systemic immune responses, as demonstrated in rat models of localized graft vs. host reaction and allogeneic kidney transplantation. Preclinical results suggest that SDZ ASM 981 has the potential to be a well-tolerated and effective drug for topical as well as oral treatment of inflammatory skin diseases.     

SDZ ASM 981: an emerging safe and effective treatment for atopic dermatitis

BACKGROUND: SDZ ASM 981 is a selective inhibitor of the production of pro-inflammatory cytokines from T cells and mast cells in vitro. It is the first ascomycin macrolactam derivative under development for the treatment of inflammatory skin diseases. OBJECTIVES: This study was designed to determine the safety and efficacy of SDZ ASM 981 cream at concentrations of 0.05%, 0.2%, 0.6% and 1.0% in the treatment of patients with atopic dermatitis and to select the concentration to be used in phase III studies. METHODS: This was a double-blind, randomized, parallel-group, multicentre dose-finding study. A total of 260 patients were randomly assigned to treatment with SDZ ASM 981 cream at concentrations of 0.05%, 0.2%, 0.6%, or 1.0%, matching vehicle cream, or the internal control 0.1% betamethasone-17-valerate cream (BMV). Treatment was given twice daily for up to 3 weeks. RESULTS: A clear dose-response relationship for SDZ ASM 981 was evident, with 0.2%, 0.6% and 1.0% SDZ ASM 981 creams all being significantly more effective than vehicle (P = 0.041, 0.001 and 0.008, respectively) in terms of baseline to end-point changes in the Eczema Area Severity Index (EASI) and pruritus score. The 1.0% cream was the most effective SDZ ASM 981 concentration. BMV was more effective than the SDZ ASM 981 creams tested in this study. It appears that the efficacy plateau was not reached with the SDZ ASM 981 creams within 3 weeks treatment. SDZ ASM 981 was well tolerated. Burning or a feeling of warmth were the only adverse events reported more frequently in the 0.6% and 1.0% SDZ ASM 981 treatment groups than in the vehicle treatment group (42.9%, 48.9% and 34.9%, respectively). Few systemic adverse events were reported during the study (headache was the most frequent systemic event reported by 15 of 252 patients) and none was considered to be related to treatment. The local tolerability profile of the 1.0% cream was similar to that of the lower concentrations. CONCLUSIONS: 1.0% SDZ ASM 981 cream, which was shown to be safe, well tolerated and the most effective concentration in this study, was selected as the concentration to be further developed in phase III studies.     

First experience of topical SDZ ASM 981 in children with atopic dermatitis

BACKGROUND: SDZ ASM 981 is a selective inhibitor of inflammatory cytokine release under development for the topical treatment of atopic dermatitis. OBJECTIVES: This first paediatric study was designed to measure the systemic exposure to SDZ ASM 981 in young children with atopic dermatitis treated on extensive skin areas. METHODS: Children 1-4 years of age referred to a tertiary care centre for their atopic dermatitis were treated twice daily for 3 weeks with 1% SDZ ASM 981 cream. SDZ ASM 981 blood concentrations were measured on day 4 and 22 (last day) of treatment, and 1 week after the last application, using a radioimmunoassay with a limit of quantification of 0.5 ng mL(-1). Efficacy was assessed by the Eczema Area Severity Index (EASI). RESULTS: The 10 patients included had 23-69% of their body surface area (BSA) affected at baseline. Of the 63 SDZ ASM 981 blood concentrations measured, 63% were < 0.5 ng mL(-1); the maximum value observed was 1.8 ng mL-1. No accumulation was evidenced between days 4 and 22. The first two patients experienced a flare of atopic dermatitis that was not controlled by the study medication. In the other patients, the EASI improved by 8-89% at 3 weeks of treatment. CONCLUSIONS: In these children 1-4 years of age, blood concentrations of SDZ ASM 981 during topical treatment with the 1% cream were consistently low even in the children with the most extensive areas treated (up to 69% of their BSA).     

Pimecrolimus (Elidel, SDZ ASM 981)—Preclinical pharmacologic profile and skin selectivity

The ascomycin macrolactam derivative pimecrolimus (Elidel, SDZ ASM 981; Novartis Pharma AG, Basel Switzerland) is a cell-selective inhibitor of inflammatory cytokines specifically developed for the treatment of inflammatory skin diseases, such as atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis, and plaque-type psoriasis. It inhibits the production of inflammatory cytokines in T cells and mast cells and prevents the release of preformed inflammatory mediators from mast cells. Topically administered pimecrolimus is as effective as the high-potency corticosteroid clobetasol-17-propionate in a pig model of allergic contact dermatitis (ACD). Unlike clobetasol, however, it does not cause skin atrophy. Given orally, pimecrolimus is as potent or superior to tacrolimus (FK 506) in treating ACD in mice and rats. Pimecrolimus also effectively reduces skin inflammation and pruritus in hypomagnesemic hairless rats, a model that mimics acute signs of atopic dermatitis. Pimecrolimus shows only a low potential to impair systemic immune responses when compared with tacrolimus as shown in rats in (1) the localized graft-versus-host reaction, (2) the antibody formation to sheep red blood cells, and (3) kidney transplantation. Pimecrolimus permeates through pig skin in vitro at a 10-times lower rate than tacrolimus, indicating a lower potential for percutaneous absorption in vivo. The data suggest that pimecrolimus combines high anti-inflammatory activity in the skin with a low potential to impair systemic immune reactions.     

The new topical ascomycin derivative SDZ ASM 981 does not induce skin atrophy when applied to normal skin for 4 weeks: a randomized, double-blind controlled study

BACKGROUND: SDZ ASM 981 is a selective inhibitor of inflammatory cytokines released from T lymphocytes and mast cells, which has been developed for the treatment of inflammatory skin diseases. OBJECTIVES: In the present study, the atrophogenic potential of SDZ ASM 981 1% cream in humans was compared with that of medium and highly potent topical steroids, and vehicle. METHODS: Four different preparations, SDZ ASM 981 1% cream, the corresponding vehicle of SDZ ASM 981 1% cream, betamethasone-17-valerate 0.1% cream and triamcinolone acetonide 0.1% cream, were applied to the volar aspect of the forearms of 16 healthy volunteers, twice daily, 6 days a week, for 4 weeks. Skin thickness was evaluated by ultrasound examination, clinical signs of atrophy by stereomicroscopy, and epidermal thickness was assessed by histology. RESULTS: Both topical corticosteroids induced a significant reduction in skin thickness, as compared with SDZ ASM 981 1% cream and vehicle, which were shown to be equivalent. The difference in skin thickness (measured by ultrasound examination) between patients treated with SDZ ASM 981 1% cream and those receiving either of the two topical steroids was significant from day 8 onwards. Histological analysis performed at day 29 showed significant epidermal thinning with topical steroids compared with SDZ ASM 981 1% cream or the vehicle. Conclusion The lack of atrophogenic properties of SDZ ASM 981 1% cream in this short-term study demonstrates its potential as long-term treatment for inflammatory skin diseases, thus overcoming a major drawback of topical steroids. This may also be important for the treatment of children, and sensitive areas of skin, such as the face and skin-folds.     

Elevated serum levels of soluble CD30 are associated with atopic dermatitis, but not with respiratory atopic disorders and allergic contact dermatitis

Type 2 helper T-cell immune responses can be demonstrated in the human atopic disorders atopic dermatitis and allergic asthma/rhinoconjunctivitis. The CD30 (Ki-1) antigen, originally described on Hodgkin and Reed-Sternberg cells, has recently been proposed as a marker of T cells with potent B-cell helper activity producing IL-5 and γ-IFN, as well as on CD4+ and CD8+ T cells with a Th2 cytokine profile. As a soluble form of CD30 (sCD30) is released by CD30+ cells in vivo , we studied its clinical significance in atopic disorders compared with allergic contact dermatitis and healthy controls. Elevated sCD30 levels were associated with atopic dermatitis ( P  < 0.0001), but not with respiratory atopic disorders or allergic contact dermatitis. sCD30 levels in patients with atopic dermatitis were independent of serum IgE. The particular occurrence of serum sCD30 in patients with atopic dermatitis indicates a special regulatory function of CD30+ cells in this disease.     

Semi-purification of the immunoglobulin E-sweat antigen acting on mast cells and basophils in atopic dermatitis

BACKGROUND: Sweating aggravates the symptoms of atopic dermatitis (AD). We have recently reported positive skin reactions and histamine release from basophils in response to autologous sweat in patients with AD. OBJECTIVE: To characterize the biochemical and immunological properties of the substance in sweat that evokes histamine release and to study the usability of the basophil-histamine release test with the sweat antigen for AD. METHODS: Sweat collected from healthy volunteers was purified using chromatographies. Serum immunoglobulin (Ig)E of four patients with AD were purified using an affinity-chromatography column with anti-IgE antibodies. The amount of semi-purified sweat antigen (138 ng protein/ml) that induced a half-maximum reaction of basophils of a patient with AD was utilized for the basophil histamine release test. The involvement of specific IgE and high-affinity IgE receptor (FcepsilonRI) in the reactions was examined using basophils of healthy volunteers, a human mast cell line (LAD2), and a rat basophilic leukemia cell line transfected with human alpha-subunit of FcepsilonRI (RBL-48). RESULTS: The semi-purified sweat antigen induced histamine release from the basophils of 47 of 61 (74.6%) patients with AD and four of 46 (8.7%) healthy controls. Both basophils and mast cells sensitized with the patient-derived IgE showed degranulation upon stimulation with the sweat antigen. However, no reaction was observed when cells were sensitized with myeloma IgE or the antigen was treated with proteases. CONCLUSION: The semi-purified standardized sweat antigen consists of a protein that induces degranulation of basophils and mast cells via antigen-specific IgE and FcepsilonRI in patients with AD.     

The influence of interferon-gamma and interleukin-4 on IgE production in B lymphocytes of patients with atopic dermatitis. A possible criterion for selection of patients for interferon therapy.

The regulation of IgE production in B lymphocytes of patients with atopic dermatitis by interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) was studied. IL-4 stimulated IgE production in vitro in B-cells of healthy donors and of children with atopic dermatitis, but had only a marginal effect on the high basal level of IgE production by lymphocytes from adult patients with atopic dermatitis. The addition of IFN-gamma prevented in all cases the stimulation of IgE synthesis induced by IL-4. The production of IgG and IgM was differently influenced. These results indicate that the in vitro production of IgE by mononuclear cells from adult patients is more resistant to the regulatory effects of IL-4 and IFN-gamma than is that in B cells of children with atopic dermatitis. We propose that a previous in vitro test of the responsiveness of IgE-producing B cells to IFN-gamma may be used to select patients with atopic dermatitis for treatment with IFN-gamma.     

IL-17: Important for Host Defense,Autoimmunity, and Allergy?

In this issue, Milovanovic and colleagues present evidence that IL-17a enhances IgE production, although the precise mechanism remains unclear. Their initial finding was that higher numbers of IL-17a-producing CD4(+) T cells were observed after polyclonal stimulation in a largely airway allergic population. These data add to the evidence that atopic disorders such as asthma and, possibly, atopic dermatitis (AD) may have distinct immunologic phenotypes. The hope is that by characterizing the immunologic basis of these common diseases we will be able to understand the heterogeneity observed in natural history, response to treatments, susceptibility to infections, genetic risk factors, and associations with other atopic disorders.     

The novel ascomycin derivative SDZ ASM 981 is effective for psoriasis when used topically under occlusion

Topical SDZ ASM 981 has been found to be highly effective in preclinical models of T-cell-mediated skin disease. T cell activation is crucial in the pathogenesis of psoriasis. It has been hypothesized that SDZ ASM 981 may prove to be an effective treatment for chronic plaque psoriasis. Therefore, the study objective was to determine the efficacy, tolerability and safety of the new topical macrolactam, SDZ ASM 981, for chronic plaque psoriasis. Ten patients with chronic plaque-type psoriasis were treated with SDZ ASM 981 (0.3% and 1.0%), the corresponding ointment base (placebo) and open-labelled clobetasol-17-propionate ointment (0.05%) in a randomized, double-blind, within-subject comparison for 2 weeks using the microplaque assay. Evaluation was performed by daily determination of clinical scores for erythema and induration. The results of the study showed that, after 2 weeks of treatment, total scores decreased by 92% for clobetasol, by 82% for 1% SDZ ASM 981, by 63% for 0.3% SDZ ASM 981 and by 18% for the ointment base (placebo). No adverse drug effects were seen in any patient throughout the study. We conclude from our results that the new macrolactam SDZ ASM 981 (1%) is similar to clobetasol-17-propionate (0.05%) in plaque-type psoriasis when applied topically under occlusion for 2 weeks using the microplaque assay.     

儿童特应性皮炎患者外周血单一核细胞IL-31与疾病严重程度相关性分析

目的 探讨IL-31在儿童特应性皮炎发病机制中的作用以及与特应性皮炎瘙痒的相关性。方法 22例特应性皮炎患儿与22例健康儿童外周血单一核细胞在葡萄球菌肠毒素B（SEB）刺激或非刺激状态下，应用实时PCR方法分析IL-31表达情况；酶联免疫吸附法测定其血清IgE水平；对患儿病情进行病情严重程度评分，分析IL-31 mRNA与IgE水平、疾病严重程度及瘙痒的相关性。结果 特应性皮炎患儿外周血单一核细胞IL-31表达显著增加，是对照组的23.2倍（P < 0.01）。特应性皮炎组和对照组外周血单一核细胞受SEB刺激后IL-31表达均有不同程度升高，以特应性皮炎组IL-31表达增加更显著，是对照组的20.44倍。患儿血清总IgE水平中位数为260.05 IU/mL（范围5.9 ～ 1131.01 IU/mL），对照组为17.7 IU/mL（范围5 ～ 140.7 IU/mL），两组比较，P < 0.01。IL-31与患儿病情严重程度以及血清总IgE水平无显著相关性（r = 0.07，P > 0.05；r = 0.22，P > 0.05）。结论 IL-31可能参与儿童特应性皮炎发病，其作用机制可能不依赖血清IgE；SEB能诱导正常人外周血单一核细胞快速表达IL-31，是IL-31产生的重要调节因素。     

Biochemical and immunologic mechanisms in atopic dermatitis: new targets for emerging therapies.

The immunologic and pharmacophysiologic features of atopic dermatitis have stimulated research seeking to identify relevant effector cells and mediators that characterize chronic skin inflammation. The theory that unifies the various abnormalities associated with atopic dermatitis suggests that hematopoietic cells carrying abnormal genetic expressions of atopy cause clinical disease once they infiltrate the skin and mucosa. The proposed underlying mechanism may be either abnormalities in cyclic nucleotide regulation of marrow-derived cells or allergenic overstimulation that causes secondary abnormalities. The primacy of one mechanism over the other remains unresolved, but this does not obviate their value in identifying two novel therapeutic targets: phosphodiesterase inhibition and immune-intervention alternatives to corticosteroids. New type IV phosphodiesterase inhibitors are proving promising in topical formulations, as are inhibitors of calcineurin, such as FK506 and SDZ ASM 981, an ascomycin macrolactam derivative that in early clinical research appears to offer the potency of a corticosteroid without its adverse side effects. The promising clinical trial profiles of these new topical agents may result in alternative therapies providing potent anti-inflammatory activity without the adverse effects that limit corticosteroid use.     

Extracellular superoxide dismutase ameliorates house dust mite‐induced atopic dermatitis‐like skin inflammation and inhibits mast cell activation in mice

Extracellular superoxide dismutase (EC‐SOD) is an enzyme that catalyses the dismutation of superoxide anions. It has multiple functions, such as reactive oxygen species scavenging, anti‐angiogenic, anti‐inflammatory, antichemotatic and antitumor activities. Recently, we demonstrated that EC‐SOD inhibits ovalbumin‐induced allergic airway inflammation in mice. However, the anti‐allergic effect of EC‐SOD on skin tissue and the role of EC‐SOD in mast cells, which are important for allergic responses, have not been well studied. In this study, we investigated whether EC‐SOD can alleviate atopic dermatitis in mice and inhibit mast cell activation. Treatment with human recombinant EC‐SOD ameliorated house dust mite‐induced atopic dermatitis in mice. Furthermore, the levels of pro‐allergic cytokine gene expression and histamine release increased in EC‐SOD KO mast cells and decreased in EC‐SOD overexpressing mast cells, suggesting that EC‐SOD inhibits mast cell activation. Consistently, a passive cutaneous anaphylaxis experiment showed more blood leakage from EC‐SOD KO mouse ear skin, implying that the lack of EC‐SOD increases allergic responses. These results suggest that EC‐SOD inhibits mast cell activation and atopic dermatitis and that the loss of EC‐SOD causes more severe allergic responses, implying that EC‐SOD might be a good drug candidate for treatment of allergic disorders, such as atopic dermatitis.     

IgG4 antibodies in patients with atopic dermatitis

The role of IgG4 in atopic dermatitis was investigated by determining the total amounts of IgG4 and of IgG4 specific for ovalbumin (a food allergen), Dermatophagoides farinae mite antigen and house dust (inhalant allergens) and Candida. These were related to the amounts of total and antigen specific IgE in patients with atopic dermatitis and normal healthy controls. Most patients with atopic dermatitis had greater amounts of total IgG4 and of antigen-specific IgG4 than did normal control individuals. Patients who had received hyposensitization treatment injections had greater amounts of IgG4 than the atopic dermatitis patients not so treated. In patients treated by hyposensitization there was a large increase in the amount of blocking antibody detected by incubating the antigen with the serum overnight before injecting the mixture into the skin of a patient sensitive to the antigen. Blocking activity was also examined by partial inhibition by the serum of IgE-mediated mast cell degranulation and by injection of serum into the skin of sensitive patients before challenge with antigens. In all tests the blocking activity of the serum was related to the amount of antigen-specific IgG4 but not related to total IgG4. In patients with atopic dermatitis who were sensitive to mite antigen, severe cases had small amounts of specific IgG4 and large amounts of specific IgE but in mild cases there was an opposite trend with relatively large amounts of specific IgG4. Large amounts of IgG4 ovalbumin specific antibody were found in children and adults with atopic dermatitis and egg allergy but small amounts of IgE. In infants most of the anti-ovalbumin antibody was IgE with little or no IgG4. The work of others has confirmed that increased amounts of total and antigen-specific IgG4 occur in atopic dermatitis, and it is concluded that IgG4 is a blocking antibody for anaphylactic sensitization responses.     

Production of interleukin-2 by mononuclear cells in vitro in patients with atopic dermatitis and psoriasis. Comparison with serum interleukin-2 receptor levels.

Atopic dermatitis is associated with profound immunological alterations, in particular decreased lymphoproliferative responses upon stimulation with T-cell mitogens. T-cell blastogenesis involves the production of the soluble cytokine interleukin-2 (IL-2), which in turn upregulates the expression of its own receptor. To investigate the potential role of this cytokine for the pathomechanisms present in atopic dermatitis, 24-h supernatants of PHA-stimulated peripheral blood mononuclear cells from patients with atopic dermatitis (n = 30) of a moderate to severe disease activity were tested for IL-2 activity. In addition, serum concentrations of soluble interleukin-2 receptor (IL-2R) were measured. Non-atopic healthy controls (n = 19) and patients with psoriasis (n = 20), an inflammatory skin disorder with distinct pathogenesis, served as controls. In comparison with psoriasis patients and normal controls, PHA-stimulated mononuclear cells of atopic dermatitis patients released significantly less IL-2 into supernatants. Moreover, there was an inverse correlation between IL-2 concentrations and body surface involvement or serum IgE levels. In contrast, serum IL-2R levels were significantly elevated in both atopic dermatitis and psoriasis, as compared with healthy controls. Furthermore, IL-2R levels in atopic dermatitis patients showed a significant correlation with IgE levels and body surface involvement. The data indicate that T cell activation may occur in both skin diseases. Atopic dermatitis, however, is further characterized by the decreased capacity of mononuclear cells to release IL-2 upon stimulation in vitro.     

Development and pre-clinical aspects of pimecrolimus

Pimecrolimus (SDZ ASM 981), an ascomycin derivative, inhibits the phosphatase calcineurin and blocks the production of inflammatory cytokines in T cells. In contrast to corticosteroids, pimecrolimus has a cell selective mode of action, exerting e.g. no effect on dendritic cells, which have a central function in the skin-associated immune system. Pimecrolimus shows less permeation through skin than corticosteroids and tacrolimus which indicates a lower potential for systemic side effects after topical application. In animal models pimecrolimus has a marked dose-dependent anti-inflammatory activity. However, treatment with pimecrolimus does not induce skin atrophy in contrast to corticosteroids. In contrast to tacrolimus, pimecrolimus does not impair the primary immune reaction in the sensitization phase of allergic contact dermatitis and has generally less effect on systemic immune reactions. In summary, the pharmacological profile of pimecrolimus suggests high clinical efficacy together with excellent safety.     

Improvement of atopic dermatitis and reduction of skin allergic responses by oral intake of konjac ceramide

Although topical application of ceramide is effective in the treatment of atopic dermatitis, its effect is transient. Thus, the effect of oral intake of ceramide on atopic dermatitis was studied. Two groups of 25 children with moderate atopic dermatitis, who were allergic to house dust mite took either milk sugar (control group) or 1.8 mg/day of konjac ceramide in milk sugar (ceramide group) once a day for 2 weeks. Before and after 2 weeks, skin symptoms were assessed using the SCORAD index, while allergic skin responses to house dust mite were assessed by skin prick test. Moreover, production of allergen-specific IgE and various cytokines by mononuclear cells was measured. After 2 weeks, SCORAD index score, allergic skin responses to house dust mite and house dust mite-specific IgE production were significantly reduced in the ceramide group, but not in the control group. Moreover, house dust mite-induced cytokine production was skewed towards the Th1 type, since production of Th1 cytokine, IFN-gamma, and IL-12, was increased, while production of Th2 cytokine, IL-4, and IL-13, was decreased. In contrast, no change of these parameters was found in control group. Collectively, oral intake of konjac ceramide improved skin symptoms and reduced allergic responses with concomitant skewing of the cytokine pattern towards the Th1 type.