Summary of five years of operation of the out-of-court system for pursuing patient claims in Poland - a retrospective analysis of applications for evaluating medical events.

OBJECTIVE: Providing health services involves a risk of medical events and adverse events. The transparency and quality of the healthcare system have a direct impact on patient's safety. One of the measures of the quality of health services is monitoring and reporting these irregularities, as well as analysing the causes of their occurrence. The aim of this study was to present the principles of the functioning of the Regional Commission for Evaluation of Medical Events in Szczecin and to analyse medical events in the West Pomeranian Voivodeship from 2012 to 2017. MATERIALS AND METHODS: The analysis included applications for evaluating medical events and documentation collected for the purpose of conducting cases by the Regional Commission for Evaluation of Medical Events in Szczecin. The study was retrospective. All applications for evaluating medical events that were received by the Regional Commission for Evaluation of Medical Events in Szczecin in 2012-2017 were analysed. The study was conducted from October 2017 to December 2018. RESULTS: The retrospective analysis of the years 2012-2017 revealed 42 medical events and 120 adverse events. The most common medical events were health disorders (33.3%) and bodily injuries (30.9%). Out of the 42 medical events, 34 (80.9%) were for surgical procedures and childbirth. The most common procedures were orthopedic (26.6%) and surgical (23.5%) procedures. CONCLUSIONS: Medical events and adverse events should be reported so that they can be analyzed, conclusions can be drawn, and remedial measures can be introduced.

Simulating the environmental performance of post-harvest management measures to comply with the EU Nitrates Directive.

Nitrate (NO3-) leaching from farmland remains the predominant source of nitrogen (N) loads to European ground- and surface water. As soil mineral N content at harvest is often high and may increase by mineralisation from crop residues and soil organic matter, it is critical to understand which post-harvest management measures can be taken to restrict the average NO3- concentration in ground- and surface waters below the norm of 50 mg l-1. Nitrate leaching was simulated with the EU-rotate_N model on a silty and a sandy soil following the five main arable crops cultivated in Flanders: cut grassland, silage maize, potatoes, sugar beets and winter wheat, in scenarios of optimum fertilisation with and without post-harvest measures. We compared the average NO3- concentration in the leaching water at a depth of 90 cm in these scenarios after dividing it by a factor of 2.1 to include natural attenuation processes occurring during transport towards ground- and surface water. For cut grassland, the average attenuated NO3- concentration remained below the norm on both soils. In order to comply with the Nitrates Directive, post-harvest measures seemed to be necessary on sandy soils for the four other crops and on silty soils for silage maize and for potatoes. Successful measures appeared to be the early sowing of winter crops after harvesting winter wheat, the undersowing of grass in silage maize and the removal of sugar beet leaves. Potatoes remained a problematic crop as N uptake by winter crops was insufficient to prevent excessive NO3- leaching. For each crop, maximum levels of soil mineral N content at harvest were proposed, both with and without additional measures, which could be used in future nutrient legislation. The approach taken here could be upscaled from the field level to the subcatchment level to see how different crops could be arranged within a subcatchment to permit the cultivation of problem crops without adversely affecting the water quality in such a subcatchment.

Non-digestible oligosaccharides modulate intestinal immune activation and suppress cow's milk allergic symptoms.

BACKGROUND: Cow's milk allergy is a common food allergy in childhood and no effective preventive or curative treatment is available. This study aimed at comparing single short-chain galacto- (scGOS), long-chain fructo- (lcFOS) or pectin-derived acidic oligosaccharides (pAOS) and/or mixtures of scGOS/lcFOS (GF) or scGOS/lcFOS/pAOS (GFA) to prevent or treat food allergy. METHODS: In the preventive protocol, C3H/HeOuJ mice were fed diets containing single oligosaccharides or mixtures GF or GFA throughout the study protocol. In the treatment protocol, GF or GFA was provided for 4 wk starting after the last sensitization. The allergic skin response and anaphylaxis scores were determined, after oral challenge whey-specific immunoglobulins were measured, and qPCR for T-cell markers and Foxp3 counts using immunohistochemistry were performed on the small intestine and colon. RESULTS: Only in the preventive setting, the GF or GFA mixture, but not the single oligosaccharides, reduced the allergic skin response and whey-IgG(1) levels in whey-sensitized mice, compared to the control diet. Both GF and GFA increased the number of Foxp3+ cells in the proximal small intestine of whey - compared to sham-sensitized mice. Expression of Th2 and Th17 mRNA markers increased in the middle part of the small intestine of whey-sensitized mice, which was prevented by GF. By contrast, GFA enhanced Tbet (Th1), IL-10 and TGF-ß mRNA expression compared to GF which was maintained in the distal small intestine and/or colon. CONCLUSIONS: Dietary supplementation with scGOS/lcFOS or scGOS/lcFOS/pAOS during sensitization, both effectively reduce allergic symptoms but differentially affect mucosal immune activation in whey-sensitized mice.

Mitigation options to reduce phosphorus losses from the agricultural sector and improve surface water quality: a review.

The EU Water Framework Directive (WFD) obliges Member States to improve the quality of surface water and groundwater. The measures implemented to date have reduced the contribution of point sources of pollution, and hence diffuse pollution from agriculture has become more important. In many catchments the water quality remains poor. COST Action 869 was an EU initiative to improve surface water quality that ran from 2006 to 2011, in which 30 countries participated. Its main aim was a scientific evaluation of the suitability and cost-effectiveness of options for reducing nutrient loss from rural areas to surface waters at catchment scale, including the feasibility of the options under different climatic and geographical conditions. This paper gives an overview of various categories of mitigation options in relation to phosphorus (P). The individual measures are described in terms of their mode of action, applicability, effectiveness, time frame, environmental side-effects (N cycling) and cost. In total, 83 measures were evaluated in COST Action 869.

Dietary long chain n-3 polyunsaturated fatty acids prevent allergic sensitization to cow's milk protein in mice.

BACKGROUND: Cow's milk allergy is one of the most common food allergies in children and no treatment is available. Dietary lipid composition may affect the susceptibility to develop allergic disease. OBJECTIVE: Assess whether dietary supplementation with long chain n-3 polyunsaturated fatty acids (n-3 LCPUFA) prevents the establishment of food allergy. METHODS: Mice were fed a control or fish oil diet before and during oral sensitization with whey. Acute allergic skin response, serum immunoglobulins as well as dendritic cell (DC) and T cell subsets in mesenteric lymph nodes (MLN), spleen and/or small intestine were assessed. RESULTS: The acute allergic skin response was reduced by more than 50% in sensitized mice fed the fish oil diet compared to the control diet. In addition, anti-whey-IgE and anti-whey-IgG1 levels were decreased in the fish oil group. Serum transfer confirmed that the Th2-type humoral response was suppressed since sera of fish oil fed sensitized mice had a diminished capacity to induce an allergic effector response in naïve recipient mice compared to control sera. Furthermore, the acute skin response was diminished upon passive sensitization in fish oil fed naïve recipient mice. In addition, the percentage of activated Th1 cells was reduced by fish oil in spleen and MLN of sham mice. The percentage of activated Th2 cells was reduced in both sham- and whey-sensitized mice. In contrast, whey-sensitized mice showed an increased percentage of CD11b+CD103+CD8α- DC in MLN in association with enhanced FoxP3+ regulatory T cells (Treg) in spleen and intestine of fish oil fed whey-sensitized mice compared to sham mice. CONCLUSIONS AND CLINICAL RELEVANCE: Dietary n-3 LCPUFA largely prevented allergic sensitization in a murine model for cow's milk allergy by suppressing the humoral response, enhancing local intestinal and systemic Treg and reducing acute allergic symptoms, suggesting future applications for the primary prevention of food allergy.

CD25+ regulatory T cells transfer n-3 long chain polyunsaturated fatty acids-induced tolerance in mice allergic to cow's milk protein.

BACKGROUND: Recently, we have shown that dietary long-chain n-3 polyunsaturated fatty acids (n-3 LCPUFA) largely prevent allergic sensitization in a murine model for cow's milk allergy. The aim of this study was to assess the contribution of regulatory T cells (Treg) in the prevention of food allergy by n-3 LCPUFA. METHODS: C3H/HeOuJ female donor mice were fed a control or fish oil diet before and during oral sensitization with cow's milk protein whey. Acute allergic skin response (ASR), anaphylaxis, body temperature, serum immunoglobulins, and mouse mast cell protease-1 (mmcp-1) were assessed. Splenocytes of sham- or whey-sensitized donor mice fed either control or fish oil diet were adoptively transferred to naïve recipient mice. Recipient mice received a whole splenocyte suspension, splenocytes ex vivo depleted of CD25+ cells, or MACS-isolated CD4+ CD25+ Treg. Recipient mice were sham- or whey-sensitized and fed control diet. RESULTS: The ASR as well as whey-specific IgE and whey-specific IgG1 levels were reduced in whey-sensitized donor mice fed the fish oil diet as compared to the control diet. Splenocytes of control-diet-fed whey-sensitized donors transferred immunologic memory. By contrast, splenocytes of fish-oil-fed whey-sensitized - but not sham-sensitized - donors transferred tolerance to recipients as shown by a reduction in ASR and serum mmcp-1, and depletion of CD25+ Treg abrogated this. Transfer of CD25+ Treg confirmed the involvement of Treg in the suppression of allergic sensitization. CONCLUSIONS: CD25+ Treg are crucial in whey allergy prevention by n-3 LCPUFA.

Depletion of CD4+CD25+ T cells switches the whey-allergic response from immunoglobulin E- to immunoglobulin free light chain-dependent.

BACKGROUND: Symptoms of allergy are largely attributed to an IgE-mediated hypersensitivity response. However, a considerable number of patients also exhibit clinical features of allergy without detectable systemic IgE. Previous work showed that Ig-free light chains (IgLC) may act as an alternate mechanism to induce allergic responses. CD4+CD25+ T cells are crucial in the initiation and regulation of allergic responses and compromised function might affect the response to allergens. OBJECTIVE: To examine the contribution of CD4+CD25+ T cells and IgLC towards the whey-allergic response. METHODS: Mice were sensitized orally with whey using cholera toxin as an adjuvant. CD25+ T cells were depleted in vivo using a CD25 mAb. The acute allergic skin response to whey and ex vivo colon reactivity was measured in the presence or absence of F991, a specific inhibitor of IgLC. Serum whey-specific antibodies and IgLC in serum and mesenteric lymph node (MLN) supernatants were measured. Depletion of CD4+CD25+ T cells was confirmed in the spleen. RESULTS: Anti-CD25 treatment strongly reduced whey-specific antibody levels and resulted in a partial depletion of effector T cells and a major depletion of Foxp3(+) regulatory T cells. Surprisingly, despite the abolished specific IgE response, the acute allergic skin response to whey was not affected. IgLC levels were enhanced in the serum and MLN supernatants of CD25-depleted sensitized mice. F991 inhibited the acute skin response and colon hyperreactivity in anti-CD25-treated mice, indicating that these responses were mainly IgLC dependent. CONCLUSIONS: Depletion of CD4+CD25+ T cells resulted in a switch from an IgE- to an IgLC-dependent acute skin response and functional hyperresponsiveness of the colon. Our data suggest that CD25+ T cells play a crucial role in balancing cow's milk allergy between IgE and IgE-independent responses and both mechanisms might play a role in allergic responses to the same allergen.

Mouse genetic model for antigen-induced airway manifestations of asthma.

Allergic asthma is a genetically complex disease characterized by allergen-specific immunoglobulin (Ig)E, eosinophilic inflammation of the lungs and airway hyper-responsiveness to bronchospasmogenic stimuli. In this study, we compared 13 recombinant congenic (RC) mouse strains in an ovalbumin model of allergic asthma. Different intensities and types of responses are observed throughout the RC strains. Intensities range from resistance to asthma in CcS05, to a very severe bronchoconstrictive reaction upon methacholine challenge for the parental STS strain. All strains show a 'modified' Th2 response except CcS14, which shows a 'true' Th2 response. When data from all strains are pooled, airway reactivity shows significant correlations with the serum Ig levels and the levels of interleukin (IL)-4, IL-5 and IL-13 in the broncho-alveolar lavage (BAL), at low dosage of methacholine (below 25 mg/ml), whereas at high dosage airway reactivity only correlates with BAL neutrophil levels. This indicates that at least two different mechanisms are involved in the airway reactivity to methacholine. None of these correlations can be found in every individual strain, which demonstrates that the asthma traits in this mouse model are genetically dissociated and that the loci can be genetically mapped.

Macrophages induce an allergen-specific and long-term suppression in a mouse asthma model.

Increasing evidence suggests that macrophages (Mphi) play a crucial downregulatory role in the initiation and progression of allergic asthma. Recently, the current authors demonstrated that ovalbumin (OVA)-loaded Mphi (OVA-Mphi) suppress subsequent OVA-induced airway manifestations of asthma and that this effect could be potentiated upon selective activation. In the present study, the authors further delineated the underlying pathway by which Mphi exert this immunosuppressive effect. To examine the migration of OVA-Mphi, cells were labelled with 5'chloromethylfluorescein diacetate (CMFDA) and were administered (i.v.) into OVA-sensitised BALB/c mice. After 20 h, the relevant organs were dissected and analysed using fluorescent microscopy. Allergen-specificity was investigated by treating OVA-sensitised mice with keyhole limpet haemocyanin (KLH)-Mphi activated with immunostimulatory sequence oligodeoxynucleotide (ISS-ODN). By lengthening the period between treatment and challenge to 4 weeks it was examined whether OVA-Mphi exerted an immunosuppressive memory response. Strikingly, CMFDA-labelled Mphi were not trapped in the lungs, but migrated to the spleen. ISS-ODN-stimulated KLH-Mphi failed to suppress OVA-induced airway manifestations of asthma. Moreover, treatment with ISS-ODN-stimulated OVA-Mphi was still effective after lengthening the period between treatment and challenge. These data demonstrate that allergen-loaded macrophages can induce an indirect immunosuppressive response that is allergen-specific and long lasting, which are both hallmarks of a memory lymphocyte response.

In-medium isovector piN amplitude from low-energy pion scattering.

Differential cross sections for elastic scattering of 21.5 MeV positive and negative pions by Si, Ca, Ni, and Zr have been measured as part of a study of the pion-nucleus potential across the threshold. The "anomalous" repulsion in the s-wave term was observed, as is the case with pionic atoms. The extra repulsion can be accounted for by a chiral-motivated model where the pion decay constant is modified in the medium. Unlike in pionic atoms, the anomaly cannot be removed by merely introducing an empirical on-shell energy dependence.

Effects of stage duration in incremental running tests on physiological variables.

To study the effect of stage duration on some physiological variables in an incremental running test, 8 well-trained runners underwent 3 running tests, with stage durations of 1, 3 and 6 min. To study maximal lactate steady state (maxLASS) and its corresponding speed, every subject underwent a 4th test with three 15-min stages at three speeds, based on the running speed at 4 mmol/l blood lactate (V4) in the 6 min per stage protocol. The first load in the 15 min per stage test was V4 - 0.5 km/h, the second at V4, and the third V4 + 0.5 km/h. To compare the maxLASS speed with outdoor performance, the subjects also ran 5 km at this speed on an outdoor track. Mean maximal running speed (V (max)) in the incremental test was significantly lower in the 6-min (15.1 km/h) and 3-min stage protocol (17.1 km/h), compared with the 1-min stage protocol (18.3 km/h). Mean peak VO (2) and mean peak heart rate were not different between the protocols with different stage duration. The mean V4 was significantly lower in the 6 min per stage protocol compared with the 3 min per stage protocol (12.9 vs. 14.4 km/h). Mean ventilatory threshold was not different between the 1, 3 and 6 min per stage protocols. No threshold behaviour was found in respiratory rate. MaxLASS can be estimated from V4 in the 6 min per stage protocol, and verified by three 15-min intensities being V4 - 0.5 km/h, at V4, and V4 + 0.5 km/h. The mean blood lactate concentration at the maxLASS speed was not different between treadmill running and outdoor running on a track. In conclusion, for measuring peak values of physiological variables in an incremental running test, the duration per stage is of less importance, however, when measuring blood lactate concentration as a function of running speed, the duration per stage should be at least 6 min.

Effects of age on coping and psychological distress in women diagnosed with breast cancer: review of literature and analysis of two different geographical settings.

Age-related differences in emotional distress were examined by studying two random samples (N=424) of women diagnosed with early stages of breast cancer in Graz, Austria and Jerusalem, Israel. We found that psychological distress, coping abilities, and different perceptions of illness are attributable to socialization differences of age experience according to young (49 or younger), intermediate (50-64) and old (65 and older) age groups. Patients were interviewed at home to obtain sociodemographic and medical background data. They also completed five standardized instruments (Brief Symptom Inventory, Psychological Adjustment to Illness Scale, Impact of Events Scale, Mental Adjustment to Cancer, and Perceived Family Support). A two-way MANOVA for all the demographic variables yielded significant main group (Graz vs. Jerusalem) effect (P<0.0001), significant main age effect (P<0.0001) and significant interaction (group by age) effect (P<0.001). Examination of the contribution of the age category to the level of the coping variables showed a different pattern in each group. The psychological distress variables revealed that, in the Jerusalem sample, there is a tendency toward decreasing distress levels with age and, in the Graz sample, elevated scores for the intermediate-age group. Age was found to be related to the level of Global Severity Index (GSI) and to the variables correlated to the GSI level. Psychological intervention should be guided to the different age groups.

Longitudinal electroproduction of charged pions from (1)H, (2)H, and (3)He.

Separated longitudinal and transverse cross sections for charged pion electroproduction from (1)H, (2)H, and (3)He were measured at Q(2) = 0.4 (GeV/c)(2) for two values of the invariant mass, W = 1.15 GeV and W = 1.60 GeV, in a search for a mass dependence which would signal the effect of nuclear pions. This is the first such study that includes recoil momenta significantly above the Fermi surface. The longitudinal cross section, if dominated by the pion-pole process, should be sensitive to nuclear pion currents. Comparisons of the longitudinal cross section target ratios to a quasifree calculation reveal a significant suppression in (3)He at W = 1.60 GeV. The W = 1.15 GeV results are consistent with simple estimates of the effect of nuclear pion currents, but are also consistent with pure quasifree production.

In situ net mineralization rates in a heterogeneous mixed deciduous forest receiving elevated n deposition.

In situ net mineralization was studied at 6 locations (E, Eb, Ec, F1, F2, F3) of a heterogeneous mixed deciduous forest ("De Gulkeputten") with oak (Quercus robur L., Quercus rubra) and birch (Betula pendula) as dominant species. Net nitrogen mineralization was determined by means of a sequential in situ incubation experiment using intact soil cores. For all incubations, the net mineralization rates of the organic (F+H) layer varied between -0.4 and 2.0 g N m(-2) month(-1), while the net nitrification rates varied between -0.6 and 0.7 g NO3- -N m(-2) month(-1). The net mineralization and nitrification rates of the mineral (0-30 cm) layer ranged from 4.5 g N m(-2) month(-1)to 8.8 g N m(-2) month(-1)and from -1.0 to 4.9 g NO3- -N m(-2) month(-1) respectively. In general, net mineralization rates increased from August 1998 to October 1998. Net mineralization rates were positively correlated with the gravimetrical moisture content and mineralization and nitrification rates were mutually positively correlated.

Effect of interleukin-16-blocking peptide on parameters of allergic asthma in a murine model.

In this study, we examined whether peptides based on the hydrophilic Cluster of Differentiation (CD) 4-binding part of the amino acid sequence of human interleukin-16 can block interleukin-16-induced chemotaxis of murine lymphocytes in vitro. Peptide 3 was capable of inhibiting interleukin-16-induced chemotaxis of murine splenocytes in vitro. Next, we compared the effects of intra-airway administration of peptide 3 with those of antibodies to interleukin-16 on antigen-induced features in a murine model of allergic asthma. Intra-airway administration of peptide 3 largely inhibited the development of antigen-induced airway hyperresponsiveness while airway eosinophilia was not affected. Similar effects were observed after intranasal application of antibodies to interleukin-16. These results indicate that treatment with peptide 3 causes the same effects as do antibodies to interleukin-16, possibly via the inhibition of interaction between interleukin-16 and its receptor CD4. Therefore, peptide 3 could be useful as a lead compound in attempting to limit airway hyperresponsiveness via binding to CD4.

Opposite effects of immunotherapy with ovalbumin and the immunodominant T-cell epitope on airway eosinophilia and hyperresponsiveness in a murine model of allergic asthma.

In the present study, we investigated immunotherapy using an entire protein or an immunodominant epitope in a murine model of allergic asthma. Immunotherapy was performed in ovalbumin (OVA)-sensitized mice before OVA challenge. Mice were treated subcutaneously with OVA, the immunodominant epitope OVA323-339, or vehicle. In vehicle-treated animals, repeated OVA challenge induced increased serum levels of OVA-specific immunoglobulin (Ig)G1, IgE, airway eosinophilia, and hyperresponsiveness, compared with saline-challenged animals. In addition, interleukin (IL)-4 and IL-5 production upon OVA restimulation of lung-draining lymph node cells in vitro were significantly increased in OVA-challenged animals. Immunotherapy using OVA significantly reduced airway eosinophilia and hyperresponsiveness. This finding was accompanied by significantly reduced OVA-specific IL-4 and IL-5 production. Further, OVA immunotherapy induced increased serum levels of OVA-specific IgG1, whereas OVA-specific IgG2a and IgE levels were not affected. In contrast to OVA immunotherapy, immunotherapy with OVA323-339 aggravated airway eosinophilia and hyperresponsiveness. OVA-specific IgG1, IgG2a, and IgE serum levels, and in vitro IL-4 and IL-5 production, were not affected. Thus, immunotherapy with protein resulted in beneficial effects on airway eosinophilia and hyperresponsiveness, which coincided with a local reduced T-helper 2 (Th2) response. In contrast, peptide immunotherapy aggravated airway hyperresponsiveness and eosinophilia, indicating a local enhanced Th2 response.

Differential effects of endogenous and exogenous interferon-gamma on immunoglobulin E, cellular infiltration, and airway responsiveness in a murine model of allergic asthma.

The inflammatory response as seen in human allergic asthma is thought to be regulated by Th2 cells. It has been shown that interferon-gamma (IFN-gamma) can downregulate the proliferation of Th2 cells and therefore might be of therapeutic use. In the present study we have investigated the in vivo role of endogenous and exogenous IFN-gamma in a murine model with features reminiscent of human allergic asthma. IFN-gamma gene knockout (GKO) and wild-type mice were sensitized with ovalbumin and exposed to repeated ovalbumin aerosol challenges. In addition, wild-type mice were treated with intraperitoneal or nebulized recombinant murine IFN-gamma during the challenge period. Sensitized wild-type mice exhibited upregulated ovalbumin-specific IgE in serum, and airway hyperresponsiveness and infiltration of eosinophils and mononuclear cells in the bronchoalveolar lavage fluid (BALF) after ovalbumin challenge. In contrast, in GKO mice only reduced eosinophilic infiltration in the BALF was observed after ovalbumin challenge. In wild-type mice, parenteral IFN-gamma treatment downregulated ovalbumin-specific IgE levels in serum, and airway hyperresponsiveness and cellular infiltration in the BALF, whereas aerosolized IFN-gamma treatment only suppressed airway hyperresponsiveness. In vitro experiments showed that these effects of IFN-gamma appear not to be mediated via a direct effect on the cytokine production of antigen-specific Th2 cells. These data indicate that airway hyperresponsiveness can be downregulated by IFN-gamma locally in the airways, whereas for downregulation of IgE and cellular infiltration systemic IFN-gamma is needed. The present study shows that exogenous IFN-gamma can downregulate the allergic response via an antigen-specific T-cell independent mechanism, but at the same time endogenous IFN-gamma plays a role in an optimal response.

Prevention of Th2-like cell responses by coadministration of IL-12 and IL-18 is associated with inhibition of antigen-induced airway hyperresponsiveness, eosinophilia, and serum IgE levels.

Allergic asthma is thought to be regulated by Th2 cells, and inhibiting this response is a promising mode of intervention. Many studies have focused on differentiation of Th cells to the Th1 or Th2 subset in vitro. IL-4 is essential for Th2 development, while IL-12 induces Th1 development, which can be enhanced by IL-18. In the present study, we investigated whether IL-12 and IL-18 were able to interfere in Th2 development and the associated airway symptoms in a mouse model of allergic asthma. Mice were sensitized with OVA using a protocol that induces IgE production. Repeated challenges by OVA inhalation induced elevated serum levels of IgE, airway hyperresponsiveness, and a predominantly eosinophilic infiltrate in the bronchoalveolar lavage concomitant with the appearance of Ag-specific Th2-like cells in lung tissue and lung-draining lymph nodes. Whereas treatments with neither IL-12 nor IL-18 during the challenge period were effective, combined treatment of IL-12 and IL-18 inhibited Ag-specific Th2-like cell development. This inhibition was associated with an absence of IgE up-regulation, airway hyperresponsiveness, and cellular infiltration in the lavage. These data show that, in vivo, the synergistic action of IL-12 and IL-18 is necessary to prevent Th2-like cell differentiation, and consequently inhibits the development of airway symptoms in a mouse model of allergic asthma.

Allergen immunotherapy inhibits airway eosinophilia and hyperresponsiveness associated with decreased IL-4 production by lymphocytes in a murine model of allergic asthma.

In the present study, we investigated whether allergen immunotherapy is effective in a murine model with immunologic and pathophysiologic features reminiscent of allergic asthma. Ovalbumin-sensitized mice received increasing (1 microgram to 1 mg) subcutaneous doses of ovalbumin twice a week for 8 wk according to a semirush immunotherapy protocol as used in allergic patients. During immunotherapy, an initial rise in serum levels of ovalbumin-specific antibodies (immunoglobulin [Ig]G1, IgE, IgG2a) occurred, after which IgE levels decreased sharply concomitant with an increase in IgG2a levels. The increase in IgG2a levels, with the decline in IgE levels, suggests that during immunotherapy interferon-gamma production is increased or interleukin (IL)-4 production is decreased. After immunotherapy, inhalation challenge of the mice with ovalbumin revealed almost complete inhibition (98%, P < 0.01) of eosinophil infiltration into bronchoalveolar lavage and airway hyperresponsiveness (100% at 320 microgram/kg methacholine, P < 0.05) compared with sham-treated animals. In addition, IL-4 production of thoracic lymph node cells stimulated with ovalbumin in vitro was largely reduced (60%, P < 0.05) after immunotherapy. Thus, effective immunotherapy in this animal model appears to be due to modulation of antigen-specific T cells. Similar effects on airway symptoms and IL-4 production can be obtained within 1 wk by three injections of the highest dose of ovalbumin (1 mg). This animal model will be used as a preclinical model to improve allergen immunotherapy and to gain more insight into the mechanisms involved.