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Background and Purpose: Fab fragments (Fabs) of antibodies have the ability to bind to specific allergens but lack the Fc portion that exerts effector functions via binding to receptors including FcεR1 on mast cells. In the present study, we investigated whether intranasal administration of the effector function-lacking Fabs of a monoclonal antibody IgG1 (mAb, P1-8) to the major allergen Cry j1 of Japanese cedar pollen (JCP) suppressed JCP-induced allergic rhinitis in mice., Experimental Approach: Balb/c mice sensitized with JCP on days 0 and 14 were challenged intranasally with the pollen on days 28, 29, 30 and 35. Fabs prepared by the digestion of P1-8 with papain were also administered intranasally 15 min before each JCP challenge., Key Results: Intranasal administration of P1-8 Fabs was followed by marked suppression of sneezing and nasal rubbing in mice with JCP-induced allergic rhinitis. The suppression of these allergic symptoms by P1-8 Fabs was associated with decreases in mast cells and eosinophils and decreased hyperplasia of goblet cells in the nasal mucosa., Conclusions and Implications: These results demonstrated that intranasal exposure to P1-8 Fabs was effective in suppressing JCP-induced allergic rhinitis in mice, suggesting that allergen-specific mAb Fabs might be used as a tool to regulate allergic pollinosis., (© 2016 The British Pharmacological Society.)

Background: Nutritional prebiotic supplementation represents an attractive approach for interventions of allergy. In this study, the potential therapeutic effect of β-1, 4 mannobiose (MNB) in a murine model of cedar pollinosis was investigated., Methods: Groups of Balb/c mice were intranasally sensitized to Japanese cedar pollen extract, and subsequently administered with low or high dose MNB. Both intraperitoneal and intranasal challenges were performed to monitor for clinical signs. Frequency of sneezing was recorded. Serum, spleen and Peyer's patches were collected for various biomarker analyses. Anti-allergic activity of MNB using RBL-2H3 cells was also evaluated., Results: Significant decrease in sneezing frequency, histamine, interleukin (IL)-4 and IL-17A and increase in TGF-β and IL-10 concentration were exhibited by the MNB-treated mice. However, Cry j1 and Cry j 2-specific IgE activity remained unaltered. The high dose MNB treatment increased total IgA activity and IL-10, TGF-β and FoxP3 and decreased IL-4, IL-17A, and RORγT mRNA expression. Inhibition of activation of RBL-2H3 cells was observed via decrease in histamine, intracellular Ca2+ concentration, and FcεRI mRNA expression., Conclusions: We demonstrated the immunomodulatory effects of MNB and conclude that MNB is a potential therapeutic molecular nutritional supplement candidate for treatment of pollen allergy.

Background: Japanese cedar pollen-induced allergic rhinitis in a guinea pig model clearly induced not only sneezing but also biphasic nasal blockage. To date, there have only been a few reports on models of murine allergic rhinitis which clearly show nasal blockage. Therefore, in order to try and develop such a model, we administered multiple dosages of intranasal pollen or purified antigen protein Cry j 1., Methods: B10.S mice were sensitized by intranasal instillations of either pollen extract or Cry j 1 twice a day for 7 days, which was adsorbed on Al(OH)(3). Subsequently, once a week, the mice were given multiple intranasal instillation challenges of either the pollen suspension or Cry j 1 and the frequency of sneezing was observed after respective challenges were made. Specific airway resistance (sRaw) was measured as an indicator for nasal blockage. Cry j 1-specific IgE levels were measured using an enzyme-linked immunosorbent assay., Results: The serum Cry j 1-specific IgE level showed clear elevation only in the group sensitized by Cry j 1 + Al(OH)(3) and then challenged by Cry j 1. No elevations were seen in the groups sensitized by pollen extract + Al(OH)(3) followed by a pollen suspension challenge. There was an immediate increase in sneezing after challenges in all of the sensitized-challenged groups. Nevertheless, no increases in sRaw in any of the groups were detected at any of the time points during the 8 hours following the challenges., Conclusions: Cry j 1 may be more effective than crude antigens for efficient sensitization/challenge in mice. No increase in sRaw occurred, even in mice that possessed high amounts of Cry j 1-specific IgE and that exhibited sneezing.

Background: Recently, some common foods in daily life, especially lactic acid bacteria, have been found to have anti-allergic effects. We previously isolated a halophilic lactic acid bacterium, Tetragenococcus halophilus Th221, from soy sauce moromi, a mixture of koji and salt solution, and showed that it possesses an immunomodulatory activity that promotes T helper type 1 immunity., Methods: To evaluate the anti-allergic effects of Th221, we performed a randomized, double-blind, placebo-controlled study in 45 subjects with perennial allergic rhinitis (PAR) treated by oral administration of Th221 (high dose, 60 mg/day, 15 subjects; low dose, 20.4 mg/day, 15 subjects) or a placebo (15 subjects) for 8 weeks., Results: There were no significant differences among the groups that ingested Th221 and the placebo group regarding the disease severities, total nasal symptom scores and total nasal sign scores examined by physicians. However, the disease severity examined by physicians significantly improved in the high-dose group at the end of the trial compared with the beginning (p < 0.05). The total score for nasal symptoms of subjects who received a high dose of Th221 also showed a significant improvement at the end of the trial compared with the beginning (p < 0.01). According to the subjects' diaries, significant improvements in sneezing and rhinorrhea were observed during some periods in the high-dose group. The change in serum total immunoglobulin E improved significantly at the end of the trial compared with the beginning in this group (p < 0.05). The safety of Th221 treatment was confirmed by laboratory tests and inspection of the general condition of each subject., Conclusions: Th221 can be expected to safely improve the symptoms of PAR.

Background: Grass and birch pollens are known to induce asthma. However there are few reports about other pollen-induced asthma. Japanese cedar is the most common allergen in rhinitis in Japan but is controversial on whether it can provoke asthma., Methods: To clarify Japanese cedar pollen-induced asthma, we studied adult patients who were sensitized only to the Japanese cedar (CAP-RAST > = 2) and had symptoms of asthma during the cedar season. We defined cedar asthma as a patient who satisfied the 2 criteria mentioned above., Results: We found 6 adult asthma patients who fulfilled the two criteria. Five patients suffered from cedar pollinosis in addition to asthma, and 1 patient had no pollinosis. The cedar pollinosis preceded asthma in 3 cases and occurred at almost the same time in the other 2 cases. Pulmonary function was normal in these cases (FEV 1%, mean +/- SD, 76.5 +/- 10%), with a high threshold value in the non-specific airway hypersensitivity test (Ach-PC20, 2,696 to 20,000 microg/ml, 9294 +/- 2) and low total IgE (101 +/- 86 IU/ml). In the allergen provocation test, 3 subjects showed both an immediate and late asthmatic reaction., Conclusions: We concluded that Japanese cedar pollen could provoke not only pollinosis but also asthma in adults.

Animal studies suggest that conjugated linoleic acid (CLA) may modulate the immune response, while studies in healthy human subjects have shown little effect and results are controversial. However, the effects of CLA may be more prominent in situations of immune imbalance, such as allergy. We studied the effects of the natural CLA isomer, cis-9, trans-11-CLA, on allergy symptoms and immunological parameters in subjects with birch pollen allergy. In a randomised, placebo-controlled study, forty subjects (20-46 years) with diagnosed birch pollen allergy received 2 g CLA/d in capsules, which contained 65.3 % cis-9, trans-11-CLA and 8.5 % trans-10, cis-12-CLA (n 20), or placebo (high-oleic acid sunflower-seed oil) (n 20) for 12 weeks. The supplementation began 8 weeks before the birch pollen season and continued throughout the season. Allergy symptoms and use of medication were recorded daily. Lymphocyte subsets, cytokine production, immunoglobulins, C-reactive protein, lipid and glucose metabolism and lipid peroxidation were assessed before and after supplementation. The CLA group reported a better overall feeling of wellbeing (P < 0.05) and less sneezing (P < 0.05) during the pollen season. CLA supplementation decreased the in vitro production of TNF-alpha (P < 0.01), interferon-gamma (P < 0.05) and IL-5 (P < 0.05). Total plasma IgE and birch-specific IgE concentrations did not differ between groups, whereas plasma IgA (P < 0.05), granulocyte macrophage colony-stimulating factor (P < 0.05) and eosinophil-derived neurotoxin (P < 0.05) concentrations were lower after CLA supplementation. Urinary excretion of 8-iso-PGF2alpha, a major F2-isoprostane (P < 0.01), and 15-keto-dihydro-PGF2alpha, a primary PGF2alpha metabolite (P < 0.05), increased in the CLA group. The results suggest that cis-9, trans-11-CLA has modest anti-inflammatory effects in allergic subjects.

Introduction: The economic and social impact of allergic rhinitis is substantial. The effectiveness of currently available medications is limited and therefore investigations for more effective drugs is essential. This study was intended to establish a model of allergic rhinitis in guinea pigs that can be utilized for further investigation of new drugs., Methods: Male Dunkin Hartley guinea pigs were sensitized intranasally to, and challenged with, ovalbumin. Sneezing (SN) and nose rubbing (NR) response to allergen challenge were observed on day 21 post-initiation of sensitization in conscious guinea pigs. Nasal blockade (NB), leukocyte infiltration, and lung inflation pressure (LIP) were assessed in the same guinea pigs 23-28 days post-initiation of sensitization. A ventilator/flow method was used to measure NB and LIP. Leukocyte infiltration into nasal lavage fluid 60 min after challenge in the same animals was recorded as total and differential cell counts., Results: Sensitized guinea pigs produced acute allergic responses after allergen challenge. This was characterized by increases in SN, NR, NB, and eosinophil infiltration. In addition, intranasal allergen challenge did not change lung inflation pressure., Discussion: Allergen-induced rhinitis in guinea pigs resembles that in humans. The model reported in this study can be used to reflect the effectiveness of drugs currently used to treat allergic rhinitis and to investigate new potential drugs for the treatment of allergic rhinitis.

Cough is a common and important symptom of asthma and allergic rhinitis. Previous experimental evidence has shown enhanced cough sensitivity during early phase of experimental allergic rhinitis in guinea pigs. We hypothesized that airway inflammation during the late phase response after repeated nasal antigen challenge may affect the afferent sensory nerve endings in the larynx and tracheobronchial tree and may also modulate cough response. In the present study we evaluated the cough sensitivity during a period of early and late allergic response in sensitized guinea pigs after repeated nasal antigen challenges. Forty-five guinea pigs were sensitized with ovalbumin (OVA). Four weeks later 0.015 ml of 0.5 % OVA was intranasally instilled to develop a model of allergic rhinitis that was evaluated from the occurrence of typical clinical symptoms. Animals were repeatedly intranasally challenged either by OVA (experimental group) or by saline (controls) in 7-day intervals for nine weeks. Cough was elicited by inhalation of citric acid aerosols. Cough was evaluated at 1 or 3 h after the 6th nasal challenge and 17 or 24 h after the 9th nasal challenge. The cough reflex was significantly increased at 1 and 3 h after repeated nasal challenge in contrast to cough responses evoked at 17 and 24 h after repeated nasal challenge. In conclusion, enhanced cough sensitivity only corresponds to an early allergic response after repeated nasal challenges.

Whether a state of nasal hyperresponsiveness influences antigen-induced biphasic nasal blockage and sneezing were examined using a guinea pig model of allergic rhinitis. Sensitized animals were challenged with an antigen, Japanese cedar pollen, once every week. Before the 13th challenge, the animals were randomly divided into 2 groups, and then the 13th challenge was performed (Groups A-0 and B-0). The 14th challenge was done on day 2 (Group A-2) and on day 7 (Group B-7) after the 13th challenge, on which nasal hyperresponsiveness was present and absent, respectively. Biphasic nasal blockage and sneezing after the challenge in Group A-2 were more severe than those in Group A-0, while those of Group B-7 were almost the same as those of Group B-0. An anti-histaminic, mepyramine, inhibited sneezing but not the biphasic nasal blockage in Group B-7. A cysteinyl leukotriene (CysLT) antagonist, pranlukast, suppressed the late nasal blockage but not the early blockage and sneezing in Group B-7. In contrast, in Group A-2, mepyramine significantly attenuated not only sneezing but also the early nasal blockage. Pranlukast significantly inhibited both nasal blockage and sneezing in Group A-2. In conclusion, nasal hyperresponsiveness aggravated the antigen-induced nasal responses, to which histamine and CysLTs considerably contributed.

We have developed an allergic rhinitis model in guinea pigs using Japanese cedar pollen as antigen. In the present study, we examined whether provocation by pollen induces similar magnitudes of rhinitis symptoms in passively and actively sensitized guinea pigs. One group of animals was actively sensitized by intranasal application of pollen extract, and another was passively sensitized by intraperitoneal injection with anti-pollen serum. Actively and passively sensitized groups were then challenged by repeated and a single pollen inhalation, respectively. In both groups, sneeze was induced immediately after the challenge. The actively sensitized animals developed not only early but also late nasal blockage, whereas the passively sensitized animals showed only early nasal blockage. In both groups, an H1 antagonist, mepyramine, inhibited the occurrence of sneezing but did not inhibit nasal blockage. Nasal hyperresponsiveness to intranasal instillation of leukotriene D4 was obvious only in the actively sensitized animals. We thus conclude that although early nasal blockage is induced by a single antigen-antibody reaction, repetitive anaphylactic reaction is required for occurrence of late nasal blockage and hyperresponsiveness to stimuli. Furthermore, histamine plays a central role in induction of sneezing but not in nasal blockage, irrespective of whether animals are actively or passively sensitized.

Nasal reactivity to histamine was determined in patients with perennial allergic rhinitis and in control subjects. A histamine titration method delivered by a metered dose pump was used. Stuffiness, itching, and the number of sneezes were recorded, nasal secretions measured, and nasal airway resistance was recorded by active anterior rhinomanometry. Increased nasal reactivity to histamine was observed among rhinitic patients and inversely correlated with the severity of nasal symptoms. A 3-fold increase of post-saline nasal airway resistance (NAR) best differentiated the nasal responses to histamine in rhinitic patients from those in control subjects. A histamine dose of < or = 2.5 microg provoked a 3-fold increase in NAR, strongly suggesting moderate or severe symptomatic rhinitis in most cases. Nasal provocation techniques might be a useful tool for objectively assessing disease severity and response to treatment in perennial allergic rhinitis.