Late Allergic Response Research Articles

Nasal IL-13 production identifies patients with late-phase allergic responses

There is limited knowledge on how local cytokine secretion patterns after nasal allergen challenge correlate with clinical symptoms especially with regard to the "late allergic response," which occurs in approximately 40% to 50% of patients with allergy. We sought to characterize the immunologic and clinical nasal responses to birch pollen allergen challenge with a special focus on the late allergic response. In this randomized, double-blind, placebo-controlled trial, birch pollen-allergic participants were challenged with birch pollen extract (n= 20) or placebo (n= 10) on 3 consecutive days. On days 1 and 3, nasal secretions were collected at selected time points over a 24-hour time course for the measurement of 33 inflammatory mediators. Clinical responses were determined through subjective symptom scores and objective nasal airflow measurements. Provoked participants had significantly greater clinical responses and showed significant increases in tryptase and the soluble IL-33 receptor serum stimulation 2 (sST2) in nasal secretions within minutes compared with the placebo group. Eight of 20 provoked participants displayed high IL-13 levels 2 to 8 hours after allergen provocation. This group also showed significant changes in clinical parameters, with a secondary drop in nasal airflow measured by peak nasal inspiratory flow and increased symptoms of nasal obstruction, which significantly differed from IL-13 nonresponders after 6 hours. IL-13 response status correlates with clinical responses and type 2 cytokine responses in the late phase after allergen provocation.

Effect of Biologic Therapies on Airway Hyperresponsiveness and Allergic Response: A Systematic Literature Review.

Airway hyperresponsiveness (AHR) is a key feature of asthma. Biologic therapies used to treat asthma target specific components of the inflammatory pathway, and their effects on AHR can provide valuable information about the underlying disease pathophysiology. This review summarizes the available evidence regarding the effects of biologics on allergen-specific and non-allergen-specific airway responses in patients with asthma. We conducted a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, including risk-of-bias assessment. PubMed and Ovid were searched for studies published between January 1997 and December 2021. Eligible studies were randomized, placebo-controlled trials that assessed the effects of biologics on AHR, early allergic response (EAR) and/or late allergic response (LAR) in patients with asthma. Thirty studies were identified for inclusion. Bronchoprovocation testing was allergen-specific in 18 studies and non-allergen-specific in 12 studies. Omalizumab reduced AHR to methacholine, acetylcholine or adenosine monophosphate (3/9 studies), and reduced EAR (4/5 studies) and LAR (2/3 studies). Mepolizumab had no effect on AHR (3/3 studies), EAR or LAR (1/1 study). Tezepelumab reduced AHR to methacholine or mannitol (3/3 studies), and reduced EAR and LAR (1/1 study). Pitrakinra reduced LAR, with no effect on AHR (1/1 study). Etanercept reduced AHR to methacholine (1/2 studies). No effects were observed for lebrikizumab, tocilizumab, efalizumab, IMA-638 and anti-OX40 ligand on AHR, EAR or LAR; benralizumab on LAR; tralokinumab on AHR; and Ro-24-7472 on AHR or LAR (all 1/1 study each). No dupilumab or reslizumab studies were identified. Omalizumab and tezepelumab reduced EAR and LAR to allergens. Tezepelumab consistently reduced AHR to methacholine or mannitol. These findings provide insights into AHR mechanisms and the precise effects of asthma biologics. Furthermore, findings suggest that tezepelumab broadly targets allergen-specific and non-allergic forms of AHR, and the underlying cells and mediators involved in asthma.

Ethanol Extract of Sesamum indicum Linn. Inhibits FcεRI-Mediated Allergic Reaction via Regulation of Lyn/Syk and Fyn Signaling Pathways in Rat Basophilic Leukemic RBL-2H3 Mast Cells.

This study is aimed at determining whether Sesamum indicum Linn. beneficially influences FcεRI-mediated allergic reactions in RBL-2H3 mast cells; it is also aimed at further investigating Lyn/Fyn and Syk signaling pathways. To examine the antiallergic effect of Sesamum indicum Linn. extract (SIE), we treated antigen/immunoglobulin E- (IgE-) sensitized mast cells with extracts of various concentrations. We examined the degranulation release and concentrations of inflammatory mediators. Additionally, the expressions of genes involved in the FcεRI and arachidonate signaling pathways were examined. SIE inhibited the degranulation and secretion of inflammatory mediators in antigen/IgE-sensitized mast cells. SIE reduced the expressions of FcεRI signaling-related genes, such as Syk, Lyn, and Fyn, and the phosphorylation of extracellular signal-regulated kinase in antigen/IgE-sensitized mast cells. Additionally, in late allergic responses, SIE reduced PGD2 release and COX-2 and cPLA2 phosphorylation expression in FcεRI-mediated mast cell activation. Lastly, 250–500 mg/kg SIE significantly attenuated the Ag/IgE-induced passive cutaneous anaphylaxis (PCA) reaction in mice. The potent effect of SIE on RBL-2H3 mast cell activation indicates that the extract could potentially be used as a novel inhibitor against allergic reactions.

Effect of Rhus verniciflua Extract on IgE-Antigen-Mediated Allergic Reaction in Rat Basophilic Leukemic RBL-2H3 Mast Cells and Passive Cutaneous Anaphylaxis in Mice.

Rhus verniciflua is widely known for its antioxidant, antibacterial, anticancer, and antiaging efficacy and α-glucosidase inhibition. This study was designed whether Rhus verniciflua extracts inhibit the IgE-antigen-mediated allergic reaction in RBL-2H3 mast cells, and it further investigated the FcεRI- and arachidonate-signaling by which Rhus verniciflua extracts exert its antiallergic effects. IgE-antigen-sensitized RBL-2H3 mast cells were investigated for the cytotoxicity of Rhus verniciflua extracts and β-hexosaminidase release, and inflammatory mediators (e.g., TNF-α, IL-4, IL-6, histamine, and PGD2) were then assessed. Additionally, we examined expressions of genes involved in arachidonate- and FcεRI-signaling pathway in RBL-2H3. Rhus verniciflua extracts inhibited β-hexosaminidase release and production of the inflammatory mediators in RBL-2H3. Rhus verniciflua extracts reduced amounts of histamine and expressions of FcεRI signaling-related genes such as Lyn and Syk and phosphorylation of extracellular signal-regulated kinase in mast cells. Finally, in late allergic responses, Rhus verniciflua extracts reduced PGD2 release and COX-2 and cPLA2 phosphorylation expressions from IgE-antigen-mediated mast cells. Lastly, 250–500 mg/kg RVE significantly attenuated the Ag/IgE-induced passive cutaneous anaphylaxis (PCA) reaction in mice. These findings provide novel information on the molecular mechanisms underlying the antiallergy properties of Rhus verniciflua extracts in FcɛRI-mediated allergic reaction.

Spirodela polyrhiza and its Chemical Constituent Vitexin Exert Anti-Allergic Effect via ORAI1 Channel Inhibition.

Intracellular calcium signaling cascades are integral to early and late allergic responses involving mast cell degranulation and type 2 helper T cell activation, respectively. Both the responses are accompanied by the movement of calcium through the calcium release-activated calcium (CRAC) channel, encoded by the ORAI1 gene. Spirodela polyrhiza (L.) Schleid (SP) has anti-inflammatory and anti-allergic effects, but its effect on calcium signaling has not been reported. This study investigated whether a 30% ethanolic SP extract (SPEtOH) and its constituents can reduce CRAC currents ([Formula: see text]), and thus inhibit mast cell degranulation and T cell activation. In Jurkat T lymphocytes, we found that 3[Formula: see text]mg/mL SPEtOH inhibited the [Formula: see text] by [Formula: see text]%, whereas one of its constituents vitexin (100[Formula: see text][Formula: see text]M) inhibited the [Formula: see text] by [Formula: see text]%. Furthermore, in the RBL-2H3 mast cell, the [Formula: see text] was inhibited by 3[Formula: see text]mg/mL SPEtOH ([Formula: see text]%) and 100[Formula: see text][Formula: see text]M vitexin ([Formula: see text]%). Investigation of human primary T cell proliferation induced by co-stimulation with antibodies to cluster of differentiation 3 and 28, and of RBL-2H3 mast cell degranulation following IgE-antigen complex stimulation revealed that 100[Formula: see text][Formula: see text]M vitexin inhibited both T-cell proliferation (by [Formula: see text]%) and mast cell degranulation (by [Formula: see text]%). These effects were concentration-dependent, and no cytotoxicity was observed. Our findings suggest that vitexin is a promising candidate compound for the development of therapeutic agents to prevent and treat allergic diseases.

Small airway involvement in the late allergic response in asthma.

Allergy and asthma are closely linked. Inhalation of allergen induces an early allergic response (EAR) within the airways of allergic asthmatic subjects, which is followed by a late allergic response (LAR) in approximately 50% of the subjects. The LAR is defined as a drop in forced expiratory volume in 1 second (FEV1 ) from baseline usually occurring 4-8 hours after exposure and is believed to affect small airways. However, FEV1 is insensitive to changes in small airway physiology. Our aim was to investigate and compare the pathophysiological processes in large and small airways during the EAR and the LAR and to characterize subjects with both an EAR and a LAR (dual responders) versus those with an EAR only (single responders). Thirty-four subjects with allergic asthma underwent an inhaled allergen challenge. Lung physiology was assessed by spirometry, impulse oscillometry (IOS), body plethysmography, inert gas washout, single breath methane dilution carbon monoxide diffusion and exhaled breath temperature (EBT), at baseline and repeatedly for 23 hours post-allergen challenge. Peripheral airway resistance, air trapping and ventilation heterogeneity were significantly increased in dual responders (n = 15) compared to single responders (n = 19) 6-8 hours post-challenge. Parameters of peripheral airway resistance and ventilation heterogeneity, measured with IOS and inert gas washout, respectively, correlated at baseline and during the allergic airway response in all subjects. The LAR involves increased resistance and ventilation defects within the peripheral airways. Alternative definitions of the LAR including small airways pathophysiology could be considered. Small airway dysfunction during the LAR suggests that dual responders may have more extensive airway pathology and underscores the relevance of small airways assessment in asthma.

Club cell protein (CC16) in plasma, bronchial brushes, BAL and urine following an inhaled allergen challenge in allergic asthmatics

Background: Club cell protein (CC16) is a pneumoprotein secreted by epithelial club cells. CC16 possesses anti-inflammatory properties and is a potential biomarker for airway epithelial damage. We studied the effect of inhaled allergen on pulmonary and systemic CC16 levels.Methods: Thirty-four subjects with allergic asthma underwent an inhaled allergen challenge. Bronchoscopy with bronchoalveolar lavage (BAL) and brushings was performed before and 24 h after the challenge. CC16 was quantified in BAL and CC16 positive cells and CC16 mRNA in bronchial brushings. CC16 was measured in plasma and urine before and repeatedly after the challenge. Thirty subjects performed a mannitol inhalation challenge prior to the allergen challenge.Results: Compared to baseline, CC16 in plasma was significantly increased in all subjects 0–1 h after the allergen challenge, while CC16 in BAL was only increased in subjects without a late allergic response. Levels of CC16 in plasma and in the alveolar fraction of BAL correlated significantly after the challenge. There was no increase in urinary levels of CC16 post-challenge. Mannitol responsiveness was greater in subjects with lower baseline levels of CC16 in plasma.Conclusions: The increase in plasma CC16 following inhaled allergen supports the notion of CC16 as a biomarker of epithelial dysfunction.

Omalizumab effectively protects against early and late allergic responses in asthma after 4 weeks.

Omalizumab is licensed for therapy in severe allergic asthma with an effect demonstrated after 8 weeks or longer treatment. As new applications for omalizumab demand precise knowledge of the onset of effects, the objective of this study was to determine the time course of the early (EAR) and late allergic reaction (LAR). Ten patients (IgE>300 IU/mL and <700 IU/mL) with a significant response to allergen challenge were treated with omalizumab according to the approved dosing table. Bronchial allergen provocations (BAP) were repeated at weeks 1, 2, 4, and 8. EAR was significantly reduced after 4 weeks (ΔFEV1 28% vs 11%; P<.001), eNO (86 vs 53 ppb; P<.05) and basophil activation after 2 weeks (CD63 expression 79% vs 32%, P<.05) and LAR already after 1 week (ΔFEV1 26% vs 13%, P<.05). These results demonstrate the onset of protective effects earlier than previously determined, potentially improving seasonal utilization and combination with immunotherapy.

Davallia mariesii Moore Improves FcεRI-Mediated Allergic Responses in the Rat Basophilic Leukemia Mast Cell Line RBL-2H3 and Passive Cutaneous Anaphylaxis in Mice.

Davallia mariesii Moore (Drynaria rhizome extract (DRE)) is widely known for its efficacy in treating inflammation, arteriosclerosis, and bone injuries. This study evaluated whether treatment with DRE inhibited FcɛRI-mediated allergic responses in the RBL-2H3 mast cells and investigated the early- and late-phase mechanisms by which DRE exerts its antiallergic effects. IgE anti-DNP/DNP-HSA-sensitized RBL-2H3 mast cells were tested for cytotoxicity to DRE, followed by the assessment of β-hexosaminidase release. We measured the amounts of inflammatory mediators (e.g., histamine, PGD2, TNF-α, IL-4, and IL-6) and examined the expression of genes involved in arachidonate and FcεRI signaling pathways. In addition, we confirmed the antiallergic effects of DRE on passive cutaneous anaphylaxis (PCA) in mice. DRE inhibited RBL-2H3 mast cell degranulation and production of allergic mediators in them. In early allergic responses, DRE reduced expression of FcεRI signaling-related genes (e.g., Syk, Lyn, and Fyn) and extracellular signal-regulated kinase phosphorylation in mast cells. In late allergic responses, DRE reduced PGD2 release and COX-2 expression and cPLA2 phosphorylation in FcɛRI-mediated mast cells. Lastly, 250–500 mg/kg DRE significantly attenuated the IgE-induced PCA reaction in mice. These findings provide novel information on the molecular mechanisms underlying the antiallergic effects of DRE in FcɛRI-mediated allergic responses.

Roflumilast for asthma: Efficacy findings in mechanism of action studies

BackgroundThe efficacy profile of roflumilast, a phosphodiesterase-4 inhibitor used for the treatment of chronic obstructive pulmonary disease (COPD), is well known. In asthma treatment, much less is understood about the role of roflumilast, particularly its mechanism of action and potential bronchodilatory effects. AimTo evaluate the therapeutic efficacy and mechanism of action of roflumilast in patients with asthma using data from eight placebo-controlled, double-blind phase I–III studies. MethodsThe studies were conducted at 14 sites in Europe, North America and South Africa from 1997 to 2005. The effect of treatment with 250 μg, 500 μg or 1000 μg roflumilast was compared with placebo in seven cross-over studies and one parallel-group study in 197 patients 18–70 years of age. Primary endpoints focused on the extent of the late allergic response after an allergen challenge, change in sputum cell eosinophil counts or exhaled nitric oxide (eNO), forced expiratory volume in 1 s (FEV1) and exercise-induced bronchoconstriction. Secondary endpoints included the extent of the early allergic response and measurements of tumour necrosis factor α (TNFα), sputum cells and inflammatory markers. ResultsRoflumilast attenuated allergen-induced bronchoconstriction (FEV1) in patients with asthma. Significant reductions in allergen-induced airway inflammation, including a reduction in both eosinophil and neutrophil counts were also observed and physiologic responses to allergen-induced challenge were confirmed by a significant reduction in TNFα. Side effects were similar to COPD, but did not include weight loss. ConclusionsThe results from these studies indicate that the anti-inflammatory effects of roflumilast observed in COPD are also seen in asthma and advance our understanding of its mechanism of action.All studies were funded by Takeda. Trial registration numbers available on ClinicalTrials.gov: NCT01365533.

The Frequency of Influenza-Like Illness in Patients with Allergic Asthma on Immunotherapy

Viral infections augment immediate and late allergic responses in the lungs of patients with allergic asthma. Certain viruses that typically exacerbate asthma have been noted to induce release of the cytokine interleukin-11 (IL-11) which is associated with airway hyperreactivity (AHR). The aim of study: To determine the frequency of influenza-like illness in patients with allergic asthma on immunotherapy compared to the patients with allergic asthma receiving only antiasthmatic pharmacotherapy during the period of 1-year follow up. Methods: In our study, we included 60 patients with allergic asthma, both genders who were subsequently divided into two treatment groups. Study group included 30 patients who received immunotherapy (immunotherapy group) and control group included 30 patients treated with standard pharmacotherapy, but not with immunotherapy (GINA proposal). Results: There was a significant difference in influenza-like illness (ILI) between immunotherapy and control group of patients. A significantly higher percentages of patients in control group experienced cold and/or flu syndrome compared to immunotherapy group, which was observed at the 2nd, 3rd and 4th trimester (X2= 20.480 p=0.0001). During the first trimester there was no difference in the number of patients with the cold/flu symptoms between the immunotherapy and control group. During the 2nd trimester, there was a significant decrease in the number of patients with cold/flu symptoms 3/30 (10%) in the immunotherapy group, while in the control group there was significantly higher number of patients with the cold/flu symptoms (11/30 (36 %)). In the 3rd and 4th trimester the frequency of patients with cold/flu symptoms was unchanged compared to the 2nd trimester in the immunotherapy group, while in the control group the frequency of patients with cold/flu symptoms increased from 20/30 (66%) at the 3rd to 27/30 (90%) in the 4th trimester. The number of patients reported to the physician due to bronchial hyperreactivity was dependent on the immunotherapy treatment (p=0.0001) Conclusions: The frequency of influenza-like illness occurrence was significantly lower in patients treated with immunotherapy during one year of follow-up compared to the patients treated with antiasthmatic pharmacotherapy. The percentage of patients with influenza-like illness was 10% in the patients treated with immunotherapy at third and fourth trimester of the follow-up, whilst in patients on antiasthmatic pharmacotherapy, the percentage of patients with influenza-like illness increased from 66% in the third to 90% in the fourth trimester.

Selected acute phase protein in the diagnosis of late allergic response and the development of tolerance in food allergy

in relation to T, IC, HC(p<0.001) and IR (p<0.01) groups. Diagnostic values of these estimations for prediction a late allergic reaction reached likelihood ratio (LR) 5.0-14.3, with high sensitivity (80-100%), specificity (67100%), predictive value positive (89-100%) and negative (86-100%). Furthermore high percentage of W4 glycoform seen in the group T had a high diagnostic value for differentiation with the LaR and HC groups. After food challenge significant changes in ACT level and its glycosylation profile were seen only in children not reacting to food: T, HC and IC (LR 3-6,4). Lack of these changes in sample 1 and 2 marks out mainly the IR group. Conclusion

Inhibitory effect of topical adelmidrol on antigen-induced skin wheal and mast cell behavior in a canine model of allergic dermatitis.

BackgroundAdelmidrol is a semisynthetic derivative of azelaic acid and analogue of the anti-inflammatory compound palmitoylethanolamide (PEA). Based upon its physicochemical properties, adelmidrol is suitable for topical application. The main objective of the present study was to evaluate the efficacy of a topical adelmidrol emulsion on early and late inflammatory responses in hypersensitive dogs. Repeated intradermal injections of Ascaris suum extract were performed in both lateral thoracic areas of six conscious hypersensitive Beagle dogs, topically treated during 8 consecutive days. Adelmidrol (2%) was applied to one side and vehicle to the other. 24 hours after the last antigen challenge, two biopsies (adelmidrol- and vehicle-treated side) were obtained for each dog at the antigen injection site.ResultsA significant reduction in the antigen-induced wheal areas was observed on the 4th and 7th day of adelmidrol treatment. Moreover, cutaneous mast cell numbers were significantly decreased in biopsies obtained after 8 consecutive days of topical adelmidrol treatment.ConclusionsThe results obtained in the present study show that topical treatment with adelmidrol might represent a new therapeutic tool in controlling the early and late allergic inflammatory skin responses in companion animals.

자소엽(紫蘇葉) 에탄올 추출물이 RBL-2H3 비만세포에서 제 1형 알레르기 반응 조절에 미치는 효과

Objectives Perillae Folium (PF) has been widely used in Korean herbal medicines used for treatment of acute and chronic inflammatory diseases, such as rhinitis, asthma, and enteritis. In this study, to investigate the protective effect of PF on type 1 allergic response, we determined whether PF inhibits early or late allergic responses. Methods The effect of PF was analyzed by ELISA,. RT-PCR and Western blot in RBL-2H3 cells. Levels of <TEX>${\beta}$</TEX>-hexosaminidase, interleukin (IL)-4 and TNF-<TEX>${\alpha}$</TEX> were measured using enzyme-linked immunosorbent assays (ELISAs). mRNA levels of cytokines and enzymes were analyzed with RT-PCR. Signal transduction was analyzed with Western blot. Results We found that PF suppressed <TEX>${\beta}$</TEX>-hexosaminidase release in RBL-2H3 by the IgE-DNP-HSA stimulation. PF also significantly inhibited enzymes level, such as COX-1, COX-2, iNOS, and HDC2, along with reduced cytokine levels, such as IL-2, IL-3, IL-4, IL-6, IL-13, and TNF-<TEX>${\alpha}$</TEX> in RBL-2H3. In addition, PF suppressed the phospholyation of ERK1/2, JNK1/2, and <TEX>$I{\kappa}B{\alpha}$</TEX>. Conclusions Our results indicate that PF protects against type 1 allergic response and exert an anti-inflammatory effect through the inhibition of degranulation and expression of cytokines and enzymes via the suppression of signal transduction.

Effect of Topical Minocycline on Immediate and Late Phase Allergic Skin Responses

Effect of Topical Minocycline on Immediate and Late Phase Allergic Skin Responses

Alerjik rinitte montelukast ve desloratadin kombinasyonunun etkinliği

Alerjik rinit dunya nufusunun %10-25'ini etkileyen onemli bir saglik sorunudur. Sinuzit, nazal polipozis, orta kulak ve alt solunum yolu enfeksiyonlarina da yol acabilmesi alerjik rinitin onemini artirmaktadir. Tedavi maliyetlerinin yani sira hastaligin yol actigi isgucu kaybi ve uretkenlikteki azalma nedeniyle, bu hastaligin toplumsal maliyeti cok buyuk olcudedir. Yasam kalitesine etkisi ise beklenenin cok uzerindedir. Son yillarda alerjik rinit tedavisinde yeni gelismeler saglanmasina ragmen, arastirmalar hastaligin sikliginda artis oldugunu gostermektedir. Hava yolu enflamasyonunun altinda yatan mekanizmalara iliskin son yillarda ortaya cikan gelismeler, alerjik rinit tedavisinde yeni stratejiler gelistirilmesini saglamistir. Montekulast ve desloratadin alerjik rinit tedavisinde kullanilan guclu etken maddelerdir. Farmakodinamik ve farmakokinetik profillerinin cok iyi olmalari ve yan etkilerinin plaseboya benzer olmasi gibi nedenlerle ayni siniftaki etken maddelere gore ustunlukleri bildirilmektedir. Semptom kontrolunun yeterince saglanamadigi durumlarda her iki ilacin birlikte kullanilmasinin alerjik rinitin kontrolunu daha iyi saglayacagi dusunulmektedir. Kombinasyon tedavisi ile alerjen inhalasyonu sirasinda erken ve gec donemlerde ortaya cikan histamin ve histamin disindaki mediatorlerin de, alerjik ve enflamatuvar yanitlari daha guclu sekilde bastirmak mumkun olabilmektedir. Bu tip hastalarda tedaviye montelukast-desloratadin fiks kombine preparatinin gunde tek doz eklenmesi rasyonel ve maliyeti azaltan bir yaklasim tarzi gibi gorunmektedir.

Histamine differentially regulates the production of Th1 and Th2 chemokines by keratinocytes through histamine H1 receptor

Histamine is a biological amine that plays an important role in allergic responses. However, the involvement of histamine signaling in late allergic responses in the skin is poorly understood. Therefore, we attempted to investigate the involvement of histamine signaling in late allergic responses, especially in keratinocytes (KCs). HaCaT KCs and normal human KCs (NHKs) predominantly expressed histamine H1 receptor (H1R) and H2 receptor (H2R). Histamine suppressed tumor necrosis factor α (TNF-α)- and interferon-γ (IFN-γ)-induced production of CC chemokine ligand 17(CCL17), a type 2 T-helper (Th2) chemokine, by HaCaT KCs. It suppressed the phosphorylation of p38 mitogen-activated protein (MAP) kinase, but not that of extracellular signal-regulated kinases (ERKs), and TNF-α- and IFN-γ-induced nuclear factor κB (NFκB) activity. In contrast, histamine enhanced the production of CXC chemokine ligand 10 (CXCL10), a Th1 chemokine, by TNF-α- and IFN-γ-stimulated HaCaT KCs and NHKs. TNF-α- and IFN-γ-induced CXCL10 production was upregulated by suppression of p38 MAP kinase or NF-κB activity, which could explain histamine involvement. We concluded that histamine suppresses CCL17 production by KCs by suppressing p38 MAP kinase and NF-κB activity through H1R and may act as a negative-feedback signal for existing Th2-dominant inflammation by suppressing CCL17 and enhancing CXCL10 production.

Effects of the Phosphodiesterase Type 4 Inhibitor Roflumilast on Early and Late Allergic Response and Airway Hyperresponsiveness in Aspergillus-fumigatus-Sensitized Mice

Background: Inhibitory effects of roflumilast on responses characteristic of allergic asthma were investigated in a fungal asthma model in BALB/c mice. Methods: Mice were sensitized with Aspergillus antigen (Afu) and exposed to Afu or vehicle, and given roflumilast 1 or 5 mg/kg. Early airway response (EAR) and late airway hyperresponsiveness (AHR) to methacholine were measured via plethysmography. Bronchoalveolar lavage (BAL) was used to assess inflammatory cell count. Results: In Afu-exposed mice, roflumilast dose-dependently reduced the EAR [26% at 1 mg/kg (NS) and 94% at 5 mg/kg (p < 0.01)] and AHR [46% at 1 mg/kg (NS) and 128% at 5 mg/kg (p < 0.05)]. Roflumilast 5 mg/kg reduced neutrophil, eosinophil and lymphocyte counts [87% (p < 0.01), 40% (NS) and 67% (p < 0.01), respectively] in BAL fluid versus controls. Conclusions: In this model, roflumilast inhibited the EAR, suppressed AHR and reduced inflammatory cell infiltration.

Interferon‐γ‐dependent inhibition of late allergic airway responses and eosinophilia by CD8+γδ T cells

We have previously shown that CD8(+)gammadelta T cells decrease late allergic airway responses, airway eosinophilia, T helper 2 cytokine expression and increase interferon-gamma (IFN-gamma) expression. We hypothesized that the effects of CD8(+)gammadelta T cells were IFN-gamma mediated. Brown Norway rats were sensitized to ovalbumin on day 1. Cervical lymph node CD8(+)gammadelta T cells from sensitized animals were treated with antisense oligodeoxynucleotide (5 micromol/l) to inhibit IFN-gamma synthesis or control oligodeoxynucleotide and 3.5 x 10(4) CD8(+)gammadelta T cells were injected intraperitoneally into sensitized recipients on day 13. Rats were challenged with aerosolized ovalbumin on day 15 and lung resistance was monitored over an 8 hr period, after which bronchoalveolar lavage was performed. Control oligodeoxynucleotide treated gammadelta T cells decreased late airway responses and eosinophilia in bronchoalveolar lavage. There was a complete recovery of late airway responses and a partial recovery of airway eosinophilia in recipients of antisense oligodeoxynucleotide treated cells. Macrophage ingestion of eosinophils was frequent in rats administered gammadeltaT cells but reduced in recipients of antisense oligodeoxynucleotide treated cells. These results indicate that CD8(+)gammadelta T cells inhibit late airway responses and airway eosinophilia through the secretion of IFN-gamma. Defective or altered gammadelta T-cell function may account for some forms of allergic asthma.

Montelukast as add-on therapy to -agonists and late airway response

The present study investigated whether single-dose oral leukotriene receptor antagonists as add-on therapy to short-acting beta-agonists, immediately after allergen challenge, block the late-phase airway response. In total, 35 mild asthmatics (mean age 24 yrs, 19 males) sensitised for house dust mites underwent two courses of bronchial allergen challenge. After the early allergic response (EAR), subjects received salbutamol once and were randomly assigned to either 10 mg of montelukast or placebo (double-blind crossover). To identify a late allergic response, forced expiratory volume in one second (FEV(1)) was monitored over the following 8 h. Baseline exhaled nitric oxide (NO) was determined ahead of each allergen challenge. Baseline NO levels differed significantly depending on the reaction to allergen challenge. In total, 12 subjects showed no significant response, 11 only showed an EAR, and 12 had a dual response and underwent further analysis. The area under the FEV(1) time-response curve 3-8 h after bronchial allergen challenge was -0.77+/-1.68 from the pre-challenge values on montelukast compared with -2.47+/-1.32 on placebo. The baseline exhaled NO fraction of subjects without an EAR was significantly lower than of those presenting a dual response. The results of the present study demonstrate that single-dose leukotriene receptor antagonists given orally right after the early allergic response can significantly inhibit the late allergic response after bronchial allergen challenge.