<b><i>Background:</i></b> Interleukin 27 (IL-27) is an initiator of the Th1 response and inhibits inflammatory responses. In a mouse model of asthma, administration of IL-27 reduced eosinophil numbers in bronchoalveolar lavage fluid and airway hyperresponsiveness. However, it is unclear whether administration of IL-27 can inhibit symptoms of allergic diseases and allergic rhinitis as a therapeutic agent. Therefore, we investigated the in vivo effect of IL-27 on nasal symptoms and allergic rhinitis. <b><i>Methods:</i></b> Mice sensitized and challenged with ovalbumin (OVA) antigen received intranasal administration of IL-27. <b><i>Results:</i></b> Intranasal administration of IL-27 significantly suppressed the number of sneezes and nasal rubbing movements, the number of eosinophils, OVA-specific T-cell responses in cervical lymph nodes, production of IL-4 and IL-5, and OVA-specific IgE in sera, compared with the administration of PBS alone. The production of IL-10 and IL-35, the percentage of CD25+Foxp3+ cells, and the gene expression of Foxp3 in mice that received intranasal administration of IL-27 were also significantly higher than those in mice that received only PBS. <b><i>Conclusions:</i></b> This study showed, for the first time, that intranasal administration of IL-27 inhibited nasal allergic responses and symptoms even after the establishment of allergic rhinitis and suggested that IL-27 is useful as an intranasal therapeutic agent.
While gastroesophageal reflux disease (GERD) is one of the commonest causes of subacute/chronic cough along with cough-variant asthma (CVA) and rhinosinusitis, its clinical impact remains unknown. Therefore, we sought to investigate the impact of GERD in patients with subacute/chronic cough.Between April 2012 and March 2018, a total of 312 patients presenting subacute or chronic cough lasting for ≥3 weeks [median cough duration, 4.9 (0.7-434) months] underwent diagnostic tests. GERD symptoms and cough-specific QoL were evaluated through the Frequency Scale for Symptoms of Gastroesophageal reflux (FSSG) and the Japanese version of the Leicester Cough Questionnaire (J-LCQ). According to the FSSG domains, patients with GERD were arbitrarily categorized into 3 groups; acid-reflux predominant, dysmotility predominant, and pauci-symptoms groups, respectively.The average scores of J-LCQ was 12.5 (SD3.7). One hundred-forty three were diagnosed as having GERD-related cough based on classical reflux symptoms including heartburn and characteristic triggers of cough such as phonation, rinsing, lying, and eating. Most of them (89.8%) had other causative diseases including CVA. Cough lasted longer (p = 0.019) and required a longer time until alleviation (p = 0.003) in patients with GERD than in those without GERD. They also scored lower J-LCQ than counterpart group (p < 0.0001). In terms of symptom stratification, dysmotility predominant group showed significant more response to specific GERD treatments than the remnants (p = 0.002).These results indicate that GERD is associated with the aggravation of other causes including CVA. Particularly, dysmotility symptoms may be potential therapeutic target for GERD-related cough.
Abstract We have recently demonstrated that dendritic cell (DC)-mediated immune modulation and deviation can be accomplished through RNA interference (RNAi), highlighting the therapeutic potential of RNAi-modified DC as antigen-specific tolerogenic vaccines. To date, an RNAi-based vaccine has not been reported. The current study was designed to develop siRNA-modified DC as antigen-specific, tolerogenic vaccines for prevention and intervention of autoimmune arthritis. Using small interfering RNA (siRNA) that specifically targets IL-12p35 gene (IL-12 siRNA), we have generated a type of DC that exhibits multiple tolerogenic characteristics. Immunization with type II collagen (CII)-pulsed and IL-12 gene-silenced DC (CII-pulsed/gene-silenced DC) resulted in antigen-specific nonresponsiveness in T cell responses. Vaccination with CII-pulsed/gene-silenced DC prevented collagen-induced arthritis (CIA) onset in a murine rheumatoid arthritis model. Furthermore, administration of CII-pulsed/gene-silenced DC was sufficient to inhibit progression of CIA. The therapeutic effects were further evidenced by decreased clinical scores, inhibited inflammatory infiltrates, and suppressed T cell and B cell responses to CII. In conclusion, this study is the first to demonstrate the therapeutic utilization of RNAi-modified DC as antigen-specific tolerogenic vaccines for autoimmune arthritis.
In view of recent studies on the mechanisms of the survival of peripheral memory T cells, we tested the biologic role of pectate lyase, a pectin-degrading enzyme, as the cross-reactive antigen required for the recurring survival signals for human T cells specific for Cha o 1, a pollen allergen molecule of the Japanese cypress. We determined a 16-mer epitope peptide for the T-cell clone, and prepared synthetic oligopeptides of homologous regions in putative pectate lyase of other plants. Of these homologous peptides, ZePel (Zinnia elegans), ban 17 (banana), and Amb a 1.1 (short ragweed) induced strong proliferative responses of the Cha o 1-specific T-cell clone in vitro. In addition, suboptimal doses of peptide homologs derived from banana and short ragweed enhanced the survival potency of this T-cell clone without detectable proliferative responses to the peptides. When there was no antigen stimulation, the T-cell clone decreased in viable cell number and lost antigen-specific proliferation activity on day 6 during in vitro incubation. On the other hand, T-cell clones incubated with these survival-inducing peptides maintained proliferative activity to Cha o 1 even on day 9. Serum derived from the donor patient did not contain detectable levels of IgE specific to banana or short ragweed by CAP-RAST. These results show that human T cells specific for pollen allergen seem to use cross-reactive pectate lyase peptides to deliver survival signals even in the absence of pollen allergen, and memory T cells maintained in such a manner might be functioning at the onset of allergic pollinosis, although pollen allergens are seasonal.
Dupilumab has clinical effects in patients with moderate-to-severe asthma. When considering interleukin (IL)-4 and IL-13 signaling, effects of dupilumab on airway mucus hypersecretion and airway remodeling are expected, but they have been reported in only a few short-term studies. Its efficacy for airway hyperresponsiveness (AHR) remains unknown. We comprehensively assessed the efficacy of dupilumab, especially for subjective and objective measures of airway mucus hypersecretion and airway dimensions in moderate-to-severe asthmatic patients. In 28 adult patients with moderate-to-severe uncontrolled asthma, the comprehensive efficacy of 48-week dupilumab treatment, including the Cough and Sputum Assessment Questionnaire (CASA-Q), radiological mucus scores and airway dimensions on computed tomography (CT), was assessed prospectively. Treatment responsiveness to dupilumab was analyzed. With 48-week dupilumab treatment, all four cough and sputum domain scores of CASA-Q improved significantly. Radiological mucus scores and airway wall thickening on CT were significantly decreased. The decreases in mucus scores were significantly associated with improvements in Asthma Control Questionnaire scores, Asthma Quality of Life Questionnaire (AQLQ) overall scores, airway obstruction, and airway type 2 inflammation. When defined by > 0.5 improvement in AQLQ overall scores, 18 patients (64%) were identified as responders. Dupilumab reversed subjective and objective measures of airway mucus hypersecretion and some aspects of airway remodeling in patients with moderate-to-severe uncontrolled asthma.
<b><i>Background:</i></b> We previously reported that siRNA-induced CD40-silenced dendritic cells (DCs) inhibit allergic responses and symptoms. However, more potent therapies are needed. To our knowledge, synergic effects of gene silencing in DCs by ≥2 siRNAs have not been reported to control allergic diseases. Therefore, we investigated the synergistic effects of the silencing of CD40 and CD86 in DCs on allergic responses. <b><i>Methods:</i></b> Mice were treated with CD40/CD86-silenced DCs, which were transfected with CD40/CD86 siRNAs and pulsed with ovalbumin (OVA) antigen. The effects of these DCs on allergic symptoms and allergic responses were estimated. <b><i>Results:</i></b> The administration of CD40/CD86-silenced OVA-pulsed DCs significantly inhibited the number of sneezes and nasal rubbing movements, the number of eosinophils in the nasal mucosa, and the level of OVA-specific IgE when compared with those for CD40- or CD86-silenced OVA-pulsed DCs alone (<i>p</i> < 0.01). These inhibitory effects were detected before sensitization as well as after the establishment of allergic rhinitis. CD40/CD86-silenced OVA-pulsed DCs did not inhibit KLH-induced allergies. <i>Foxp3</i> gene expression was significantly upregulated in CD40-silenced DCs compared to in CD86-silenced DCs (<i>p</i> < 0.01). IL-4 production by T cells was suppressed more substantially when using CD86-silenced DCs than with CD40-silenced DCs (<i>p</i> < 0.01). <b><i>Conclusions:</i></b> These results indicate, for the first time, that siRNA-induced CD40/CD86-silenced antigen-specific DCs have greater inhibitory effects against allergic responses than those of CD40- or CD86-silenced antigen-specific DCs alone. This study also suggests that the synergic effects of gene silencing in DCs by ≥2 siRNAs are useful for the control of allergic diseases. Thus, owing to the synergistic effects, CD40 and CD86 silencing has the potential to substantially improve the treatment of allergic diseases.
