The Effect of Allergen Immunotherapy on Anti-viral Immunity in Patients With Allergic Asthma - A Randomized, Double-blind, Placebo-controlled Trial of HDM-AIT
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 39
- 试验地点
- 1
- 主要终点
- ΔIFN-λ gene and/or protein expression
研究概览
简要总结
Aim: To investigate the possible immune modulatory effects of allergen immunotherapy (AIT) on respiratory immunity in patients with allergic asthma (AA).
Background: Allergic sensitization to aeroallergens is a common co-morbidity in asthma that is associated with more frequent and severe asthma attacks. The investigators have recently shown that patients with allergic asthma also have an increased risk of pneumonia, and hence allergy in asthma may be associated with a relative respiratory immunodeficiency. However, the increased risk was obliterated in patients treated with AIT.
Methods: Patients with asthma sensitized to house-dust mite (HDM) is enrolled in a randomized, double-blind, placebo-controlled study of HDM-AIT. Patients will be scheduled for 9 visits through 8 months including, randomization to 6 months of treatment with either HDM-AIT (Acarizax/Odactra) or placebo. Primary interferons (IFN) type I and III will be investigated in human bronchial epithelial cells as the primary outcome. Secondary outcomes such as: Inflammatory cytokines, immunologic phenotype and immunohistochemistry will be investigated in bronchial biopsies, blood, bronchoalveolar lavage fluid, sputum and HDM-patch biopsies as well as a thorough respiratory and allergic evaluation.
Expected outcomes: The investigators expect that, patients with AA have 1) decreased production of anti-viral type I and III IFN and that AIT increases these measures. 2) Anti-bacterial response is reduced through IL12, ß-defensin and IFN-γ and that AIT increases these measures. 3) Lastly, the investigators expect that T-cell response is dysregulated (Th1↓1/Th2↑) in patients with AA and that these findings are modulated in an immuno-protective direction after AIT.
Perspectives: This project will expand our understanding of the clinical significance of allergy in asthma in a completely novel direction and show how AIT may modulate the immune response to prevent infections.
详细描述
1.1 Background Respiratory viral infections are the major cause of acute worsening of asthma. Importantly too, these infections may also predispose to bacterial infections. Patients with allergic asthma suffer from more frequent lower respiratory tract infections, more severe and longer lasting lower respiratory tract symptoms compared to healthy controls. Hence, the need to use antibiotics may reflect in part the increased susceptibility to viral infection in allergic asthma. The investigators have recently demonstrated that patients with allergic asthma have an increased risk of being prescribed antibiotics for respiratory infections compared to non-allergic patients with asthma. Other studies have identified allergic sensitization and respiratory viral infections as synergetic risk factors in asthma exacerbations. These findings suggest a possible link between the allergic sensitization, asthma and an impaired immune response against respiratory infections. Furthermore, the investigators have found that allergen-specific immunotherapy (AIT) reduces the risk of being prescribed antibiotics for respiratory infections in patients with allergic asthma. These novel observations make it of interest to investigate mechanistic pathways in target cells subjected to AIT.
In a recent study, investigating potential mechanisms involved in the interaction between allergen and viral infection the investigators found that house dust mite (HDM) impairs viral stimulus (TLR3)-induced type I and type III interferons in bronchial epithelial cells from asthmatic patients and similarly in an in vivo mouse model of asthma exacerbation. This novel finding was accompanied with a direct effect of HDM on reducing TLR3 glycosylation. Hence, HDM exposure in patients with allergic asthma may also contribute to a defect antiviral response by interfering with components important for the anti-viral signalling such as TLR3. Furthermore, the investigators have observed that HDM has a capacity to induce over-expression of upstream Th2 cytokines such as IL-33, which may contribute to asthma exacerbations. In our studies HDM stands out amongst different allergens in causing both release of inflammatory inducing damage-associated metabolic patterns and impaired interferon response.
Inferentially, in this study the investigators will have the unique opportunity to examine effects of human in vivo HDM-AIT on the bronchial epithelial cell production of type I and type III interferons as well as the balance between Th1/and Th2 inflammation in response to viral and bacterial triggers. The investigators speculate that exposure to HDM-allergen may predispose to asthma exacerbations by causing dysregulation of the anti-viral interferon system as well as Th1/and Th2 inflammation and then that desensitization of patients with HDM-sensitive allergic asthma (AA) increases innate interferon response.
1.2 Hypothesis
- Viral induced type I and type III IFN is increased in HBECS from patients with allergic asthma sensitized to HDM, after 24 weeks of Acarizax.
- Viral induced type I and III IFN response is impaired in HBECs from patients with allergic asthma sensitized to HDM, before 24 weeks of Acarizax.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Odactra 12-sq HDM sublingual tablet
House Dust Mite, sublingual tablet
干预措施: ODACTRA 12 SQ-HDM Sublingual Tablet (Drug)
Placebo sublingual tablet
Placebo, sublingual tablet
干预措施: Placebo sublingual tablet (Drug)
结局指标
主要结局
ΔIFN-λ gene and/or protein expression
时间窗: Baseline and 24 weeks
To investigate the potential change in viral induced interferon response in HBECs from V3, V12, after 24 weeks of HDM-SLIT therapy or placebo, after stimulation with a combination of: HDM-allergen +/- viral infection mimics (RV16 or Poly(I:C))
ΔIFN-ß gene and/or protein expression
时间窗: Baseline and 24 weeks
To investigate the potential change in viral induced interferon response in HBECs from V3, V12, after 24 weeks of HDM-SLIT therapy or placebo, after stimulation with a combination of: HDM-allergen +/- viral infection mimics (RV16 or Poly(I:C))
ΔViral load
时间窗: Baseline and 24 weeks
To investigate the potential change in viral load in HBECS from from V3, V12, after 24 weeks of HDM-SLIT therapy or placebo, after stimulation with a combination of HDM-allergen +/- viral infection mimics (RV16 or Poly(I:C))
次要结局
- SOCS 1 immunohistochemistry.(Baseline and 24 weeks)
- ΔNK-cells(Baseline and 24 weeks)
- IFN-ß/TSLP ratio(Baseline and 24 weeks)
- Number / percentage of eosinophils and neutrophils in sputum.(Baseline and 24 weeks)
- ΔIFN-ß gene and/or protein expression in viral/bacterial co-stimulation assay(Baseline and 24 weeks)
- ΔIFN-λ gene and/or protein expression in viral/bacterial co-stimulation assay(Baseline and 24 weeks)
- ΔIFN-γ(Baseline and 24 weeks)
- Th1/Th2 balance(Baseline and 24 weeks)
- Mast cells, eosinophils, Neutrophils, pDC's(Baseline and 24 weeks)
- IFN-ß(λ)/SOCS1/(3)-ratio(Baseline and 24 weeks)
- Δß-defensin(Baseline and 24 weeks)
- ΔCD8+ T-cells.(Baseline and 24 weeks)
- Inflammatory cytokines such as but not restricted to: IL-4, IL-5, IL-13, IL-33, IL-25, IL-ß and TSLP(Baseline and 24 weeks)
- IFN-ß(λ)/TLR3(7)-ratio(Baseline and 24 weeks)
- ΔIL-12(Baseline and 24 weeks)
研究者
Celeste Porsbjerg
Professor
Bispebjerg Hospital