The combination of allergen immunotherapy with anti-IL-4 receptor-alpha antibody (dupilumab) for induction of human allergen-specific tolerance

过敏原免疫疗法与抗 IL-4 受体-α 抗体（dupilumab）相结合，用于诱导人类过敏原特异性耐受

• 批准号: MR/T00164X/1
• 负责人: Natasha Chamali Gunawardana
• 金额: $ 33.76万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT00164X%2F1
• 关键词: combination; allergen; immunotherapy; anti; IL

Hay fever is caused by seasonal pollen exposure, particularly grass pollen. It affects one in four of the UK population and has a significant impact on sleep, interferes with usual daily activities and may impair performance at work or school. Antihistamines and corticosteroid nasal sprays may be effective but only provide short-term benefit. 40% of patients in a primary care setting fail to respond to these medicines. An alternative in these patients is grass pollen sublingual allergen immunotherapy (SLIT) which involves taking a daily allergen tablet under the tongue. SLIT is effective and when given continuously for 3 years and provides benefits that persist for years after stopping the treatment (long-term tolerance). Hay fever is caused by an abnormally strong immune response to seasonal pollen. The immune system recognizes the allergen and makes antibodies called immunoglobulin (Ig)E against the allergen. When exposed to the allergen again, it rapidly binds to IgE, causing the swelling and inflammation that leads to symptoms. A vital part of this response involves substances that signal from one cell to another, causing them to act in an allergic manner and help make IgE. Interleukin 4 and interleukin 13 are particularly important signaling molecules in this process. They act on cells via receptors which a share a common subunit. Allergen immunotherapy gradually causes the immune system to stop reacting to the given allergen. The immune response changes from being allergic to becoming tolerant. If allergic inflammation could be suppressed at the same time as the administration of immunotherapy this might allow immunotherapy to re-train the immune system faster and more effectively. Dupilumab is a licensed medicine in the UK and is given by subcutaneous injection (under the skin), every other week in severe eczema (and recently in the USA for severe asthma as well). Dupilumab suppresses allergic inflammation by blocking the shared receptor of interleukin 4 and interleukin 13. To date, no trials have studied dupilumab in hay fever, nor has dupilumab been combined with allergen immunotherapy.In this study we shall take blood samples from volunteers with severe hay fever. We shall study the effects of dupilumab plus grass pollen in the test tube on patients' immune cells purified from blood samples. In this way we can assess the effect of dupilumab in blocking the immune response to the allergen and suppressing allergic inflammation. If successful, we shall perform a randomised controlled trial of dupilumab (DUPIXENT) alongside SLIT tablet (GRAZAX) over 2 years in patients with moderate-severe hay fever. Control groups for comparison will include patients receiving SLIT alone and patients receiving placebo treatment only. All 3 groups will be followed in blinded fashion for a further year after stopping treatment. We shall undertake nasal allergen challenges where we administer grass pollen into a person's nose and assess their symptoms. We will do this before treatment, during treatment and one year after treatment has finished to assess the long-term effects. We will also assess their hay fever symptoms during the grass pollen season over the 3 years.In summary, this study will explore the ability of dupilumab to block human allergen-stimulated allergic responses and explore the underlying mechanisms. This will be achieved first by studying the combination of dupilumab + grass pollen on patients' blood samples in the test tube, and secondly in the context of a controlled clinical trial of dupilumab + SLIT in patients with moderate-severe hay fever. We propose that the combination will provide more effective long-term tolerance and enable a shorter course of SLIT with fewer side-effects.

花粉热是由季节性花粉暴露引起的，特别是草花粉。它影响四分之一的英国人口，对睡眠有重大影响，干扰日常活动，并可能影响工作或学校的表现。抗组胺药和皮质类固醇鼻腔喷雾剂可能有效，但只能提供短期的好处。在初级保健环境中，40%的患者对这些药物无效。这些患者的另一种选择是草花粉舌下过敏原免疫疗法（SLIT），该疗法包括每天在舌下服用过敏原片剂。SLIT是有效的，当连续给予3年，并提供的好处，持续多年停止治疗后（长期耐受性）。花粉热是由对季节性花粉的异常强烈的免疫反应引起的。免疫系统识别过敏原并产生称为免疫球蛋白（IG）E的抗体来对抗过敏原。当再次接触过敏原时，它会迅速与IgE结合，引起肿胀和炎症，从而导致症状。这种反应的一个重要部分涉及从一个细胞向另一个细胞发出信号的物质，使它们以过敏的方式起作用并帮助产生IgE。白细胞介素4和白细胞介素13是这一过程中特别重要的信号分子。它们通过具有共同亚基的受体作用于细胞。过敏原免疫疗法逐渐导致免疫系统停止对给定过敏原的反应。免疫反应从过敏转变为耐受。如果过敏性炎症可以在免疫治疗的同时得到抑制，这可能会使免疫治疗更快，更有效地重新训练免疫系统。Dupilumab是英国的一种许可药物，通过皮下注射（皮下）给药，每隔一周用于严重湿疹（最近在美国也用于严重哮喘）。Dupilumab通过阻断白细胞介素4和白细胞介素13的共同受体来抑制过敏性炎症。到目前为止，还没有试验研究dupilumab治疗花粉热，也没有dupilumab与过敏原免疫疗法联合使用。我们将研究试管中dupilumab加草花粉对从血液样本中纯化的患者免疫细胞的影响。通过这种方式，我们可以评估dupilumab在阻断对过敏原的免疫应答和抑制过敏性炎症方面的作用。如果成功，我们将在中重度花粉热患者中进行一项为期2年的dupilumab（DUPIXENT）与SLIT片剂（GRAZAX）联合治疗的随机对照试验。用于比较的对照组将包括仅接受SLIT治疗的患者和仅接受安慰剂治疗的患者。在停止治疗后，将以设盲方式对所有3个组再随访一年。我们将进行鼻过敏原的挑战，我们管理草花粉到一个人的鼻子，并评估他们的症状。我们将在治疗前、治疗期间和治疗结束后一年进行评估，以评估长期效果。我们还将评估他们在3年的草花粉季节期间的花粉热症状。总之，本研究将探索dupilumab阻断人类过敏原刺激的过敏反应的能力并探索其潜在机制。这将首先通过研究dupilumab +草花粉对试管中患者血液样本的组合来实现，其次是在中重度花粉热患者中进行dupilumab + SLIT的对照临床试验。我们建议，联合用药将提供更有效的长期耐受性，并使SLIT的疗程更短，副作用更少。