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

花粉热是由季节性花粉，特别是草花粉引起的。四分之一的英国人患有此病，严重影响睡眠，干扰日常活动，并可能影响工作或学习表现。抗组胺药和皮质类固醇鼻腔喷雾剂可能有效，但只能提供短期效果。在初级保健机构中，40%的患者对这些药物没有反应。这些患者的另一种选择是草花粉舌下过敏原免疫疗法（SLIT），包括每天在舌下服用一片过敏原片。SLIT是有效的，如果连续给予3年，并且在停止治疗后提供持续数年的益处（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免疫球蛋白（Ig）E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到从一个细胞到另一个细胞的信号物质，导致它们以过敏的方式行动，并帮助产生IgE。在这个过程中，白细胞介素4和白细胞介素13是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使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被抑制，这可能会使免疫治疗更快更有效地重新训练免疫系统。Dupilumab在英国是一种获得许可的药物，每隔一周通过皮下注射（在皮肤下）给药，治疗严重湿疹（最近在美国也用于治疗严重哮喘）。Dupilumab通过阻断白细胞介素4和白细胞介素13的共享受体来抑制过敏性炎症。迄今为止，尚无研究dupilumab治疗花粉热的试验，也未将dupilumab与过敏原免疫疗法联合使用。在这项研究中，我们将从患有严重花粉热的志愿者身上采集血液样本。我们将在试管中研究dupilumab加草花粉对从血样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反应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）和SLIT片（GRAZAX）的随机对照试验。对照组包括单独接受SLIT治疗的患者和仅接受安慰剂治疗的患者。所有3组在停止治疗后将进行盲法随访一年。我们将进行鼻腔过敏原挑战，我们将草花粉注入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一年后进行这项研究，以评估长期效果。我们还将在3年内的草花粉季节评估他们的花粉热症状。综上所述，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 +草花粉在试管患者血液样本中的组合来实现，其次在dupilumab + SLIT在中重度花粉热患者中的对照临床试验中实现。我们建议该组合将提供更有效的长期耐受性，并使SLIT疗程更短，副作用更少。

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.