Exploring mechanisms to optimise the duration of oral immunotherapy for peanut allergy

花生过敏影响1 / 30的儿童，是这个年龄组中最常见的危及生命的反应（过敏反应）的触发因素。这是一个重大的公共卫生问题，对工业、教育和医疗系统都有实际影响。口服免疫疗法（OIT）是一种新兴的治疗选择，即使用小剂量、不断增加的食物过敏原来引起“脱敏”，使患者在接触食物后不再出现症状。然而，OIT的频繁过敏反应（包括过敏反应）是常见的，因此是一个限制因素。此外，治疗效果需要持续的OIT剂量：超过一半的患者在停止OIT 4周后失去脱敏。这是一个问题，因为患者通常也不喜欢他们过敏的食物的味道，这影响了依从性和治疗的成功。持续脱敏，不需要持续的定期维持剂量，可以说是患者及其家属最重要的结果。OIT的生物学机制，特别是脱敏的持久性，目前还不清楚。这极大地限制了我们识别可能需要不同方案的患者的能力，以尽量减少不良反应，实现更持久的脱敏，并提高患者的安全性。免疫疗法广泛用于治疗花粉热和对昆虫叮咬的过敏，治疗成功取决于治疗的持续时间。因此，我们预计，对于食物过敏，OIT的持续时间可能是实现长期疗效的关键。在口服花生免疫治疗（BOPI）研究（NCT02149719，部分由TURNER的MRC奖学金资助）中，75%的参与者达到了研究的主要结果，并在治疗1年后的双盲、安慰剂对照食物挑战中耐受1.4克花生蛋白（约6-8颗花生）。停用花生OIT 4周后，53%的患者仍保持脱敏；经过2年的进一步维持治疗后，这一比例增加到72%。我们将评估更长时间花生- oit（长达3年）对免疫系统变化的影响，以及这与临床结果的对应关系，包括花生- oit患者的脱敏（以及是否持续）和安全性。我们将应用新技术，不仅研究导致脱敏的最初变化，而且研究当患者随后停止OIT剂量和治疗效果可能丧失时会发生什么。我们已经成功地将这种方法应用于花粉热的免疫治疗。因此，我们将能够更好地了解OIT对免疫系统的影响，以及脱敏效果是如何持续的。我们将分析原始BOPI研究中接受OIT长达3年的患者的血液样本（根据现有的伦理批准）。结合BOPI现有的临床和实验室数据，这将形成最全面的数据集，评估OIT持续时间对临床和机械结果的影响。在我们确定关键发现的地方，我们将寻求在进一步的花生- oit研究（BOPI-2研究；NCT03937726；目前正在进行中）中复制（并因此验证）这些研究，该研究也对患者进行了3年的随访)。这种强大的方法将使我们能够评估与花生过敏儿童经历长达3年的OIT诱导和脱敏丧失相关的机制。我们将使用机器学习方法来了解这些免疫变化如何与临床结果相关，从而建立一个模型（包括患者特征和对治疗的初始反应），从而预测长期治疗结果。如果成功，这将促进OIT方案的个性化，最大限度地提高治疗成功率，并带来更安全的患者结果。

Peanut allergy affects 1 in 30 children and is the commonest trigger for life-threatening reactions (anaphylaxis) in this age group. It is a major public health issue, with practical implications for industry, education and healthcare systems.Oral immunotherapy (OIT) is an emerging treatment option, where small, increasing doses of a food allergen are used to cause "desensitisation", so that patients no longer experience symptoms upon exposure to the food. However, frequent allergic reactions to OIT (including anaphylaxis) are common, and thus a limiting factor. Furthermore, treatment effect requires ongoing OIT dosing: over half of patients lose their desensitisation after stopping OIT for 4 weeks. This is a problem, as patients are usually averse to the taste of the food they are allergic too, which affects compliance and treatment success. Persistence of desensitisation, without the need for ongoing regular maintenance dosing, is arguably the most important outcome for patients and their families. The biological mechanism(s) underlying OIT - and in particular, the persistence of desensitisation - are unclear. This significantly limits our ability to identify patients who may need a different protocol to minimise adverse reactions, achieve longer-lasting desensitisation, and improve patient safety. Immunotherapy is widely undertaken for the treatment of hay fever and allergy to insect stings - where treatment success is dependent on the duration of treatment. We therefore expect that for food allergy, the duration of OIT may be of critical importance in achieving longer-term efficacy.In the Boiled Oral Peanut Immunotherapy (BOPI) study (NCT02149719; part-funded through an MRC Fellowship to TURNER), 75% of participants achieved the primary outcome for the study, and tolerated a dose of 1.4 grams peanut protein (approximately 6-8 peanuts) at double-blind, placebo-controlled food challenge after 1 year of treatment. 53% maintained their desensitisation after stopping peanut OIT for 4 weeks; this increased to 72% after up to 2 years of further maintenance treatment.PROJECT PLANWe will evaluate the impact of longer durations of peanut-OIT (up to 3 years) on changes in the immune system, and how this corresponds to clinical outcomes, including desensitisation (and whether this is sustained) and safety, in patients undergoing peanut-OIT. We will apply novel techniques to study not just the initial changes that result in desensitisation, but also what happens when patients subsequently stop OIT doses and the treatment effect may be lost. We have successfully applied this approach to hay fever immmunotherapy. We will therefore be able to better understand the impact of OIT on the immune system, and how the desensitisation effect is sustained. We will analyse blood samples which have been bio-banked from patients in the original BOPI study who have undergone OIT for up to 3 years (under existing ethics approval). Together with existing clinical and laboratory data from BOPI, this will form the most comprehensive dataset evaluating how duration of OIT impacts on both clinical and mechanistic outcomes. Where we identify key findings, we will seek to replicate (and therefore validate) these in a further peanut-OIT study (BOPI-2 study; NCT03937726; currently underway) which also follows patients through to 3 years).This robust approach will allow us to assess the mechanisms associated with both the induction and loss of desensitisation in peanut-allergic children undergoing up to 3 years of OIT. We will use machine learning approaches to understand how these immune changes correlate to clinical outcomes, and so build a model (including both patient characteristics and initial response to treatment) which can predict longer-term treatment outcomes. If successful, this will facilitate the personalisation of OIT protocols, maximising treatment success and leading to safer patient outcomes.