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

花生过敏影响30名儿童中的1名，并且是该年龄组中危及生命的反应（过敏反应）的最常见触发因素。口服免疫疗法（OIT）是一种新兴的治疗选择，通过小剂量、递增剂量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，对OIT的频繁过敏反应（包括速发型过敏反应）很常见，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周后失去脱敏作用。这是一个问题，因为患者通常不喜欢他们过敏的食物的味道，这会影响依从性和治疗成功。脱敏的持续性，而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-特别是脱敏的持续性-尚不清楚。这大大限制了我们识别可能需要不同方案的患者的能力，以最大限度地减少不良反应，实现更持久的脱敏，并提高患者安全性。免疫疗法被广泛用于治疗花粉热和对昆虫叮咬的过敏-其中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的持续时间可能是至关重要的，在实现长期疗效。（NCT02149719;部分资金通过MRC奖学金到特纳），75%的参与者实现了研究的主要成果，并且在治疗1年后，在双盲、安慰剂对照的食物攻击中耐受1.4克花生蛋白（大约6-8个花生）的剂量。停药4周后53%的患者保持脱敏效果;这增加到72%后，长达2年的进一步维护治疗。项目计划我们将评估的影响，更长的时间花生OIT（最多3年）免疫系统的变化，以及这如何对应于临床结果，包括脱敏（以及这种情况是否持续）和安全性，在接受花生OIT的患者中。我们将应用新技术来研究不仅是导致脱敏的最初变化，而且当患者随后停止OIT剂量时会发生什么，治疗效果可能会丧失。我们已经成功地将这种方法应用于花粉热免疫治疗。因此，我们将能够更好地了解OIT对免疫系统的影响，以及脱敏效应如何持续。我们将分析原始BOPI研究中接受OIT长达3年（根据现有伦理批准）的患者的生物库血液样本。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持续时间如何影响临床和机制结局。当我们确定了关键发现时，我们将在进一步的花生OIT研究（BOPI-2研究; NCT 03937726;目前正在进行中）中复制（并因此验证）这些研究，该研究也随访患者3年）。这种稳健的方法将使我们能够评估与花生过敏儿童接受长达3年的OIT的脱敏诱导和丧失相关的机制。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），可以预测长期治疗结果。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局。

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.