IgE Suppressing Berberine Nanomedicine for Treatment of Peanut and Tree nut Allergies

摘要(30行) 食物过敏(FA)是美国一个重大的公共卫生问题，影响着3000多万人，1-3个人导致81% 儿科过敏反应。除了抢救药物和避免，目前的FA治疗是有限的，没有 长效疗法。正常情况下，产生IgE的B细胞和浆细胞是极少数 IGE制作。这些细胞的失调会导致IgE的过度产生，这是一个关键的病理机制 关于FA过敏性休克。足协是高度多样化的。花生和坚果过敏(PNA和TNA)最严重， 树坚果(TN)之间的交叉反应进一步增加了反应的风险 使当前的做法复杂化。尽管几十年来人们意识到食物中过敏原特异性IgE的中心地位 过敏反应7，抑制B细胞/血浆产生IgE仍然是一个主要挑战。奥马珠单抗，抗- 免疫球蛋白抗体，“捕获”免疫球蛋白E，但不以生产为目标。口服免疫疗法(OIT)，包括Palforzia® 花生(PN)可能会矛盾地增加IgE.8-13因此，新的治疗方法应该针对广泛的FA 停药后口服可持续抑制食物特异性免疫球蛋白E和过敏反应 治疗。 我们首次证明了一种小分子化合物黄连素(BBR)，它是从 抑制FA患者外周血单个核细胞(PBMC)产生IgE 14使用BBR的真正临床障碍是口服生物利用度较差。15-17我们进一步 开发了一种创新的纳米颗粒配方，名为NIT-X。初步数据显示口服NIT-X 与母体化合物相比，生物利用度显著提高，具有极好的临床前安全性(无不良反应 每天喂食14倍有效剂量后的效果)，以及PN致敏小鼠每天口服4周一次 NIT-X，2毫克BBR，在纳米颗粒内(相当于人体剂量0.3g/天，基于体表 区域18)减少95%-100%的PN特异性IgE和100%的PN过敏反应，效果持续至少28周 治疗，不影响免疫球蛋白和免疫球蛋白A水平。IgE+B细胞和IgE+浆细胞几乎减少到 很正常。一项正在进行的实验表明，NIT-X对腰果(CSH)和核桃(WN)过敏也有效 加用小鼠PN变态反应模型。因此，我们假设NIT-X，作为非食品限制 理论上，通过恢复正常的IgE调节，治疗性干预对所有FA都是有效的。目标是 这笔为期2年的R21赠款的目的是探索NIT-X作为一种新的治疗方法，以解决专注于和 几乎所有的TN过敏，并探索其机制可能正常化的IgE调节。目标1：确定多头- NIT-X对PN中IgE介导的过敏反应和多发性TN过敏的长期保护作用，目标2： 确定NIT-X持续抑制IgE产生的机制。成功 这项提议的完成将为进一步研究NIT-X作为一种安全有效的 即使是对多种食物过敏或有高反应风险的人也要进行治疗。非食物限制的NIT-X疗法可能 通过恢复IgE调节改变FA的病程，推进临床实践。

Abstract (30 lines) Food allergy (FA) is a substantial US public health problem, affecting over 30 million people, 1-3 causing 81% of pediatric anaphylaxis. 4 Outside of rescue medication and avoidance, current FA treatment is limited with no long-lasting therapeutics. Normally, IgE producing B cells and plasma cells are minor population with minimal IgE production. Dysregulation of these cells causes excessive IgE production, a key pathological mechanism of FA anaphylactic shock. FA is highly diverse. Peanut and tree nut allergies (PNA and TNA) are most severe, rarely outgrown, and often co-exist.5,6 Cross reactivity among tree nut (TN) further increase the risk of reactions complicate current practice. Despite decades of awareness about the centrality of allergen-specific IgE in food anaphylaxis7, inhibiting IgE production by B cells/plasma remains a major challenge. Omalizumab, the anti- IgE antibody, “traps” IgE but does not target production. Oral immunotherapy (OIT), including Palforzia® for peanut (PN) OIT, may paradoxically increase IgE.8-13 Therefore, novel therapeutics should address broad FA and be orally administered with sustainable suppression of food specific IgE and anaphylaxis after stopping treatment. We, for the first time, demonstrated that a small molecule compound berberine (BBR), isolated from Philodendron cortex, inhibited IgE production by peripheral blood mononuclear cells (PBMC) from FA patients at very low doses.14 real clinical barrier to use of BBR use is poor oral bioavailability.15-17 We further developed an innovative nanoparticle-based formulation, named NIT-X. Preliminary data showed oral NIT-X is significantly more bioavailable than parent compound with an excellent preclinical safety profile (no adverse effects found after feeding 14x effective daily dose), and that in PN-sensitized mice 4-weeks of once-a-day oral NIT-X at 2mg BBR within the nano particle (equivalent to a human dose of 0.3g/day, based on body surface area18) reduced 95-100% PN-specific IgE and 100% PN anaphylaxis with effects lasting at least 28 weeks post treatment, without affecting IgG and IgA levels. IgE+ B cells and IgE+ plasma cells were reduced nearly to normal. An ongoing experiment showed NIT-X also worked in cashew (CSH) and walnut (WN) allergy in addition to PN allergy in murine model. We therefore hypothesize that NIT-X, as non-food restricted therapeutic intervention, will be effective, theoretically, for all FA by restoring normal IgE regulation. The goal of this 2-year R21 grant is to explore NIT-X as a novel therapeutic to resolve multiple FA focusing on and nearly all TN allergy and explore its mechanisms possibly normalize IgE regulation. Aim # 1: Determine long- term protection against IgE-mediated anaphylaxis in PN and multi-TN allergies by NIT-X, and Aim #2: Identify the mechanisms contributing to sustained suppression of IgE production by NIT-X. Successful completion of this proposal would provide a strong rationale to further investigate NIT-X as a safe and effective treatment even for those with multi-food allergies or high reaction risk. Non-food-restricted NIT-X therapy may change the course of FA by restoration of IgE regulation, and advance clinical practice.