CN101460067B - 诱导对卵蛋白的耐受 - Google Patents
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Abstract
本发明提供了具有15％和28％之间水解度的酶水解卵蛋白在制备组合物中的用途，所述组合物用于在哺乳动物中诱导对卵蛋白的口服耐受。
Description
技术领域
本发明涉及使用水解卵蛋白在很可能对卵有变应性反应的哺乳动物中诱导对完整卵蛋白的口服耐受(oral tolerance)。
背景技术
在大部分情况下，食物变态反应主要由与食物中蛋白质的反应引起，所述食物变态反应中最常见的是牛乳变态反应。在生命的早几年中，免疫系统仍在发育并且可能不能识别和耐受这样的膳食蛋白质。结果是婴儿或儿童或年幼动物将膳食蛋白质作为外源物质对待，并对其产生变应性应答。食物变态反应可不仅影响人，而且影响其他动物如犬和猫。
T辅助细胞在适应性免疫中起主要作用。Th1细胞对于细胞介导的免疫应答是至关重要的，Th2细胞促进体液免疫。Th1和Th2应答是反调节的(counter-regulative)，即由Th1细胞生产的细胞因子抑制Th2的功能，反之亦然。已显示Th2-偏好的(skewed)免疫应答对于维持成功的妊娠是决定性的，并且在出生和生命的最先数月内占优势。出生后暴露于微生物抗原优先地引发Th1应答，已经提出其平衡新生儿中偏向于Th2的细胞因子生产。在早期微生物暴露不足的情况下，Th2-型细胞因子(IL-4、IL-5和IL-13)的生产进一步增加，导致IgE生产并因此导致变应性疾病。然而，该Th2范例很快被证明不足以解释特应性疾病的整体免疫病理学，并且最近假设特应性疾病初期应当是T调节(Treg)细胞不完全活化的结果，而不是提高的Th2活化的结果。Treg细胞是能够诱导免疫耐受的小T细胞群。已描述了表达抑制性细胞因子(IL-10，TGF-β)的若干种重叠的Treg细胞亚群(Th3，TrI，CD4+，CD25+)。
口服耐受现象是下述性能：通过口服途径的抗原施用能够预防随后对以免疫原性形式给予的相同抗原的系统性免疫应答。如果口服耐受的机制未充分发育，或如果对某些抗原耐受的生理学状态中存在故障，则这可导致过敏性反应的发生。该机制可解释如下：在与抗原第一次接触后，IgE抗体产生并迁移至肥大细胞和嗜碱细胞的表面，在那里它们与特异的受体结合。与变应原第二次接触时，表面IgE被交联在肥大细胞或嗜碱细胞上，导致细胞活化和包括组胺的化学介质的释放。该现象导致病理作用，例如局部的或系统性的血管舒张。
通常，食物过敏性反应仅出现在易感的婴儿、儿童或年幼动物第一次遭遇新食物后。人类婴儿普遍遭遇的第一种膳食蛋白质至少为牛乳蛋白质，并且如上所述，牛乳变态反应是最常见的食物变态反应。普遍接受的是具有确定的牛乳变态反应的婴儿具有提高的对其他膳食蛋白质如卵蛋白和谷物蛋白发生变态反应的风险，但是当这些膳食蛋白质被引入断奶膳食中时，即便是已经成功地对牛乳蛋白质产生口服耐受的那些婴儿仍可随后发生对这些膳食蛋白质的变态反应。
从膳食的观点来看，存在治疗确定的变态反应的两种途径：或者必须完全避免含有变应原的食物，或者必须处理食物以降低其变应原能力，例如通过充分水解进行。为后一目的制备含有被充分水解的牛乳蛋白质(由不多于五种氨基酸组成的肽)的婴儿配方。
然而，存在对下述产品的需要，所述产品帮助降低发生变态反应的风险，并促进产生对完整蛋白质的耐受，尤其是在被认为处于变态反应风险的儿童中(即至少一个亲密的家庭成员具有变态反应的儿童)。例如，已经提出喂养部分水解的牛乳蛋白质，从而在婴儿中诱导对牛乳的口服耐受。Fritsché等人(J.Allergy Clin.Immunol，第100卷，第2期，266-273页)已使用动物模型显示具有18％水解度的牛乳蛋白质酶水解产物能够诱导对完整牛乳蛋白质的口服耐受，而具有28％水解度的水解产物则不能。这些实验的结果显示用此类适度水解的牛乳配方预防性喂养大鼠抑制了来自肠肥大细胞的特异IgE和介质释放，所述IgE和介质释放均为即发型(immediate type)变应性反应的参数，所述适度水解的牛乳配方的变应原性与标准配方相比被降低了超过100倍。该工作证明对于牛乳蛋白质而言，可能限定酶水解的程度，从而维持肽诱导口服耐受的能力同时充分降低其变应原性。
已经提出了改进对牛乳蛋白质口服耐受的诱导的多种其他途径，包括如WO2003/099037中所提出的施用益生菌，或如WO02/051437中所提出的施用能够提高COX-2活性的化合物。然而，人们相对较少关注对频繁引起变应性反应的其他膳食蛋白质如卵蛋白的耐受的诱导。事实上，考虑到在两岁和五岁年龄之间对牛乳蛋白质的变态反应通常自发消失而对卵蛋白的变态反应一般消失得更慢并且甚至可以持续终生，这可能是甚至更强烈的需要。因此，提供诱导对卵蛋白口服耐受的方法是本发明的一个目的。
发明概述
因此，本发明提供了具有15％和28％之间水解度的酶水解卵蛋白在制备组合物中的用途，所述组合物用于在哺乳动物中诱导对卵蛋白的口服耐受。
本发明扩展至通过对需要的哺乳动物提供下述组合物诱导对卵蛋白的口服耐受的方法，所述组合物含有治疗量的具有15％和28％之间水解度的水解卵蛋白。
附图概述
图1显示卵水解产物残余的OVA-特异的抗原性。
图2显示功能性肥大细胞触发(trigger)测定中降低的变应原性。
图3显示不同卵蛋白水解产物抑制特异性IgE抗卵蛋白应答的能力。
图4显示不同的卵蛋白水解产物下调肠肥大细胞的触发的能力。
图5显示充分水解的卵蛋白不能抑制特异性IgE抗卵蛋白应答或下调肠肥大细胞的触发。
发明详述
在该说明书中，以下的术语具有以下的含义：
蛋白质的“水解度”或“DH”表示游离NH2基团中的氮数量除以总氮数量(NH和NH2基团)，以百分比表达
“口服耐受”表示对通过口服途径递送的抗原的免疫低反应性活性状态。
除非另有说明，所有涉及的百分比均是按重量计的百分比。
优选水解度在18％和25％之间，更优选在23％和25％之间。
使用水解卵蛋白成功诱导对完整卵蛋白的口服耐受要求在水解蛋白质的残余抗原性及其诱导口服耐受的能力之间达到平衡。一般地，水解蛋白质的残余抗原性应当比完整蛋白质至少小100倍。
如通过Fritsche等人(Int.Arch.Aller and Appl Imm.，93，289-293，1990)描述的技术所测量的，发现具有20％和28％之间水解度的水解卵蛋白具有与完整卵蛋白相比被降低至少100倍的变应原性。
可以通过本领域已知的任何合适方法酶水解卵蛋白。合适水解方法的一个实例是从巴氏消毒的液态全卵开始的两阶段酶水解。将液态卵加热至60℃到65℃范围内的温度保持约10分钟，然后冷却至约55℃。添加蛋白酶如细菌丝氨酸内切蛋白酶枯草杆菌蛋白酶(例如以商标Alcalase
出售)，将混合物在约55℃下保持至少两个小时达到部分水解。然后将混合物的温度提高至70℃到75℃并保持约10分钟。再次将混合物冷却至约55℃并添加更大量的酶。将混合物在约55℃至少再保持量小时以达到需要的水解度。然后将温度提高至85℃和95℃之间并保持多达30分钟的时间，使酶失活并终止水解。得到的液态水解卵可以在该状态下使用，或可以优选喷雾干燥产生粉末产物。
适用于本发明的组合物可以是其中常规掺入了全卵被替换为水解卵的任何食品，其中卵蛋白具有20％和28％之间的水解度。如上所述制备的水解卵粉例如可以在如烘焙的蛋挞(custard)、乳蛋饼(quiche)、焦糖布丁(creme caramel)的配方中代替全卵粉使用。或者，水解卵粉可以用水重溶并用于制备盘装菜如煎蛋和炒蛋。水解卵粉是尤其合适的婴儿和幼儿食物成分，尤其是适用于断奶早期阶段的食物中。水解卵粉也可以代替常规用于制备这类产物的全卵粉使用。
如上所述，对膳食蛋白质的变态反应不仅限于人，且本发明的方法也可以用于在其他哺乳动物(尤其是伴侣动物如犬和猫)中诱导对卵蛋白的口服耐受。因此具有15％和28％之间水解度的水解卵蛋白也可以用于代替伴侣动物食物中的全卵，所述食物尤其是例如旨在用于断奶中幼犬和幼猫的食物。
现在将参考以下的实施例进一步描述本发明。
制备卵水解产物
初始材料为经巴氏消毒的全卵，FT/OVO/0105R，ABCD S.A.，AvicoleBretonne Cecab Distribution(
，法国)。
实施例1
将30Kg液态全卵在65℃加热10分钟并以250转/分钟搅拌。冷却至55℃后，添加2％
酶(批次PW2A1006，NOVOZYMES A/SBagsvaerd，丹麦)并将混合物在55℃保持2小时。在该第一步水解步骤后，添加1％
1000L酶(批次400904，NOVOZYMES A/SBagsvaerd，丹麦)并将混合物在75℃加热10分钟。然后将混合物冷却至55℃，再添加1％ Flavourzyme酶并将混合物在55℃保持2小时。该第二水解步骤后，将混合物在90℃加热30分钟然后喷雾干燥获得水解卵粉，所述卵粉保存于铝袋中。
实施例2
将35Kg液态全卵在65℃加热10分钟并以250转/分钟搅拌。冷却至55℃后，添加5％
酶(批次PW2A1006，NOVOZYMES A/SBagsvaerd，丹麦)并将混合物在55℃保持2小时。在该第一步水解步骤后，添加1％
1000L酶(批次400904，NOVOZYMES A/SBagsvaerd，丹麦)并将混合物在75℃加热10分钟。然后将混合物冷却至55℃，再添加4％Flavourzyme酶并将混合物在55℃保持2小时。该第二水解步骤后，将混合物在90℃加热30分钟然后喷雾干燥获得水解卵粉，所述卵粉保存于铝袋中。
实施例3
将30Kg液态全卵在65℃加热10分钟并以250转/分钟搅拌。冷却至55℃后，添加10％
2.4L酶(批号500357，NOVOZYMES A/SBagsvaerd，丹麦)并将混合物在55℃保持2小时。在该第一步水解步骤后，将混合物在75℃加热10分钟。然后将混合物冷却至55℃，再添加10％Alcalase酶并将混合物在55℃保持2小时。该第二水解步骤后，将混合物在90℃加热30分钟然后喷雾干燥获得水解卵粉，所述卵粉保存于铝袋中。
含有水解全卵的产物
实施例4
含水解卵的甜卵布丁的成分的一个实例如下：
成分 ％
全乳(3.5％脂肪) 62.0
水 24.3
糖 5.5
低变应原性卵粉 2.5
玉米淀粉 3.0
木薯淀粉 2.0
香草矫味剂 0.7
可以通过本领域已知的任何合适方法制备布丁。
实施例5
含水解卵的可口卵布丁的成分的一个实例如下：
成分 ％
全乳(3.5％脂肪) 62.0
水 21.5
冷冻胡萝卜块 10.0
低变应原性卵粉 1.5
玉米淀粉 3.0
木薯淀粉 2.0
可以通过本领域已知的任何合适方法制备布丁。
实施例6
含水解卵的卵意大利面食(pasta product)的成分的一个实例如下：
成分 ％
杜兰小麦粉(Durum wheat semolina) 70.6
水 21.6
低变应原性卵粉 5.9
葵花子油 1.9
可以通过本领域已知的任何合适方法制备意大利面食。
卵水解产物的残余抗原性
用多克隆兔抗OVA蛋白抗血清通过ELISA抑制测定实施例1、2和3的水解产物中蛋白质卵清蛋白(OVA)的残余抗原性。用碳酸盐-碳酸氢盐缓冲液中50μg/ml的OVA(100μl)包被微量滴定板的孔，并在4℃下孵育24小时。将平板在PBS-Tween缓冲液中洗涤4次，通过添加200μl/孔鱼明胶(PBS-Tween中0.5％)封闭游离的反应位点。将平板在室温(RT)下孵育1小时并在PBS-Tween中再次洗涤4次。
在分离的管中，将1份标准OVA制剂或测试样品与1份兔抗OVA蛋白抗体(1:20′000稀释)在RT下孵育1小时。孵育后向上述被包被和封闭的微量滴定孔中添加100μl该抑制混合物并在室温下孵育2小时。将平板在PBS-Tween中洗涤4次。然后添加山羊抗兔过氧化物酶标记的缀合物(0.1 ml 1:2000的稀释液)，将平板在室温下孵育1小时并在PBS-Tween中洗涤4次。添加显色底物(0.1ml邻苯二胺)。孵育15分钟后，在ELISA平板读数器上于492nm处读数光密度。
结果显示在图1中，从图1中可以看出来自实施例1到3的水解产物的OVA特异抗原性与完整的卵蛋白相比被降低了超过10,000倍。
卵水解产物的残余变应原性
如先前所述(Fritsché等人，J.Allergy Clin.Immunol，第100卷，第2期，第266-273页)，使用由致敏的大鼠肥大细胞释放的氚标记的5-羟色胺的功能性体外测定法测定抗原分子(OVA)的IgE依赖的变应原性。简言之，通过在含10％胎牛血清的Dulbecco′s改良的Eagle′s培养基中的腹膜洗涤物获得来自正常Sprague-Dawley大鼠的肥大细胞。在该培养基中洗涤细胞并在4℃保持过夜。在pH7.0的磷酸盐-HEPES-鱼明胶缓冲液(PHG)中洗涤两次后，将细胞以5x105细胞/ml重悬于相同的缓冲液中，并用一倍体积的富含IgE抗OVA抗体的大鼠血清稀释，所述血清含5μCi/ml3H 5-羟色胺。在37℃孵育2小时后，将细胞在PHG中再洗涤三次并以2.5x105细胞/ml重悬于PHG中。致敏的肥大细胞被分配至微量滴定板(0.1ml/孔)中并与0.05ml根据实施例2生产的水解卵蛋白的连续稀释液(从10mg/ml开始1/10稀释)混合。将混合物在37℃孵育60分钟并离心。将上清液的等分式样(0.05ml)与2ml闪烁液混合并使用Packard β-计数器测量3H释放。
结果显示于图2中，从中可以看出水解卵具有显著降低的变应原性(25μg OVA/g蛋白质当量)，并且当水解卵被掺入果馅饼(flan)型甜点中时维持该低值。
通过喂养卵蛋白水解产物诱导对卵蛋白的口服耐受
使用体内大鼠模型研究卵制品的口服耐受诱导能力。对用无卵蛋白膳食饲养的六组Sprague-Dawley大鼠(6只动物/组)，在实验的第1天到第19天，在其饮水瓶中无限制地给予不同的实验性液态卵蛋白/卵水解产物或水(对照)和固体的无卵蛋白膳食。对动物给予以下的产物：
A组 全卵粉(20g/l)；
B组 来自实施例3的水解卵粉(120g/)，DH 25％；
C组 来自实施例2的水解卵粉(120g/l)，DH 23％；
D组 来自实施例1的水解卵粉(120g/l)，DH 20％；
E组 来自实施例3的经超滤的水解卵粉(120g/l)，DH 31％；
F组 H2O(对照)。
如下获得喂养E组的经超滤的水解卵粉。使用具有100μm袋式滤器(PGF 51 E 02)的过滤组件(Sefiltec，FBF 0102)对实施例3中获得的底物水解液态卵微孔过滤。在该微孔过滤步骤后，使用带有4000道尔顿的膜(ES404，PES，4000MWCO，PCI Membrane Systems)的自制UF组件对滤出物进行超滤。然后冻干滤出物。
通过Dumas方案(Carlo Erba方法)测定水解产物中的总氮。根据Adler-Nissen(J.Agric.Food.Chem.1979 27：1256-1262)通过TNBS方法测量水解度。
在实验的第5天通过皮下注射0.1mg卵清蛋白+0.2ml3％Al(OH)3对所有的大鼠进行免疫。在第19天处死所有的动物。采血并如先前所述(Fritsché R，Bonzon M.Int Arch Allergy Appl Immunol1990；93：289-93)通过ELISA针对特异性IgE抗体(抗卵清蛋白)分析血清。简言之，用OVA在4℃下包被微量滴定板24小时。用PBS Tween 20洗涤平板并用鱼明胶饱和1小时。添加连续稀释(1/2)的待测血清并孵育2小时后，添加山羊抗大鼠IgE抗血清。室温下1小时后，添加过氧化物酶标记的第二抗体1小时，然后添加底物(邻苯二胺)。1：5稀释的正常大鼠血清集合体在492nm处的光密度被认为是非特异性背景。根据该值(above this value)，特异抗体的浓度表述为测试血清的最大稀释度。
在IgE介导的肠肥大细胞触发后，大鼠肥大细胞蛋白酶(RMCPII)被释放进血中。对RMCPII释放的口服激发是在肠肥大细胞水平上IgE致敏或致耐受(tolerization)的度量。用基于夹层测试原理的市售ELISA试剂盒(Moredun Animal Health Ltd.，Edinburgh，Scotland)测定RMCPII水平，其中用单克隆抗RMCPII抗体制备平板包衣，然后添加测试血清和与辣根过氧化物酶偶联的第二山羊抗RMCPII多克隆抗体。
结果显示在图3、4和5中。从图3中可以看出，与非致耐受的(non-tolerised)对照(F组)相比，当来自实施例1到3的卵蛋白水解产物在19天内无限制地喂养给动物时，所述卵蛋白水解产物能够抑制特异的IgE抗卵蛋白应答，所述应答诱导高水平的IgE抗卵蛋白抗体。更确切地，IgE抗OVA水平(表达为log抗体效价)如下：A组，4+/-1.1；B组，4.1+/-0.9；C组，3.3+/-1.1；D组，4.1+/-2.0；F组，6.1+/-0.3。比较各组时，A到D的所有组与F组(对照)差异显著(p<0.05)。
图4也显示在A、B、C和D组中肠巨大细胞触发被下调，而F组(对照)中则没有。以μg RMCPII/ml表达的数值如下：A组，0+/-0.0；B组，0.6+/-1.0；C组，1.2+/-1.7；D组，0.6+/-0.8；F组，2.8+/-0.7。比较各组时，A到D的所有组与F组(对照)差异显著(p<0.05)。
图5显示如通过对特异IgE抗卵蛋白应答的抑制或肠肥大细胞触发的下调所测量的，给E组喂养的充分水解的卵蛋白未诱导对OVA的口服耐受：IgE抗OVA和RMCPII水平与得自对照组的值没有差异。
Claims (6)
1.具有15％和28％之间水解度的酶水解卵蛋白作为唯一活性成分在制备组合物中的用途，所述组合物用于在哺乳动物中诱导对卵蛋白的口服耐受。
2.权利要求1的用途，其中哺乳动物是人。
3.权利要求2的用途，其中组合物是婴儿的断奶食物。
4.权利要求1的用途，其中哺乳动物是伴侣动物。
5.权利要求4的用途，其中伴侣动物是猫或犬。
6.权利要求1-5中任一项的用途，其中水解度在23％和25％之间。
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| EP06115533.9 | 2006-06-15 | ||
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| PCT/EP2007/055882 WO2007144397A1 (en) | 2006-06-15 | 2007-06-14 | Induction of tolerance to egg proteins |
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| EP2508193A1 (en) | 2011-04-05 | 2012-10-10 | Nestec S.A. | Use of a hypoallergenic cereal composition for inducing specific oral tolerance |
| US11324247B2 (en) | 2019-06-13 | 2022-05-10 | Lil Mixins, Llc | Food products for infants and babies and method of making same |
| US11154082B2 (en) * | 2019-06-13 | 2021-10-26 | Lil Mixins, Llc | Egg product for infants and babies and method of making same |
| US11154081B1 (en) | 2021-03-16 | 2021-10-26 | Lil Mixins, Llc | Well cooked egg powder |
| US11439173B1 (en) | 2021-09-22 | 2022-09-13 | Lil Mixins, Llc | Low allergenicity well cooked food powder |
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| GB9312369D0 (en) * | 1993-06-16 | 1993-07-28 | Sandoz Nutrition Ltd | Organic compounds |
| FI104465B (fi) * | 1995-06-14 | 2000-02-15 | Valio Oy | Proteiinihydrolysaatteja allergioiden hoitamiseksi tai estämiseksi, niiden valmistus ja käyttö |
| PT827697E (pt) * | 1996-09-06 | 2002-11-29 | Nestle Sa | Inducao da tolerancia ao leite de vaca |
| MY129566A (en) * | 1999-01-19 | 2007-04-30 | Nestle Sa | A hypoallergenic composition containing tolerogenic peptides inducing oral tolerance |
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Non-Patent Citations (1)
| Title |
|---|
| 安 毅等.大豆蛋白活性肽在功能性食品中.《大豆通报》.2004,(第4期),27-29. * |
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| Publication number | Publication date |
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| PT2031986E (pt) | 2013-04-19 |
| ES2403644T3 (es) | 2013-05-20 |
| MX2008015690A (es) | 2008-12-19 |
| AU2007259231A1 (en) | 2007-12-21 |
| EP2031986A1 (en) | 2009-03-11 |
| WO2007144397A1 (en) | 2007-12-21 |
| PL2031986T3 (pl) | 2013-08-30 |
| EP2031986B1 (en) | 2013-03-20 |
| US20100255039A1 (en) | 2010-10-07 |
| AU2007259231B2 (en) | 2013-05-09 |
| CN101460067A (zh) | 2009-06-17 |
| BRPI0713596A2 (pt) | 2012-10-30 |
| RU2445992C2 (ru) | 2012-03-27 |
| RU2009101018A (ru) | 2010-07-20 |
| CA2653157A1 (en) | 2007-12-21 |
| ZA200900309B (en) | 2010-03-31 |
| MY180578A (en) | 2020-12-02 |
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