CN101808532B - 在断奶时的过敏反应的预防 - Google Patents
在断奶时的过敏反应的预防 Download PDFInfo
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- CN101808532B CN101808532B CN2008801087005A CN200880108700A CN101808532B CN 101808532 B CN101808532 B CN 101808532B CN 2008801087005 A CN2008801087005 A CN 2008801087005A CN 200880108700 A CN200880108700 A CN 200880108700A CN 101808532 B CN101808532 B CN 101808532B
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- lactalbumin
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Abstract
本发明涉及营养组合物，其包含水解度15至25％的部分水解的奶蛋白和就每100ml即用组合物而言的50至1000毫微克的TGF-β，以及用于初级预防在断奶的幼小哺乳动物对新引入的食物蛋白的过敏反应的方法和预防在断奶的幼小哺乳动物发生特应性疾病的方法，其包括以治疗量的所公开组合物喂养幼小哺乳动物。
Description
发明领域
本发明涉及营养组合物及该组合物在降低断奶过程中发生过敏反应和特应性疾病的风险中的应用。
发明背景
食物过敏反应(其中生命中首先发生的是牛奶过敏反应)在大多数情况下由对食物中蛋白的反应而引起。在生命早期，免疫系统仍在发育中，可能不能对食物性抗原产生耐受(这也可被描述为口服耐受的诱导不足)。其结果是婴儿或儿童或幼小动物对食物蛋白产生过度的免疫应答并对其产生过敏反应。食物过敏反应不仅会影响人类还会影响其他哺乳动物如狗和猫。
通常，食物超敏反应仅在易感的婴儿、儿童或幼小动物初次遇到含有潜在变应原的新食物后产生。除其母乳之外，至少人类婴儿一般最早遇到的食物蛋白是牛奶蛋白，并且如上所述，牛奶过敏反应是人类婴儿中最常见的食物过敏反应。一般认为，有确立的牛奶过敏反应的婴儿对其它食物蛋白如鸡蛋和谷物蛋白产生过敏反应的风险增加。这些过敏反应临床上会表现为特应性疾病如特应性皮炎、湿疹和哮喘。即使是那些对牛奶蛋白成功产生口服耐受的婴儿，当断奶时饮食中引入其它食物蛋白如鸡蛋和谷物蛋白时，也可能随后对其发生过敏反应。
从饮食的观点来看，治疗确立的过敏反应只有两种方法——必须全部避免含变应原的食物，或者必须处理食物例如通过广泛水解以降低其变应原潜能。为后者目的生产了含有广泛水解的牛奶蛋白(所含的肽由不多于5个氨基酸构成)的婴儿配方。相似地，例如在美国专利US6403142中，已计划为怀疑产生食物过敏反应的伴侣动物制备具有减低的变应原性的宠物食品。然而，由于在避免式饮食(avoidance diets)的情况下可用的食材非常有限，而在使用广泛水解产物的情况下口味差，排除式饮食(exclusion diets)具有顺应性低的缺点。另外，总是存在仍然遇到完整变应原的危险。
因此，特别是对被认为有过敏反应风险的儿童(即，具有至少一个患有过敏反应的近亲的儿童)而言，设计了有助于降低产生最初过敏反应风险的产品。这种产品的实例之一是基于部分水解的乳清蛋白的婴儿配方，所述乳清蛋白的商标是NAN HA1和NAN HA2。这些产品被证明能积极诱导对牛奶蛋白的口服耐受。Fritsché等(J.Allergy Clin.Immunol，第100卷，第2期，第266-273页，1997)用动物模型显示具有18％水解度的牛奶蛋白的酶水解物能够诱导对完整牛奶蛋白的口服耐受，而具有28％水解度的水解物则不能。这些实验的结果显示，用这种适度水解的牛奶配方对大鼠进行的预防性给食抑制了特异性IgE和肠肥大细胞的介质释放(均为直接型过敏反应的参数)，与标准配方相比上述配方的变应原性被降低超过100倍。这项工作证明，对牛奶蛋白而言，限定酶水解度由此保持肽类诱导口服耐受的能力同时显著降低其变应原性是可能的。
在人奶中发现的生物活性肽---转化生长因子β，已被证实为特应性疾病的潜在调节剂。整合分析(meta analysis)为人奶中TGF-β的总体过敏反应预防效果提供了证据(Gdalevich，2001)。根据Kalliomaki等(J AllergyClin.Immunol.1999年12月；104(6)：1251-7)，初乳中的TGF-β能够在仅母乳喂养期预防特应性疾病的发生并促进人类个体中特异性IgA产生。相似地，Oddy等报道了在相当长时期内母乳喂养并因此与较短时期母乳喂养的儿童相比接收到的TGF-β的总量高的儿童中，喘鸣(指示发生呼吸器官过敏反应)的发病率降低(Oddy等，J Allergy Clin Immunol)。近来，在大鼠模型中显示向牛奶配方加入TGF-β降低了对牛奶的变应性致敏(Pentilla等，Pediatr Research 2006)。
幼小哺乳动物仅靠奶喂养的时期是相对短的范围，例如，从对大鼠和小鼠而言几周，到对人类婴儿而言四至六个月。在这段时期后，其它含有不同食物蛋白的食材逐渐地被引入饮食中，在通常被称为断奶的阶段，对用来提供所有生长发育必需营养素的奶的依赖被相应地降低。
一般而言，幼小哺乳动物遇到的第二食物蛋白是谷物蛋白，其在断奶开始即被引入，对人类婴儿而言通常以婴儿谷物的形式引入。即使奶蛋白已被成功地引入，谷物蛋白当最初被引入幼小哺乳动物饮食中时也可能引起过敏反应。此后，幼小哺乳动物将快速连续地遇到其它食物蛋白包括鸡蛋、花生、鱼和肉，每次都有导致过敏反应的风险。
然而，与奶蛋白相比，对其它食物蛋白如谷物和鸡蛋蛋白的过敏反应的初级预防或通过饮食干预预防对其它抗原如花粉的过敏反应发生的可能性相对几乎没有引起关注。事实上，考虑到对牛奶蛋白的过敏反应通常在二至五岁间自发消失而对例如谷物和鸡蛋蛋白的过敏反应一般较慢消失甚至可能持续终生，其可能是更值得关切的事。
因此，特别是在有过敏反应发生风险的婴儿中，有需要通过降低对除了奶蛋白的食物蛋白发生过敏反应的风险以促进所述蛋白在断奶幼小哺乳动物饮食中的引入，以及有需要降低随后的特应性疾病的发生，无论其是否由食物性抗原引起。
发明概述
本发明人惊奇地发现，当被引入在断奶的幼小哺乳动物饮食中时，使用部分水解的奶蛋白和TGF-β的组合有助于诱导对其它食物蛋白如谷物和鸡蛋蛋白的耐受，同时保持先前确立的对牛奶蛋白的耐受。
因此，在第一方面，本发明提供了营养组合物，其包含水解度在15至25％的部分水解的奶蛋白和就每100ml即用组合物而言的50至1000毫微克的TGF-β。
本发明还涉及对在断奶的幼小哺乳动物对新引入的食物蛋白的过敏反应的初级预防的方法，其包括对断奶期幼小哺乳动物给食治疗量的包含水解度15至25％的部分水解的奶蛋白和TGF-β的组合物。
本发明进一步涉及在断奶的幼小哺乳动物中特应性疾病的初级预防的方法，其包括对断奶期幼小哺乳动物给食治疗量的包含水解度15至25％的部分水解的奶蛋白和TGF-β的组合物。
特应性疾病如特应性湿疹、过敏性鼻炎和哮喘可能是对食物蛋白的过敏反应或对其它类型抗原如空气传播型抗原的过敏反应的临床表现。例如，哮喘的流行在近几十年里显著增加，极可能是环境因素(如病原体、变应原、空气污染及饮食)改变的结果。已证明，空气传播型抗原能有效地通过奶由母亲转移给婴儿，以及耐受诱导不需要免疫球蛋白的转移。母乳喂养诱导的耐受依赖于哺乳期间TGF-β的存在，由CD4+T淋巴细胞介导并依赖于T细胞中的TGF-β信号传导。总之，母乳介导的空气传播型抗原向婴儿的转移使口服耐受被诱导，导致抗原-特异性保护以免发生过敏性气道疾病。不希望受理论的约束，发明人相信，对空气传播型抗原的耐受诱导不需要免疫球蛋白的转移但是却依赖于母乳中TGF-β的作用，这一令人惊奇的发现导致实现了通过基于部分水解的奶蛋白与TGF-β联合的营养干预以降低对食物蛋白的过敏反应和特应性疾病发生的风险的可能性。换句话说，在断奶期间施用部分水解的奶蛋白和TGF-β的组合在当婴儿初次遇到其它食物蛋白如鸡蛋蛋白和谷物蛋白时有助于降低对新蛋白的致敏风险及随之对这些蛋白发生的过敏反应，以及降低特应性疾病发生的风险。
发明详述
在本说明书中，下列术语具有下列含义：
“特应性疾病”表示变应性致敏的临床表现，并包括特应性皮炎、特应性湿疹、变应性鼻炎和哮喘；
蛋白的“水解度”或“DH”表示完整蛋白在水解时被裂解的肽键数除以完整蛋白中的肽键数，以百分比表达；
“婴儿”表示年龄小于12个月的儿童；
“成长配方(follow-on formula)”表示预期用于年龄在4个月以上的婴儿、并在所述婴儿逐渐变化的饮食中构成主要液体成分的组合物；
“口服耐受”表示对经口服途径递送的抗原有免疫低反应性的活性状态；
“对食物蛋白过敏反应的初级预防”表示防止建立该过敏反应，并包括降低该过敏反应的风险；
“TGF-β”或“转化生长因子β”是指一组至少5种不同但密切相关的生物活性肽，其称为TGF-β1、TGF-β2等，尤其在人奶中被发现(TGF-βl和TGF-β2)(Li等，免疫应答的转化生长因子-β调节(Transforming GrowthFactor-β Regulation of Immune Responses)，Annu.Rev.Immunol.200624：99-146)；
“断奶”表示在幼小哺乳动物的饮食中引入食物而非其母乳或基于奶的替代品如婴儿配方；
“断奶期”表示在幼小哺乳动物生命中的一个时期，以食物而非其母乳或基于奶的替代品的引入为开始，以停止母乳喂养或婴儿配方或成长配方的施用为终止。
除非另有说明，所有提及的百分比都是重量百分比。
本发明提供了营养组合物，其包含水解度15至25％的部分水解的奶蛋白和就每100ml即用组合物而言的50至1000毫微克的TGF-β。
奶蛋白可以是乳清蛋白、酪蛋白或其混合物，但优选乳清蛋白。如果使用乳清蛋白，优选水解度在15至19％。
优选地，部分水解的奶蛋白具有至少低于完整乳清蛋白100倍的残留抗原性。部分水解的奶蛋白的残留变应原性可通过由Fritsché等(Int.Arch.Aller and Appl Imm，93，289-293，1990)描述的技术来测量。按照EU导则96/4/EC的规定，所述部分水解的奶蛋白及含有其的产品可以被描述为低变应原的。
本发明的组合物可以被用于断奶的幼小哺乳动物包括人类婴儿、幼儿以及幼小的伴侣动物如狗和猫。
优选地，本发明的营养组合物是婴儿配方、更优选用于年龄在4个月以上婴儿的成长配方。
奶蛋白可以以本领域已知的任何适合方式水解。在乳清蛋白的情况下，合适的方法被描述于欧洲专利EP322,589，其内容在此引入作为参考。经发现，如果用作起始材料的乳清片段基本上无乳糖，则蛋白在水解和其后的加热过程中受到较少的赖氨酸的阻碍。这使得赖氨酸阻碍的范围从约15％重量的总赖氨酸降低到小于约10％重量的赖氨酸；例如约7％重量的赖氨酸阻碍，这极大地改善了蛋白源的营养质量。
乳清蛋白的源可以是酸乳清、甜乳清、乳清蛋白分离物或其混合物。然而，优选地，蛋白源是基于乳清蛋白分离物或改良的甜乳清。甜乳清是乳酪生产中容易获得的副产品并常用于生产基于牛奶的婴儿配方。然而，甜乳清包含称为酪蛋白糖巨肽(CGMP)的成分，其不期望地富含苏氨酸而少含色氨酸。从甜乳清中去除CGMP以产生具有更接近于人奶苏氨酸含量的蛋白片段。从甜乳清中去除CGMP的过程被描述于EP 880902。
如果用改良的甜乳清或乳清蛋白分离物作为蛋白源，优选用游离组氨酸以0.1至3％重量的蛋白的量加以补充。
本发明的婴儿配方可包含就每100ml即用配方而言的1.0至2.0克部分水解的乳清蛋白，更优选1.5至1.9g/100ml。
本发明的成长配方含有就每100ml即用配方而言的50至1000毫微克的TGF-β，更优选50至500毫微克/100ml，最优选200至300毫微克/100ml。优选地，本发明的成长配方含有TGF-β1和TGF-β2，更优选以1∶5至1∶50的比例存在。
TGF-β可以以富含生物活性肽如来自于Armor Protéines(法国)的TM0301或XP-828L的乳清蛋白片段的形式，或以例如如EP313515或WO92/00994中所述的从奶中分离的多肽生长因子的形式加入配方中。或者，如果优选可以用重组TGF-β。
本发明的成长配方可含有碳水化合物源。尽管优选的碳水化合物源是乳糖，可以使用任何常规存在于婴儿配方中的碳水化合物源如乳糖、蔗糖、麦芽糖糊精、淀粉及其混合物。优选地，碳水化合物源贡献配方总能量的35至65％。
本发明的成长配方可含有脂类源。脂类源可以是任何适合用于婴儿配方的脂质或脂肪。优选的脂肪源包括棕榈三油酸甘油酯、高油酸葵花籽油和高油酸红花油。也可加入必需脂肪酸亚油酸和α-亚麻酸，也可加入少量含有大量的预先形成的花生四烯酸和二十二碳六烯酸的油，如鱼油或微生物油。总之，脂肪含量优选地例如贡献配方总能量的30至55％。优选地，脂肪源中n-6至n-3脂肪酸的比例是约5∶1至约15∶1；例如约8∶1至约10∶1。
所述成长配方还可以以营养学上有意义的量含有所有被认为在日常饮食中必要的维生素和矿物质。对一些维生素和矿物质而言已建立最小需求量。矿物质、维生素和其它任选地存在于婴儿配方中的营养素的实例包括维生素A、维生素B1、维生素B2、维生素B6、维生素B12、维生素E、维生素K、维生素C、维生素D、叶酸、肌醇、烟酸、生物素、泛酸、胆碱、钙、磷、碘、铁、镁、铜、锌、锰、氯化物、钾、钠、硒、铬、钼、牛磺酸和L-肉碱。矿物质通常以盐的形式加入。特定矿物质和其它维生素的存在及用量的变化取决于目标婴儿群。
如果有必要，配方可含有乳化剂和稳定剂如大豆卵磷脂、单和双甘油酯的柠檬酸酯等。
配方任选地含有可具有有益影响的其它物质如乳铁蛋白、核苷酸、核苷等。
最后，配方可含有不能消化的寡糖如半乳寡糖(galacto-oligosaccharides)，例如含量是0.3至7％。
配方可以以任何合适的方式制备。例如，可通过以适当的比例混合部分水解的奶蛋白、碳水化合物源以及脂肪源而制备。如果使用乳化剂，则可在此时加入。TGF-β也可在此时加入。维生素和矿物质可在此时加入但通常稍后加入以避免热降解。任何亲脂性维生素、乳化剂等可在搅拌前溶解于脂肪源中。然后可将水、优选已进行反渗透的水加入混合以形成液体混合物。水的适宜温度为约50℃至约80℃以利于成分的分散。可使用商购可得的液化器以形成液体混合物。然后将液体混合物(例如分两个阶段)均化。
然后可将液体混合物热处理以降低细菌载量，例如通过快速加热液体混合物至约80℃至约150℃的温度范围约5秒至约5分钟来进行。这可通过注蒸汽、高压釜或通过热交换器进行；例如板式热交换器。
然后，可将液体混合物冷却至约60℃至约85℃；例如通过瞬时冷却法进行。然后可将液体混合物再次均化，例如分两个阶段，第一阶段约10MPa至约30MPa，第二阶段约2MPa至约10MPa。然后可将均化的混合物进一步冷却以加入任何热敏感成分，如维生素和矿物质。此时适宜地调节均化混合物的pH和固体成分。
将均化的混合物转移至合适的干燥装置如喷雾干燥器或冷冻干燥器并转化成粉末。该粉末的含水量应小于约5％重量。TGF-β如果未在之前加入则可在此时通过干燥混合加入。
如果优选是液体产品，则可将均化的混合物灭菌并无菌填装于合适的容器中。
实施例1
下列给出本发明的成长配方组合物的实施例。该组合物仅为说明意图而给出。
Claims (9)
1.营养组合物，其包含
就每100ml即用组合物而言的1.0至2.0克部分水解的乳清蛋白，其中所述部分水解的乳清蛋白具有15至25％的水解度和
就每100ml即用组合物而言的50至1000毫微克的TGF-β，所述TGF-β是TGF-β1和TGF-β2的混合物，其中TGF-β1与TGF-β2的比例是1∶5至1∶50。
2.根据权利要求1的组合物，其为成长配方。
3.根据权利要求1或2的组合物，其中所述部分水解的乳清蛋白具有至少低于完整蛋白100倍的残留抗原性。
4.根据权利要求1的组合物，其中所述部分水解乳清蛋白的水解度是15至19％。
5.根据权利要求1的组合物，其包含就每100ml即用组合物而言的1.2至1.9克部分水解的乳清蛋白。
6.根据前述权利要求1的组合物，其包含就每100ml即用组合物而言的200至300毫微克的TGF-β。
7.治疗量的根据权利要求1至6中任意一项的组合物在制备用于在断奶的人类婴儿对新引入的食物蛋白的过敏反应的初级预防的产品中的应用。
8.治疗量的根据权利要求1至6中任意一项的组合物在制备用于在断奶的人类婴儿中特应性疾病的初级预防的产品中的应用。
9.根据权利要求7或8的应用，其中人类婴儿的年龄在4个月以上。
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| Effects of Transforming Growth Factor-Beta and Formula;IRMELI PENTTILA;《PEDIATRIC RESEARCH》;20061231;第59卷(第5期);650-655 * |
| IRMELI PENTTILA.Effects of Transforming Growth Factor-Beta and Formula.《PEDIATRIC RESEARCH》.2006,第59卷(第5期),650-655. |
Also Published As
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|---|---|
| US8383587B2 (en) | 2013-02-26 |
| US9226945B2 (en) | 2016-01-05 |
| CN101808532A (zh) | 2010-08-18 |
| US20130165374A1 (en) | 2013-06-27 |
| RU2010116199A (ru) | 2011-11-10 |
| BRPI0817267A2 (pt) | 2014-10-07 |
| EP2044851A1 (en) | 2009-04-08 |
| RU2489888C2 (ru) | 2013-08-20 |
| ZA201002897B (en) | 2011-10-26 |
| EP2194799A1 (en) | 2010-06-16 |
| UA103754C2 (ru) | 2013-11-25 |
| MY160943A (en) | 2017-03-31 |
| AU2008303622A1 (en) | 2009-04-02 |
| TW200922477A (en) | 2009-06-01 |
| WO2009040310A1 (en) | 2009-04-02 |
| MX2010003253A (es) | 2010-04-09 |
| AU2008303622B2 (en) | 2014-02-20 |
| CA2700670A1 (en) | 2009-04-02 |
| US20110021428A1 (en) | 2011-01-27 |
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