CN1187772A - 预防或治疗过敏的方法 - Google Patents
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Abstract
本发明涉及抑制遭受食物过敏的病人的食物引发的过敏反应的方法和途径。本发明尤其提供了制备一种抑制过敏反应和提高消化道免疫屏障物的蛋白质水解产物配方的方法,和预防或治疗过敏,尤其是婴儿的牛奶过敏的方法,这是通过用从胃肠道中获得的合适的益生菌(probiotic bacteria),尤其是乳杆菌,来强化牛奶消食而进行的。而且,施用一种由胃肠细菌免疫反应改性的过敏原的片断可以将敏感反应转变为全身性的反应低下。用于本发明的一种优选细菌是乳杆菌GG(ATCC53103)。
Description
本发明涉及对患食物过敏的病人抑制由食物引发的过敏反应的方法和途径。本发明尤其提供了预防或治疗过敏症，特别是婴儿的牛奶过敏症的方法。本发明也涉及研制用于带有消化道屏障功能损害的过敏婴儿的特殊配方。
牛奶过敏症(CMA)被定义为对牛奶蛋白的一种免疫介导的不良反应。本选择的治疗是彻底除去牛奶抗原。对于有CMA的婴儿，当不能获得人奶时，有必要用一种替代配方。基于从牛奶中获得的乳清或酪蛋白的水解配方，被用于来提供足够的营养并有减少的抗原负荷。对牛奶的初步热处理主要影响蛋白的构象，并且使它们易于水解。用胃蛋白酶，胰蛋白酶，胰提取物和肠粘膜提取物的随后的酶水解导致顺序抗原决定基的逐渐破坏和将配方精制为最少的抗原和过敏形式。
大多数情况下，可安全地采用彻底水解的牛奶衍生配方，这些有效且在临床和代谢上有好的耐受性。但是，酶水解不一定使配方非过敏，因为最佳的水解程度不知道且在水解物中可以测到微量的最初蛋白。因此要小心地将这些替代物引入有牛奶过敏症的小孩。
通过除去抗原来控制过敏性炎症的方法不能令人满意，尤其是对患有多种食物过敏的患者(Sampson等，1992)。这些患者经常表现出增强的肠渗透性和肠防御屏障的机能异常(Majamaa等，1996，Majamaa和Isolauri，1996)。这增大了生长紊乱和对多种食物敏化的危险性。迫切需要有新方法来治疗牛奶过敏以提高CMA中替代物配方。
肠抗原处理决定着随后的对抗原的免疫反应。在健康方面，抗原沿着二条功能路径而越过上皮被吸收。主要路径是降解性地减少了抗原的免疫原性，次要路径可以运输对于特定抗原免疫反应关键的完整的蛋白质。异常的抗原吸收提高了致敏过程(Fargeas等，1995)。
在免疫反应中通过T辅助细胞(Th)的细胞因子的产物差别对免疫反应本质有重要的调控效应。天然的免疫反应的细胞因子轮廓决定着随后的特定的免疫反应的表现型。除了控制IgE的合成外，IL-4对于Th2表现型，过敏炎症的特征的发育和成熟是关键的。
这个过程对于发展对摄入的蛋白的耐受性是关键性的。口服耐受性是一种抗原-特异的全身性非反应状态，其特征是局部抗原-特异性的IgA反应。
分离的人肠菌株，乳杆菌菌株GG(Lactobacillus GG，ATCC 53103)最近已表现出提高局部IgA的抗肠道中遇到的饮食的抗原的反应性，因而有助于免疫消除(Isolauri等，1993)。但是还不知道特定的肠细菌菌株是否能直接改变食物抗原的免疫原性，因而抑制过敏反应。
健康肠的微生物群中包括乳杆菌。有假定认为在肠道中乳杆菌通过与肠粘膜上的病原的微生物竞争受体和营养来起作用。
益生的(probiotics)制剂是活的微生物制品，它通过维持消化道中的天然的微生物群落来提高健康。如果起作用的微生物和它们的行为模式已知，那么可将一种微生物制品认作是一种益生制剂。这些益生制剂附着于肠粘膜上，集居于人的肠道，阻止了有害微生物的附着。一个关键的假设是它们到达消化道的粘膜并且在胃肠道的上部不被破坏。乳杆菌GG就是有益生制剂特性的已知的细菌之一。
本发明者现在已发现胃肠道中的某些细菌，尤其是乳杆菌和有益生制剂特性的细菌，可用于增强清除饮食(elimination diets)的功效，提高口服耐受性，预防和治疗病人的食物引起的过敏性。
本发明的一个方面是用上述的胃肠的细菌进行蛋白水解获得的蛋白水解物也可用于达到所说的目的。在这里我们表明根据本发明所得的蛋白水解物有提高低变应原性的免疫学效应。此水解物抑制过敏性反应，因而提高消化道免疫屏障机能，即稳定消化道粘膜屏障。
本发明提供了一种改进的蛋白质水解物的配方，这种配方抑制过敏性反应且提高消化道免疫屏障机能。用从益生制剂的胃肠细菌中获得的酶，尤其是有附着和集居(colonizing)特性以及与那些乳杆菌GG(ATCC 53103)菌株相似的蛋白酶体系的乳杆菌，和胰蛋白酶和/或胃蛋白酶来水解蛋白质，可以获得水解物配方。
另外，本发明的蛋白质水解配方可通过胰蛋白酶和/或胃蛋白酶水解蛋白，且加入到水解物中获得，这样就得到了一种细菌制剂，它包含益生制剂的胃肠细菌，尤其是有附着和集居特性和与同那些乳杆菌GG菌株(ATCC53103)相似的蛋白酶体系的乳杆菌。将这些细菌加入到水解物配方中，优选地作为一种冻干的制品。
当对病人用这种水解物配方时，期望正在水解的细菌酶在体内释放，借此获得的效果与用以上所定义的改进的水解物配方相同。而且，活的细菌稳定消化道粘膜屏障，增强了局部防御。
本发明的一个实施方案是预防或治疗婴儿由食物引起的过敏反应的一个方法，它包含的步骤是对处于危险中的婴儿给予本发明的改进的蛋白质水解物配方，或是给予一种蛋白质水解物的配方，同时用包含益生制剂的胃肠细菌，尤其是乳杆菌的细菌制品，这种乳杆菌有附着和集居特性，以及同那些菌株乳杆菌GG(ATCC 53103)相似的蛋白酶体系。
本发明的一个进一步实施方案是治疗病人牛奶过敏的一个方法，它包含对病人给予本发明的改进的蛋白质水解物的配方，或是实施一种蛋白质水解物的配方，同时使用包含益生制剂的胃肠细菌，尤其是乳杆菌的细菌制品，这种乳杆菌有附着和集居特性，以及同那些菌株乳杆菌GG(ATCC 53103)相似的蛋白酶体系。
本发明也提供了提高病人对食物抗原耐受原的免疫反应的一种方法，这包括对病人口服本发明的改进的蛋白质水解物的配方，或口服一种包含益生制剂的胃肠细菌，尤其是乳杆菌的细菌制品，这种乳杆菌有附着和集居特性，以及同那些菌株乳杆菌GG(ATCC 53103)相似的蛋白酶体系，或是口服一种蛋白质水解物的配方，同时用包含益生制剂的胃肠细菌，尤其是乳杆菌的细菌制品，这种乳杆菌有附着和集居特性，以及同那些菌株乳杆菌GG(ATCC53103)相似的蛋白酶体系。
在本发明以上所定义的方法中，当一种蛋白质水解物的配方与前面所定义的选择的益生制剂的细菌结合使用时，这样的配方可以是任何合适的蛋白质水解物配方，已知的或新颖的。它可以是部分的蛋白水解物，或是一种彻底的水解的配方。适合于此目的的蛋白质水解物的制备公开于如EP专利申请No.601 802中。
用于本发明的配方和方法中的优选的细菌是乳杆菌GG(ATCC 53103)。
在本说明书和所附的权利要求书中，片语“细菌，尤其是有附着和集居特性，以及同那些菌株乳杆菌GG(ATCC 53103)相似的蛋白酶体系的乳杆菌”应该理解为其附着和集居特性与那些LGG菌株相当的细菌，例如EP专利199 535中定义的。这些细菌也被设想为与LGG有相同的酶体系，这意味着从这种细菌中获得的酶能把蛋白质降解产生水解产物，这与那些从LGG中衍生的酶获得的效果一样。
缩写：
CI 置信区间
IFN-γ 干扰素-γ
IgA 免疫球蛋白A
IgE 免疫球蛋白E
IL-4 白细胞介素-4
LGG 乳杆菌GG(ATCC 53103)
OKT3 抗CD3抗体
PBMC 外周血单核细胞
TNF-α 肿瘤坏死因子-α
WF 受到彻底水解的乳清配方的测试组
WF-GG 受到彻底水解的乳清配方和LGG制品的测试组
P/T-酪蛋白(casein)＝由胃蛋白酶和胰蛋白酶水解的酪蛋白
P/T-αS1-酪蛋白(casein)＝由胃蛋白酶成胰蛋白酶水解的αS1-酪蛋白
附图说明：
图1A-1D：体外由有丝分裂原引起的PBMCs的增殖反应，分别对于：P/T-酪蛋白(1A)，P/T-αS1-酪蛋白(1B)，用LGG衍生的酶额外水解的P/T-酪蛋白(1C)，用LGG衍生的酶额外水解的P/T-αS1-酪蛋白(1D)。结果表达为对无水解的产物(PHA-RPMI 1640)和有三种浓度(0.1，10和1000微克/毫升)下的水解产物的培养物每分钟的平均计数。水平线代表6个实验的每分钟的几何平均计数，对每一个个体计数相同。
图2：每个患者特应性皮炎的临床值(SCORAD)和其程度中值(A)，强度中值(B)和主观值(C)，以上值是对婴儿在处理前(O)和用彻底水解的乳清配方(WF)或同样的用彻底水解的乳清配方和乳杆菌GG(WF-GG)处理一个月后的值(I)。
图3：酪蛋白和乳杆菌GG降解的酪蛋白对特异反应性的患者(a，b)和在非特异反应性的健康孩子由PBMC的IL-4产物和IFN-γ产物的影响。白柱代表的是在对照培养物中中值细胞因子产物；黑柱代表在含有纯化的酪蛋白的培养物中；阴影柱代表在含有乳杆菌GG降解的酪蛋白的培养物。横切线代表上部和低处的四分位数。
*统计学意义上对比于空白样培养物是显著的双向(pairwise)。
图4：αS1-酪蛋白和乳杆菌GG降解的αS1-酪蛋白对由PBMC的IL-4产物和IFN-γ产物的影响，这是在特异反应性的患者(a，b)和非特异反应性的健康孩子。白柱代表在对照培养物中的中值细胞因子产物；黑柱代表在含有纯化的αS1-酪蛋白的培养物中的；阴影柱代表在含有乳杆菌GG降解的αS1-酪蛋白的培养物中的。横切线代表上部和低部的四分位数(quartiles)。*统计学意义上对比到对照培养物明显的双向
下面的实施例进一步阐明本发明。描述了制备改进的水解物的方法，和本研究中可以观察到表现出良好的治疗效应的实验。
实施例1：用乳杆菌GG获得的酶水解的牛酪蛋白在体外抑制淋巴细胞增殖
1.a.牛奶蛋白的水解
牛的全部酪蛋白和酪蛋白组分(αS1-酪蛋白)从牛奶中提纯(Syvaoia，1992)。用以乳杆菌GG中获取的酶混合物的水解对酪蛋白和αS1-酪蛋白分别进行。用改进的Exterkate和de Veer，1985的方法来分离酶。简而言之，通过对冷冻的细菌细胞超声处理释放出酶。分离出离心的细胞的上层清液，将其用在对酪蛋白和αS1-酪蛋白的水解中，水解于34℃下进行24小时。
如此所得的GG-水解物进一步用胃蛋白酶和胰蛋白酶水解。简单地，样品首先用0.1摩尔/升盐酸中含0.1％的胃蛋白酶溶液在37℃下水解3小时，其溶液pH值为2.5。用250毫克碳酸氢钠和2摩尔/升氢氧化钠调节pH值后，加入0.1％的胰蛋白酶，它们在37℃，pH 8.0下水解5小时。
P/T-酪蛋白和P/T-αS1-酪蛋白样品通过只用胃蛋白酶和胰蛋白酶如上所述那样水解纯化的酪蛋白和αS1-酪蛋白而获得，只是不用GG-水解过程。
1.b.淋巴细胞转化测试
要对有丝分裂原诱导的淋巴细胞转化的全血液微量法做一个变更。本实验需6至8个健康的自愿者作供血者。简单地，获得肝素抗凝的静脉血液，并用含有抗菌素的RPMI 1640培养介质(Grand Island Biological Co.NY.USA)将其稀释为1∶7。植物凝集素(PHA)(Difco Laboratories，Detroit，Mich.，USA)用含抗菌素的RPMI 1640进行稀释，培养液中其最终的浓度范围是5到1250微克/毫升。酪蛋白和αS1-酪蛋白的冻干水解物用RPMI 1640进行稀释到其最终浓度为0.1微克/毫升(低)，10微克/毫升(中等)和1000微克/毫升(高)，已证明在用伊红的染料排斥研究中对T细胞是无毒的。
采用2套实验研究有丝分裂原引起的外周血单核细胞(PBMCs)的增殖反应，对于(A)用胃蛋白酶和胰蛋白酶水解的酪蛋白(＝P/T-酪蛋白)，(B)用胃蛋白酶和胰蛋白酶水解的αS1-酪蛋白(＝P/T-αS1-酪蛋白)，(C)另外用乳杆菌GG中获得的酶水解的P/T-酪蛋白，和(D)另外用从乳杆菌GG中获得的酶水解的P/T-αS1-酪蛋白。
实验包含了四种对照培养物，它们是培养介质和有丝分裂原的不同稀释物，而且相应的测试培养液是三种不同浓度的25微升的水解产物。检测如Sutas等，1996中所描述那样进行。
有丝分裂原引起的PBMCs增殖反应以扣除本底后每分钟的计数表示。给出对于含125微克/毫升的PHA和RPMI 1640的对照培养液和含有125微克/毫升的PHA及在低、中、高浓度下的水解产物的三个测试培养液的结果。
1.c.统计分析
用一种非参数的配对检验(Wilcoxon signed-rank测试)来对比每个测试培养介质与那些对照培养介质中每分钟计数值的变化。显著水平P＜0.05。根据测试培养介质中每分钟计数值的减少或增大，双向比较的明显结果表示为抑制或刺激作用。
1.d.结果
在用乳杆菌中获得的酶的水解P/T-酪蛋白和P/T-αS1-酪蛋白所做的实验中，同用P/T-酪蛋白和P/T-αS1-酪蛋白(图1A和图1B)相比，在0.1，10和1000微克/毫升(p＝0.03，p＝0.03，和p＝0.03)(图1C和图1D)的有丝分裂原引致的PBMCS的增殖明显被抑制。
实施例2.用乳胶菌补加的蛋白质水解物配方来治疗有特应性皮炎的婴儿
2.a.患者和研究设计
此研究包含31名婴儿，年龄从2.5到15.7(平均为8)个月，他们符合孩子特异反应性湿疹的Hanifin标准(Hanifin，1987)。根据特异反应性湿疹他们被归于儿科诊所并被怀疑是牛奶过敏。这种症状的平均开始时间为2.4个月，哺乳期为5.9个月。在第一级亲属中有特异反应性疾病(哮喘，特应性湿疹和过敏性鼻炎)或食物过敏的阳性家族史的有26(占84％)位患者。湿疹病斑用润肤剂和局部的皮质类固醇来处理。但是没有一位患者接受全身性皮质类固醇治疗。除了特应性湿疹外，9位患者(占19％)可发现有胃肠紊乱，如拉稀，呕吐或腹泻。在完成研究期间后，将这些患者进行双盲空白对照剂对照的牛奶刺激实验。只有那些有阳性反应的(27/31)包括于最终的研究人口中。
将这些患者在一个月随机地分为两组。一组(WF， n＝14)接受彻底水解的乳清配方(Valio Ltd，Helsinki，Finland，EP-A-601802)，另一组(WF-GG，n＝13)接受同样的配方，只是其中另有乳杆菌GG制品(5×108cfu/g)(由Valio Ltd，Helsinki，Finland提供)。在用他们指定的配方治疗一个月后，这两组都接受一种彻底水解的乳清配方(Valio Ltd)再额外治疗一个月。在饮食前，测定所有患者的血清总IgE浓度，牛奶特定的IgE(RAST，pharmacia，Uppsala，瑞典)和皮刺试验。用一种市售的牛奶过敏原ALK(Allergologisk Laboratorium，Horsholm，丹麦)和稀释到正常进食浓度测试配方来在前臂手掌面进行皮刺试验。用一个1毫米单峰有钝边小刀以防止较深的刺穿(ALK)，以每毫升10毫克的二盐酸组胺(ALK)作为阳性对照。15分钟后观察反应，如果刺痕的平均直径至少是3毫米，而同时阴性对照仅0毫米，那么将组胺反应尺寸一半或以上的反应记录为阳性。
在实验开始前，一个月后(相当于研究期间)和二个月后，收集粪便样品以测定α-1抗胰蛋白酶和THF-α。
根据由European Task Force对特应性皮炎建立的SCORAD方法(1993)，评价特应性皮炎的严重程度。简单地说，皮炎的程度(score A)用九级规则(ruleofnines)来评估，皮炎的强度(score B)是红斑，浮肿，和/或丘疹、脱皮，地衣化和干燥的单个值的总和。主观值(score C)表现形式(scored 1-10)包括瘙痒和睡眠损失是由父母的评估来确定的。SCORAD由下式计算出：A/5+3.5×B+C
此研究方案得到了Tanpere大学医院伦理检查委员会的批准。征得了婴儿父母的同意。
2.b.粪便样品中α-1抗胰蛋白酶的测定
冷冻的粪便样品在室温下融化并搅匀，取约1克放入玻璃试管中并冻干。将所得的干材料研磨，将50毫克转入一只Eppendorf试管中，加入1毫升0.15M的氯化钠溶液，在一个涡旋混合器中在室温下剧烈混合20分，提取α-1抗胰蛋白酶。所得悬浮液以25,000g离心10分钟除去残渣，将上层清液用于测定α-1抗胰蛋白酶，其使用的是根据制造商说明书的BehringBNA浊度计。结果表示为每克干冻干的粪便中抗胰蛋白酶的毫克数。
2.c.粪便样品中TNF-α的测定
深冻的粪便样品在室温下融化，悬浮于1∶1(w/v)的生理盐水中，使其沉淀下来。将0.5-1.0毫升的上层清液转到一Eppendorf试管中在25,000g下离心十分钟，然后，将此上层清液用于测定TNF-α。使用一种商品化的酶免疫分析药盒(Human TNF-α ELISA Kit，Endogen Inc.，Boston，Massachusetts，USA)，如在血清样品所示的那样以测定粪便的TNF-α。
2.d.统计学
因为血清IgE浓度的非对称分布，因而用对数(ln)转变且数据以置信区间(CI)为95％的平均值给出。炎性参数的浓度以较低和较高四分位数的中值给出。将Wilcoxon signed rank测试和Mann-Whitney U-测试用于统计比较中。
2.e.结果
2.e.1：临床资料
平均(95％CI)血清总IgE为31(15-61)kU/1，这是对接受水解物配方的病人而言的。在10/37(37％)的特应性湿疹患者中，牛奶的RAST是阳性的(＞0.4 kU/l)。在8/31(30％)的患者中，牛奶的皮刺测试为阳性的。
在开始用药前以及用药1个月后，即研究期间后，每个患者中特应性皮炎的严重性表现于图2中。在用药前，WF组和WF-GG组的中(低四分位数-高四分位数)SCORAD值分别为21(14-31)和26(17-38)且(p＝0.33)。在那些用乳杆菌GG的患者中，一个月后，其SCORAD值有明显的提高(p＝0.008)，但对那些仅用彻底水解的配方而无乳杆菌GG的患者，一个月后，其SCORAD值无明显增加(p＝0.89)。这时，WF组的SCORAD值为19(13-31)，而WF-GG组的SCORAD值为15(7-28)。WF-GG的SCORAD值下降是由于特应性皮炎，程度(score A，p＝0.004)，强度(score B，p＝0.05)和主观值(score C，p＝0.01)的下降(图2)。在WF组中，2个月可以实现SCORAD值的增加，而对WF-GG组在停止施用乳杆菌GG后，SCORAD值保持不变。在2个月时，中(低四分位数-高四分位数)SCORAD值在WF组是14(2-38)而WF-GG组是16(6-25)。
2.e.2.粪便中的α-1抗胰蛋白酶和TNF-α的浓度。
在健康的对照(n＝9)中，α-1抗胰蛋白酶中值(低四分位数-高四分位数)浓度是0.5(0.5-1.7)毫克/克。在施药前，WF组和WF-GG组之间的α-1抗胰蛋白酶浓度是相当的(p＝0.22)。如表1中指示的，在一个月的研究期间中，WF-GG组的α-1抗胰蛋白酶浓度明显下降(p＝0.03)，但WF组中的α-1抗胰蛋白酶浓度却无明显下降(p＝0.68)。在二个月时，α-1抗胰蛋白酶浓度对WF为1.2(0.5-1.6)而WF-GG为0.5(0.5-0.7)。
在健康的对照中，粪便的TNF-α浓度为0(0-0.08)皮克/克。在特异反应性的孩子中，粪便的TNF-α浓度明显较高，P＜0.0001(表1)。施药前，WF组和WF-GG组间TNF-α的浓度是相当的(p＝0.57)。在一个月的研究期间中(表1)，粪便的TNF-α浓度对于WF-GG组明显下降(p＝0.003)，但WF组中不是这样(p＝0.38)。在2个月时WF组的TNF-α浓度下降，而在也施用彻底的水解配方但无乳杆菌GG的WF-GG组，可以测到TNF-α增加的趋势。此时TNF-α的浓度在WF中为84(25-129)而WF-GG中为144(20-338)
表1：在用药前(0)和婴儿接受彻底水解的乳清配方(WF)或还含有乳杆菌GG细菌的配方(WF-GG)一个月后的情况(I)下粪便的α-1抗胰蛋白酶和TNF-α的浓度，数据表示为中值(低四分位数-高四分位数)。
| WF | WF-GG | |
| α-1抗胰蛋白酶 O(mg/g) | 1.7(1.5-2.3) | 1.4(0.5-1.9) |
| α-1抗胰蛋白酶 I(mg/g) | 1.7(1.1-2.8) | 0.5(0.5-1.0) |
| TNF-α 0(pg/g) | 632(126-1880) | 709(91-1131) |
| TNF-αI(pg/g) | 494(147-1009) | 34(19-103) |
实施例3通过特异反应性孩子中的外周血单核细胞抑制细胞因子产物
3.a患者和方法
研究了总共有14名年龄为5-29(平均为16)个月的患者，他们符合特应性皮炎的Hanifin标准(Hanifin，1987)，另外有8名年龄相符的非特异反应的健康儿童。在研究期间，他们中没有一人接受全身性的皮质类固醇。
含有腹水流体的OKT3(抗-CD3-抗体)是由芬兰赫尔辛基的赫尔辛基大学的细菌学和免疫学系的M.Kaartinen博士惠赠。如Syvaoja(1992)所叙述的那样，牛的全酪蛋白从牛奶中纯化而来。纯化的酪蛋白是用实施例1中描述的从乳杆菌GG中获得的酶来水解的。将纯化的酪蛋白或乳杆菌GG降解的酪蛋白冻干并贮于室温中。在实验前，它们用RPMI 1640来稀释并且应用过滤消毒装置(0.1μm，Millipore corporation，Bedford，MA，USA)。
完全的培养介质由含有10％的胎牛血清，10mM Hepes缓冲液，2mML-谷氨酰胺(Gibco Life Technologies，Paisley，UK)，50 U/ml的青霉素G(Sigma，St.Louis，MO，USA)，10mg/ml庆大霉素素(Roussel Laboratories Ltd，Uxbridge，Middlesex，UK)的RPMI 1640所组成。取得5ml的周围静脉血液。含有90％的淋巴样细胞的PBMC用FicollPaque(Pharmacia Biotech，Uppsala，Sweden)梯度离心，并以1×106细胞/毫升悬浮于完全的培养介质中。用含有腹水流体的抗-CD3-抗体以预测定的最佳稀释度预先涂到培养孔上。测试培养液还含有酪蛋白或乳杆菌GG降解的酪蛋白的稀释物，它们的最终浓度为1mg/ml。对纯化的αS1-酪蛋白或乳杆菌GG降解的αS1-酪蛋白，重复以上的实验。在一湿润的含5％的二氧化碳37℃下培养24小时后，收集上层清液，贮于-70℃下以用于细胞因子分析。根据制造商的说明，用商购的ELISA试剂盒来测定培养物上层清液中的IL-4和IFN-γ(IL-4：CLB，Compact Human Interleukin-4 ELISA Kit，Central Laboratory of theNetherlands Red Cross B1ood Transfusion Service，Amsterdam，The Netherlands；IFN-γ，EIFNG，Endogen Inc.，Cambridge，MA，USA)。比较于标准曲线，不同途径所得的结果相等，并以皮克/毫升表示。此检测的灵敏度对IL-4为2.3皮克/毫升，而IFN-γ为5皮克/毫升。Wilcoxon signed-rank测定用于统计比较测试培养物和对照培养物。显著性水平为p＜0.05。
3.b.结果
在特异反应性患者中，与对照培养液相比，含有纯化的酪蛋白的培养液中的IL-4和IFN-γ产物均有增加，它们p值分别为0.008和0.008(图3a，b)。当用乳杆菌GG的酶降解时，牛酪蛋白中观察不到这种效应。相反，在含有乳杆菌GG降解的酪蛋白的培养液中，IL-4产物比对照的培养液中的明显减少，p＝0.003(图3a)，而这些培养液中IFN-γ产物与对照培养液中的相当，p＝0.10(图3b)。
在健康的儿童中，含有纯化的酪蛋白的培养液中的IL-4和IFN-γ产物均与对照培养液中的相当，p＝0.10和p＝0.10(图3c，d)。与特异反应性的患者的发现相平行，对健康儿童在含有乳杆菌GG降解的酪蛋白的培养液中，同对照培养液中相比，IL-4产物也明显要少，p＝0.01(图3c)，而这些培养液中IFN-γ产物与对照培养物中的保持相当，p＝0.50(图3d)。用αS1-酪蛋白和乳杆菌降解的αS1-酪蛋白可以获得平行的结果(图4)。参考文献
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Claims (12)
1.一种制备用于抑制过敏反应和提高消化道免疫屏障机能的蛋白质水解物配方的方法，它包括以下步骤：用从包含益生的(probiotic)胃肠细菌，尤其是有附着和集居特性以及与那些乳杆菌GG(ATCC 53103)菌株相似的蛋白酶体系的乳杆菌的细菌制品中取得的酶来水解蛋白质和用胃蛋白酶和/或胰蛋白酶来水解蛋白质。
2.权利要求1中所述的方法，其中的酶是从包含乳杆菌GG(ATCC 53103)的细菌制剂中制备的。
3.一种制备蛋白质水解物配方以抑制过敏反应和提高消化道免疫屏障机能的方法，它包括的步骤如下：用胃蛋白酶和/或胰蛋白酶水解蛋白质，并在水解物中添加一种包含益生的胃肠道细菌，尤其是有附着和集居特性以及与那些乳杆菌GG(ATCC 53103)菌株相似的蛋白酶体系的乳杆菌的细菌制品。
4.根据权利要求3的方法，其中的细菌制品包括乳杆菌GG(ATCC53103)。
5.一种用于抑制过敏性反应和促进消化道免疫屏障机能的蛋白质水解物配方，该水解物可用权利要求1到4中定义的任一种方法获得。
6.一种预防或治疗由食物引起的婴儿过敏性反应的方法，包含对处于危险中的婴儿施以根据权利要求5所得的蛋白质水解物配方。
7.一种治疗患者牛奶过敏的方法，包括对患者给予根据权利要求1制备的蛋白质水解物配方。
8.一种提高患者对食物抗原的耐受原免疫反应的方法，它包括口服根据权利要求5的蛋白质水解物的配方。
9.一种预防或治疗婴儿的食物引起的过敏性反应的方法，包括对处于危险中的婴儿施用一种根据权利要求1制备的蛋白质水解物的配方，同时施用一种生细菌制品，其包含益生的胃肠细菌，尤其是有附着和集居特性以及与那些乳杆菌GG(ATCC 53103)菌株相似的蛋白酶体系的乳杆菌。
10.一种治疗患者牛奶过敏反应的方法，包括对患者施用一种蛋白质水解物配方和一种细菌制品，它包含益生的胃肠细菌，尤其是有附着和集居特性以及与那些乳杆菌GG(ATCC 53103)菌株相似的蛋白酶体系的乳杆菌。
11.一种促进患者对食物抗原的耐受原免疫反应的方法，包括口服一种细菌制品，这种制品包含益生的胃肠细菌，尤其是有附着和集居特性以及与那些乳杆菌GG(ATCC 53103)菌株相似的蛋白酶体系的乳杆菌，或是一种蛋白质水解物配方和一种细菌制品，这种细菌制品包含益生的胃肠细菌，尤其是有附着和集居特性以及与那些乳杆菌GG(ATCC 53103)菌株相似的蛋白酶体系的乳杆菌。
12.一种根据权利要求9到11任何之一的方法，其中的细菌制剂包含乳杆菌GG(ATCC 53103)。
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100400645C (zh) * | 2001-01-25 | 2008-07-09 | 瓦利奥有限公司 | 益生菌的联合 |
| CN101325880B (zh) * | 2005-11-14 | 2012-03-28 | 雀巢技术公司 | 用糖化蛋白质促进口服耐受性 |
| WO2008116356A1 (fr) * | 2007-03-28 | 2008-10-02 | Beijing Ferment Bio-Tech.Com, Ltd | Procédé de préparation d'un lait fermenté stable à température ambiante présentant des taux élevés de bactéries d'acide lactique viables |
| US10072310B2 (en) | 2007-03-28 | 2018-09-11 | Beijing Yiheoun Tech. Co., Ltd. | Process of preparing fermented milk beverage keeping high viable cell count at ambient temperature |
| CN102575224A (zh) * | 2009-09-11 | 2012-07-11 | 美赞臣营养品公司 | 用于预防和治疗过敏的益生菌衍生的无活力材料 |
| CN103355405A (zh) * | 2013-04-07 | 2013-10-23 | 苏州旭优食品科技有限公司 | 一种低过敏性含乳制品的加工工艺 |
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