CN101938912A - 使用富含IgA的乳预防和治疗中耳炎 - Google Patents
使用富含IgA的乳预防和治疗中耳炎 Download PDFInfo
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- CN101938912A CN101938912A CN2008801264974A CN200880126497A CN101938912A CN 101938912 A CN101938912 A CN 101938912A CN 2008801264974 A CN2008801264974 A CN 2008801264974A CN 200880126497 A CN200880126497 A CN 200880126497A CN 101938912 A CN101938912 A CN 101938912A
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Abstract
本发明涉及适用于预防或治疗中耳炎的组合物,其包含源自成熟牛乳且对肺炎链球菌、流感嗜血菌和卡他莫拉菌中的至少一种具有特异性的IgA。本发明还涉及所述组合物在预防或治疗中耳炎中的应用。
Description
发明领域
本发明涉及中耳炎的预防和治疗,特别是婴儿和幼儿的中耳炎的预防和治疗。
发明背景
呼吸道的感染是非常常见的,尤其是在婴儿和幼儿中是如此。例如,在生命的第一年中,婴儿通常会经历三到六次这类感染。这类感染可以是细菌或病毒引起的。呼吸道病毒感染的实例包括普通感冒、流行性感冒和呼吸道合胞病毒。呼吸道细菌感染的实例包括肺炎和中耳炎。
频繁的呼吸道感染常伴随着急性中耳炎。这是一种中耳感染,其中经由口连接中耳腔与外部环境的咽鼓管开始发炎随后阻滞,将细菌困于中耳中。中耳腔也开始发炎并伴随流体的累积,导致被患者感受为疼痛的压力升高,这归因于不能像健康个体那样通过咽鼓管平衡中耳和外部环境之间的压力。在严重的病例中,鼓膜可能在压力下胀裂,使得感染液达到内耳。这是潜在的危险情况,如果鼓膜没有彻底愈合的话,其能够导致永久性听力损伤。另一方面,如果鼓膜没有破裂,则结果可能是乳突炎,一种严重的中耳炎并发症,其中乳突(头骨的颞骨的一部分)会感染或发炎。如果不治疗,这可能导致脑膜炎或形成脑脓肿。
50%的儿童在生命的第一年中会经历至少一次急性中耳炎发作,35%的一岁到三岁龄的儿童中急性中耳炎复发。这随后可导致发生被称作胶耳(glue ear)的病症,其中数次感染之间流体未从中耳中完全排出。如果确认了该病症,则手术介入是必需的。
急性中耳炎与通常发现与鼻咽腔的固有微生物群中的致病菌的活性有关联。就数量而言,最主要的病原体为肺炎链球菌(Streptococcuspneumoniae)(35%的病例)、未分类的流感嗜血菌(Haemophilusinfluenzae)(30%的病例)和卡他莫拉菌(Moraxella catarrhalis)(10%的病例)。因此,通常通过施用抗生素治疗急性中耳炎,特别是在婴儿中。事实上,比起婴儿期的任何其他疾病,为了治疗中耳炎而开出抗生素处方更加频繁。这不可避免地导致与中耳炎相关的细菌菌株中产生对常用抗生素的抗性。例如,认为至少20%的肺炎链球菌菌株是抗青霉素和头孢菌素的。类似地,至少30%的流感嗜血菌菌株和大部分卡他莫拉菌菌株已经产生了抗生素抗性。这样的处方频率至少部分归因于患有中耳炎的婴儿和幼儿经历的疼痛,他们对疼痛的反应是长期哭泣,这是父母和其他的照料者非常急于解决的。因此,显然需要备选的方法,其用于降低该痛苦的和潜在严重的病症在婴儿和幼儿中的发病率。
已知人乳有抵抗中耳炎的保护作用,这被认为是由于人乳中具有特异性免疫球蛋白。例如Harabuchi等人已提出人乳抵抗中耳炎的保护作用可能部分是由于通过人乳中的分泌型IgA抗体对未分类的流感嗜血菌的鼻咽建群的抑制(J Pediatr.1994二月;124(2):193-8)。
已经提出了基于该假设的多种疗法。例如,在WO 97/17089中提出使用所谓的免疫乳制备物预防中耳炎。该制备物含有得自牛初乳的直接抵抗中耳炎病原体的IgG型免疫球蛋白,以补充被动的免疫防御。
最近在WO2006/022543中提出含半乳糖的低聚糖和具有对抗致病微生物的活性的免疫球蛋白的组合在病毒感染诸如由呼吸道合胞病毒和轮状病毒引起的感染的预防或治疗中的使用。依据WO2006/022543的发明人,RSV可引起咽鼓管机能障碍,从而在中耳内导致暂时性负压,因而促成耳部的继发性细菌感染诸如中耳炎。WO2006/022543还提出使用源自牛初乳或牛奶的免疫球蛋白,优选用呼吸病毒抗原免疫的母牛产生的IgG和IgA的混合物。
根据前文可以看出,仍然需要预防和治疗急性中耳炎的有效方法,所述方法不依赖于抗生素的使用并且可以被便利、安全地和经济地施用。
发明概述
因此,本发明提供了适用于预防或治疗中耳炎的组合物,其包含源自成熟牛乳且对肺炎链球菌、流感嗜血菌和卡他莫拉菌中的至少一种具有特异性的IgA。
本发明涉及源自成熟牛乳的、对肺炎链球菌、流感嗜血菌和卡他莫拉菌中的至少一种具有特异性的IgA在制备用于预防或治疗中耳炎的药物或治疗性营养组合物中的用途。
本发明还涉及用于预防或治疗中耳炎的方法,其包括向有需要的个体施用治疗量的源自成熟牛乳的、对肺炎链球菌、流感嗜血菌和卡他莫拉菌中的至少一种具有特异性的IgA。
本发明还包括具有浓度为至少1.5μg/ml、优选至少2.5μg/ml的对肺炎链球菌、流感嗜血菌和卡他莫拉菌中的至少一种具有特异性的IgA的成熟牛乳,以及源自该成熟牛乳的乳清部分。所述成熟牛乳(或某种情况可能为乳清部分)得自对所述病原体高度-免疫的母牛,其中高度免疫包括将病原体经由选自母牛气道的粘膜内途径、阴道内、直肠内和鼻内施用,以及施用于母牛的乳腺和/或乳腺上淋巴结。本发明还涉及所述成熟牛乳和/或所述乳清部分在制备用于预防或治疗中耳炎的药物或治疗性营养组合物中的用途。
优选地,所述组合物包含对肺炎链球菌、流感嗜血菌和卡他莫拉菌中的至少两种、更优选对三种都具有特异性的IgA。最优选地,组合物包含至少为10μg/ml的量的对肺炎链球菌、流感嗜血菌和卡他莫拉菌中的所有三种都具有特异性的IgA。
不希望受理论束缚,本发明人认为如上所述的源自乳汁的抗体在预防和治疗中耳炎中的功效可能是由于IgA类抗体更适于靶向于该疾病的病理学这个事实。已将人乳中的IgA与其抵抗中耳炎的保护作用潜在地联系起来,其理论依据是以下事实:已知IgA类的免疫球蛋白与保护粘膜诸如鼻咽部粘膜对抗致病菌诸如肺炎链球菌、流感嗜血菌和卡他莫拉菌建群的作用相关。
例如从UK专利1573995已知免疫球蛋白可得自初乳和高度免疫母牛的乳汁。然而,每次生小牛后初乳的分泌只持续2至3天,一旦母牛进入成熟泌乳期,免疫球蛋白的水平急剧降低。此外,初乳中的免疫球蛋白主要是IgG类。因而,初乳不是一种经济上可行的IgA类抗体来源。此外,从实际的观点来看,牛初乳不是用于施用给人类婴儿的任何种类的免疫球蛋白的适合来源,例如在婴儿配方产品或相似的营养组合物中。例如,在德国法律禁止售卖牛初乳用于制备食品产物。这是因为牛初乳没有被广泛证实为可用作制备人类食物的原料,因为其包含许多激素且还可能包含抗生素。初乳供应商不知道其产品的激素或抗生素含量。
附图简述
图1显示通过由全细胞ELISA所测定的针对整个细菌细胞的特异性SIgA效价;
图2显示对于混合肺炎链球菌细胞和四个肺炎链球菌血清型的混合CPS的特异性SIgA抗体应答;
图3显示在混合的成熟乳汁中的抗肺炎链球菌细胞血清型特异性SIgA水平;
图4显示在混合的成熟乳汁中的抗肺炎链球菌CPS特异性SIgA水平;
图5显示在中耳炎小鼠模型在用肺炎链球菌攻击后0至80小时的时期内所检测到的急性中耳炎减少%。
发明详述
在本说明书中,下列表述具有以下含义:
“婴儿”:12个月龄以下的儿童;
“婴儿配方产品”:预期用于在生命最初的四到六个月的婴儿的特定营养用途、且其自身满足这类人群的营养需求的食品。
“第二阶段配方产品(follow-on formula)”是指预期用于在4个月龄以上的婴儿的特定营养用途、并在该类人群逐渐变化的饮食中构成主要液体成分的食物;
“成长乳(growing up milk)”是指适合幼儿特定营养需求的基于乳的饮料;
“对与中耳炎的发展相关的病原体具有特异性的IgA”包括对该病原体自身以及对该病原体所产生的毒素特异的IgA,诸如在肺炎链球菌情况中的肺炎链球菌溶血素;
“与中耳炎的发展相关的病原体”是指肺炎链球菌、未分类的流感嗜血菌和卡他莫拉菌中的一种或多种;
“预防中耳炎”是指预防中耳炎形成,且包括降低所述形成的风险;
“幼儿”表示一岁和六岁之间的儿童。
除非另有说明,所有提及的百分比为以重量计的百分比。
如上文所讨论,本发明涉及源自成熟牛乳、并显示出对与中耳炎的发展相关的病原体的特异性的IgA。所述IgA可得自例如依据van Dissel等人所述方法(J.Med.Microbiol.54,197-205,其全部内容被引入本文作为参考)而高度免疫的母牛的成熟乳汁。简言之,所述母牛是用特别设计的免疫刺激物进行粘膜免疫的母牛。免疫方法基于免疫系统的粘膜刺激,并包括鼻内给予的启动免疫和经由乳腺上的淋巴结局部给予的加强免疫。经鼻(粘膜的,每两周)、经皮下的(每两个月)及经乳腺上淋巴结(经皮的;每月一次)施用来保持免疫刺激,所述施用在当母牛在生完小牛后4至6周开始分泌成熟乳汁时的泌乳期时进行。所述免疫方法特别增加整个泌乳期的母牛乳汁中的IgA水平。
乳清由牛奶制备,因而免疫的乳清包含高浓度的针对肺炎链球菌溶血素以及针对整个细菌细胞的特异性抗体。免疫方法主要增强在成熟乳汁中的特异性IgA应答。实际上,免疫乳的特异性IgA浓度至少达到在同样免疫母牛的混合初乳中的浓度(IgG的浓度是那个浓度的十分之一)。在免疫的母牛中,在整个成熟乳汁分泌期保持高效价。这使得能够收集大量的免疫乳,且因此可以使用容易得到的成熟乳汁而不是短暂出现的初乳来作为原料用于生产免疫乳清和包含其的食品组合物。
Van Dissel等人还描述了使用乳品工业中目前使用的标准技术从免疫母牛的乳汁得到乳清蛋白部分的方法。简言之,将免疫母牛的乳汁在<8℃储备,并在得到24小时内用巴氏法消毒。巴氏消毒法的温度和时间可在在63至72℃和15秒至30分钟的范围内选择,但通常优选相对低的巴氏消毒温度(例如65℃)和相对长的处理时间(例如10分钟)的组合,因为这种情况较少引起IgA分解。在巴氏消毒后48小时内,通过离心分离法除去脂肪,并通过酸化或通过使用粗制凝乳酶酶法除去酪蛋白。将得到的乳清部分进行巴氏消毒,通过超滤浓缩以达到所需的蛋白浓度,并喷雾干燥。或者,可通过微量过滤技术除去酪蛋白,这也是本领域已知的。使用微量过滤的优势是得到的乳清部分几乎是无菌的。同样地,可按照需要浓缩蛋白质成分。
优选地,组合物是作为液体而消耗的营养组合物,且适于婴儿和幼儿消耗。组合物可以是营养完全配方产品,诸如婴儿配方产品、第二阶段配方产品或成长乳。或者对于目标婴儿和幼儿群体中年长部分的群体,所述组合物例如可以是例如汁类饮品或其他冷冻的或常温稳定的饮料或汤。
优选地本发明的营养组合物包含3至150μg/g(干重)的对与中耳炎的发展有关的病原体具有特异性的IgA。
现在通过举例方式描述本发明的婴儿配方产品的通用组成。所述配方产品包含蛋白质源。通常,婴儿配方产品中的蛋白质源基于乳清或乳清和酪蛋白的混合物。在该类型的婴儿配方产品中,可通过用依据本发明上文所述的来自成熟牛乳的乳清部分替代全部或部分的乳清成分来将IgA以需要的量掺入婴儿配方产品中。或者,如果使用脱脂乳作为婴儿配方产品中的乳清和酪蛋白的来源,则部分或全部的所述脱脂乳可被依据上文所述得到的免疫乳替代,而不需要进一步处理免疫乳以制备乳清部分。又一个可选择方案是用由免疫乳制备乳蛋白质浓缩物替代一些或全部的脱脂乳。在另一方面,认为蛋白质的种类对于本发明不是至关重要的,只要满足必需氨基酸含量的最小要求并且确保良好的生长即可。因此,如果优选在婴儿配方产品中不包含乳清蛋白,或如果配方产品基于水解的乳清蛋白,则IgA可依据本发明从成熟牛乳中例如通过相继进行微量过滤和超滤步骤或通过离子交换色谱而分离,并照此加入。在该情况下,可使用基于酪蛋白和大豆的蛋白质源,同样可使用部分水解的乳清蛋白。
本发明的婴儿配方产品包含碳水化合物源。尽管优选的碳水化合物源是乳糖,但是可以使用在婴儿配方产品中常规存在的任何碳水化合物源诸如乳糖、蔗糖、麦芽糖糊精、淀粉及其混合物。优选地,碳水化合物源提供配方产品总能量的35至65%。
本发明的婴儿配方产品包含脂质源。脂质源可以是适合用于婴儿配方产品的任何脂质或脂肪。优选的脂肪源包括棕榈油酸甘油酯、高油酸向日葵油和高油酸红花油。也可加入必需脂肪酸亚油酸和α-亚麻酸,同样可加入少量的包含大量预制的花生四烯酸和二十二碳六烯酸的油,例如鱼油或微生物油。总之,脂肪含量优选例如提供配方产品总能量的30至55%。脂肪源优选具有的n-6比n-3脂肪酸的比率为约5∶1至约15∶1,例如约8∶1至约10∶1。
婴儿配方产品还可包含认为在日常饮食中是必需的所有维生素和矿物质,并且以营养显著的量包含之。已确定了某些维生素和矿物质的最小需要量。任选存在于婴儿配方产品中的矿物质、维生素和其他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。通常以盐的形式加入矿物质。特定矿物质和其他维生素的存在和量将根据预期婴儿群体而变化。
如果需要,婴儿配方产品可包含乳化剂和稳定剂,诸如大豆卵磷脂、甘油单酯和甘油二酯的柠檬酸酯等。
婴儿配方产品可任选包含具有有益作用的其他物质,诸如益生菌、乳铁蛋白、核苷酸、核苷等。
最后,该配方产品中的每克婴儿配方产品粉末包含3至150μg源自成熟牛乳、并显示出对与中耳炎的发展相关的病原体的特异性的IgA。
所述配方产品可以使用考虑到IgA可能在超过60℃的温度下变性这一事实的任何合适的方式制备。例如,配方产品可通过以适当的比例将碳水化合物源和脂肪源混合在一起而制备。如果使用乳化剂,则可在此时加入。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)匀化。
然后可将液体混合物热处理以降低细菌载量(load),例如通过快速加热液体混合物至约80℃至约150℃的温度范围达约5秒至约5分钟来进行。这可通过蒸汽注射、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匀化,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。然后可将匀化的混合物进一步冷却以加入任何热敏感成分,诸如维生素和矿物质。此时适宜地调节匀化混合物的pH和固体成分。
将匀化的混合物转移至合适的干燥装置诸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。然后将该粉末与依据本发明通过本领域技术人员已知的超滤和喷雾干燥方法由成熟牛乳得到的乳清部分干混合。乳清部分应当满足通过干混合添加的微生物学标准。
在另一个实施方案中,所述组合物可以是包含以在个体中足以达到所需要的作用的量存在的IgA的补充剂。这种施用形式更适合较目标年龄组中年长部分的儿童。优选地IgA的日剂量是2500至30000μg。补充剂中所包含的IgA的量将依据如何施用补充剂而相应地选择。例如,如果补充剂每天施用两次,各补充剂将包含1250至15000μg的抗体。补充剂可以是例如片剂、胶囊剂、锭剂或液体的形式。补充剂还可包含保护性水胶体(如树胶、蛋白质、改性淀粉)、粘合剂、成膜剂、包囊剂/材料、壁/壳材料、基质化合物、包衣剂、乳化剂、表面活性剂、增溶剂(油、脂肪、蜡、卵磷脂等)、吸附剂、载体、填充剂、共化合物(co-com pound)、分散剂、润湿剂、加工助剂(溶剂)、助流剂、味道掩蔽剂、增重剂、成凝胶剂和胶凝剂。补充剂还可包含常规的药物添加剂和辅助剂、赋形剂和稀释剂,其包括但不限于水、任何来源的明胶、植物胶、木质素磺酸盐、滑石粉、糖、淀粉、阿拉伯胶、植物油、聚亚烷基二醇、矫味剂、防腐剂、稳定剂、乳化剂、缓冲剂、润滑剂、着色剂、润湿剂、填充剂等。
此外,补充剂可包含适于口服或经肠施用的有机或无机载体物质,以及根据政府机构如USRDA建议的维生素、矿物质微量元素和其他的微量营养素。
实施例1
下面提供本发明的婴儿配方产品的组成的实例。该组成仅仅是以举例说明的方式给出。
实施例2
免疫刺激物的制备
选择以下的病原体菌株制备免疫刺激物:肺炎链球菌血清型23F(ATCC 700669)、19F(ATCC 700905)、6B(ATCC 700670)和9V(ATCC700671)和无毒力、无包膜的R6菌株、流感嗜血菌(040921临床分离株)和卡他莫拉菌(035E野生型中耳分离株)。将所述菌株在无血清和来源于动物组织的组分的更确定成分的培养基中培养。培养基基础组分是酵母提取物和大豆胨-木瓜蛋白酶消化物(用磷酸盐和碳酸氢盐缓冲(pH7.4))。向用于培养肺炎链球菌的培养基中加入1%(w/v)葡萄糖,并向用于培养流感嗜血菌的培养基中加入1%(w/v)葡萄糖、15mg/L氯化血红素和15mg/L NAD。将所述菌株培养10至15小时。
通过使用0.37%(v/v)甲醛在37℃通常处理6天或在70℃通常加热2小时灭活细菌细胞组分。通过渗滤除去甲醛至最终浓度在0.2%(w/v)以下。
使用细菌培养物的上清液或细胞裂解物作为分泌的细菌蛋白质产物的来源。通过使用0.37%(v/v)甲醛在37℃通常处理6天将其灭活。通过渗滤除去甲醛(最终浓度在0.2%(w/v)以下)。
将细胞组分和蛋白质组分合并以得到包含与中耳炎的发展相关的全细胞病原体及其粘附/毒力抗原的免疫刺激物。
实施例3
针对肺炎链球菌、流感嗜血菌和卡他莫拉菌的SIgA特异性抗体的效价
依据Van Dissel等人使用上文实施例2中所述的免疫刺激物对健康的奶牛进行粘膜免疫。
通过ELISA测定特异性SIgA抗体效价。由来自依据Van Dissel等人使用上文实施例2中所述的免疫刺激物在妊娠晚期免疫的4头奶牛的单独的组的最初3-5L初乳制备ELISA标准品,并以单位/ml表示,其基于未稀释的标准制备物是1000单位/ml这一假定条件。乳清样品特异性抗体值以单位/ml表示,并与标准制备物中的各水平进行比较。
简言之,ELISA依据下文进行。使用标准制备物优化试验,且每次试验选择三个变量(例如包被抗原稀释度、鼠单克隆抗体-抗牛IgA-地高辛(Moab-anti-bovine IgA-dig)稀释度和辣根过氧化物酶标记的绵羊抗地高辛(HRP-labelled sheep anti-dig)(罗氏)稀释度)的一种组合作为最佳设置。用于包被的抗原为1)整个肺炎链球菌细胞,每个血清型优化的稀释度和混合(1∶1)血清型;2)全卡他莫拉菌细胞(O35E临床中耳分离株);3)全流感嗜血菌细胞(040921临床分离株);4)荚膜多糖——CPS,浓度10μg/ml的单一的CPS 19F/23F/6B/9V和9N/14或1∶1混合的CPS(19F/23F/6B/9V,总浓度10μg/ml)。
图1显示如通过全细胞ELISA测定的针对整个细菌细胞的特异性SIgA抗体效价。所述效价在由12头免疫奶牛个体在两个月的时期内获得的成熟乳汁的乳清中测定。可观察到平均的特异性抗-肺炎链球菌SIgA抗体效价达到了来自同样免疫的奶牛的初乳中的水平。泌乳期期间保持了特异性SIgA抗体的水平(图1显示了两个相连的月份)。对于针对流感嗜血菌和卡他莫拉菌全细胞的特异性抗体水平,得到了相似的数据。
在未免疫乳清中背景抗体水平是低的,且大多数低于ELISA试验的检测水平。
针对血清型特异的肺炎链球菌的SIgA特异性抗体效价
还直接使用纯化的多糖类(得自ATCC 19F、23F、6B、9V、9N和14)作为包被抗原测定针对特异性荚膜多糖(CPS)的抗体应答。使用免疫刺激物中的四种CPS作为混合的包被抗原(1∶1,浓度10μg/ml)(图2)或作为单一的CPS(10μg/ml)(图4)。不出现在免疫刺激物中的两种CPS(9N和14)也使用ELISA测试以显示交叉反应性水平。
图2显示对于混合肺炎链球菌细胞和四个肺炎链球菌血清型的混合CPS的特异性SIgA抗体应答。数据表示从12头免疫奶牛个体在它们的泌乳期期间在2008年的前3个月所获得的成熟乳汁的乳清中的平均的特异性抗体水平。
在未免疫乳清中背景抗体水平是低的,大约在0.5-1.0单位/ml。
特异性的抗血清型特异的肺炎链球菌SIgA在贯穿奶牛泌乳期的免疫期间升高。如可从图2中所看到的,在相连的两个月中,在在12头免疫的奶牛的乳汁中保持了高特异性抗体应答。
在混合的成熟乳汁中的抗肺炎链球菌细胞血清型特异的和CPS特异的SIgA水平
由从12头免疫的奶牛在2008年4月份期间获得的乳汁的混合物制备抗体制备物。在一天收集来自12头奶牛的混合的免疫乳,并制备包括浓缩成分的乳清制备物。分析特异性SIgA抗体乳清部分的抗体特异性和体外(凝集试验)与体内(中耳炎的鼠模型)的生物活性。
图3和4概括了混合免疫乳清部分针对肺炎链球菌血清型和CPS的类型特异性抗体应答(分别以一式四份和一式二份地进行)。为更精确地测定针对个体的特异性血清型的抗体应答,将乳清样品与纯化的商购C型多糖(Statens Serum研究所)预孵育(60分钟,37℃),之后在CPS-ELISA中测试。使用C型多糖作为包被抗原在ELISA中检测对于C型多糖的抗体部分的消耗。
乳清制备物中的SIgA抗肺炎链球菌全细胞(混合)和CPS(混合)水平为大约1000单位/ml(也如在图2中所示)。针对血清型23F、19F和9V的SIgA特异性抗体应答同样高,这表明在这三种血清型之间所存在的抗原性没有实质性差别。针对血清型6B的应答是所有四种之中最高的,这表明其是最突出的抗原(图3和4)。在特异性抗体乳清制备物内存在与不包括在免疫刺激物之内的其它两种CPS类型(9N、14)的交叉反应性(图4),这表明免疫刺激物在识别更多不同类型的特异性CPS的免疫奶牛中引起了广泛的多克隆抗体应答。
特异性抗肺炎链球菌SIgA抗体在体外(凝集试验)与体内(中耳炎的鼠模型)的功能性活性
针对特异性细胞壁的抗体与整个细菌细胞之间的相互作用是对于防止细菌通过结合于上皮细胞在粘膜表面建群的重要特性之一。在凝集试验中,通过测试特异性的有针对性的源自乳清的抗体制备物,对肺炎链球菌菌细胞凝集的诱导进行测定。该试验使用肺炎链球菌血清型19F在96孔板上进行。简言之,使用固定细菌密度1.0(OD600nm)的肺炎链球菌血清型19F(甲醛灭活的)。将PBS、对照乳汁乳清和乳汁乳清测试样品制备物两倍系列稀释于96孔板中,每孔的终体积为50μl。向板的每个孔中加入50μl的细菌培养物,并在4℃孵育过夜。对各板评分,其表明了显示菌细胞的凝集的最高的样品稀释度。
以下表1显示凝集试验的结果。未免疫乳清显示低的本底信号,在>2倍的样品稀释度时检测不到。由混合的乳汁制备的免疫乳清样品具有平均8倍稀释度的效价。对于来自个体奶牛的牛奶,凝集效价在8倍稀释度和64倍稀释度之间,这表明个体奶牛的牛奶之间的差异和抗体制备物的多克隆特征的重要性。
表1
凝集效价 | 总蛋白质含量(mg/ml) | |
免疫乳清(混合乳汁,12头奶牛) | 16 | 10.8 |
凝集效价(个体奶牛,12头) | 8至64 | |
未免疫乳清(混合乳汁,3头奶牛) | 2 | 9.3 |
对于体内研究而言,使用McCullers等人开发的中耳炎的鼠模型(McCullers等人,“Novel Strategy to Prevent Otitis Media Caused byColonising Streptococcus pneumoniae”(预防由建群的肺炎链球菌引起的中耳炎的新对策)PLoS Pathogens,2007年3月,第3卷,第3期)。简言之,将养在BL2设施内的小鼠组用10e5或10e6CFU的肺炎链球菌的有菌毛菌株经鼻内感染,已知所述菌株有效地在粘膜表面建群(19F型菌株,得自B.Henriques-Normark ST16219F),并对其进行了设计以表达萤光素酶。两周内每天跟踪动物的感染进展,之后四周每周跟踪三次。在肺炎球菌感染的72小时内,细菌明显地在所有小鼠的鼻的前面部分建群,且70%发展为急性中耳炎(AOM)。这些中耳感染都在48小时内通过生物荧光成像确定,且攻击发生六天或更久后没有小鼠有AOM的迹象。
该模型用于评价与体外试验中所测试的抗体制备物相同的本发明的源自乳清的抗体制备物的功效。在使用2.5x10e5 CFU的生物荧光的肺炎链球菌攻击前两天,小鼠通过经口管饲法接受100μl的抗体制备物或对照的乳清制备物(每组n=10)。每日处理持续七天。结果在图5中显示,从中可看出试验组中的中耳炎减少。
实施例4
乳清部分的制备
成熟乳汁得自使用如实施例2中所述的免疫刺激物所免疫的奶牛。将所述乳汁在8℃以下的温度储藏,并在得到24小时内进行巴氏法消毒(在65℃10分钟)。通过将所述乳汁离心以除去脂肪,并通过微量过滤除去酪蛋白,得到富含对在免疫刺激物的制备中所使用的各菌株具有特异性的IgA的乳清部分。将由此得到的乳清部分使用相同条件再次进行巴氏法消毒,通过超滤浓缩,并喷雾干燥得到粉末。乳清部分的蛋白质含量为约40%,所述蛋白质中约10%是免疫球蛋白类。
Claims (12)
1.适合用于预防或治疗中耳炎的组合物,其包含源自成熟牛乳且对肺炎链球菌、流感嗜血菌和卡他莫拉菌中的至少一种具有特异性的IgA。
2.依据权利要求1的组合物,其中IgA对肺炎链球菌、流感嗜血菌和卡他莫拉菌都具有特异性。
3.依据权利要求1或2的组合物,其为营养组合物。
4.依据前述权利要求中任意一项的组合物,其为婴儿配方产品、第二阶段配方产品或成长乳。
5.依据权利要求4的组合物,其中每克组合物基于干重包含3至150μg的IgA。
6.依据权利要求1至3中的任意一项的组合物,其为补充剂,且其的日剂量包含2500至30000μg的IgA。
7.权利要求1或2中所述的组合物在制备用于预防或治疗中耳炎的药物或治疗性营养组合物中的应用。
8.成熟牛乳,其具有浓度为至少1.5μg/ml的、对肺炎链球菌、流感嗜血菌和卡他莫拉菌中的至少一种具有特异性的IgA。
9.依据权利要求8的成熟牛乳,其具有浓度为至少2.5μg/ml的所述IgA。
10.依据权利要求8的成熟牛乳,其具有浓度为至少10μg/ml的、对肺炎链球菌、流感嗜血菌和卡他莫拉菌中的所有三种都具有特异性的IgA。
11.依据权利要求10的成熟牛乳,其具有浓度为至少12μg/ml的对肺炎链球菌、流感嗜血菌和卡他莫拉菌中的所有三种都具有特异性的IgA。
12.由依据权利要求8至11中任意一项的成熟牛乳所制备的乳清部分。
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