CN101679938A - 益生双歧杆菌菌株 - Google Patents
益生双歧杆菌菌株 Download PDFInfo
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Abstract
本发明涉及口服摄取之后具有免疫调节作用且可用于预防和/或治疗炎性活性，例如不良胃肠道炎性活性，例如炎性肠病的益生双歧杆菌菌株AH1205或其突变株或变异株。
Description
引言
本发明涉及双歧杆菌菌株及其作为益生菌具体是作为免疫调节生物治疗剂的用途。
保护人类胃肠道免受肠道细菌定植的防御机制相当复杂并涉及到免疫学和非免疫学的领域(1)。先天防御机制包括胃的低pH，胆汁盐，蠕动，黏蛋白层以及抗微生物化合物，例如溶菌酶(2)。免疫学机制包括分布于整个小肠和结肠的特发性淋巴集结，基础性M细胞，又称为派伊尔淋巴集结(3)。腔内抗原在这些位点上的提呈导致了对适当T和B细胞亚型的刺激，从而建立了细胞因子网络并将抗体分泌至胃肠道中去(4)。此外，可通过上皮细胞将抗原提呈至上皮内淋巴细胞以及基础粘膜固有层免疫细胞(5)。因此，宿主相当程度地依赖于胃肠道的免疫防御。然而，由于胃肠道粘膜是宿主与外界环境相互作用的最大表面，发生于其上的具体控制机制必需能够适当地对平均寿命期间由胃肠道处理的上百吨食物进行免疫应答的调节。不仅如此，消化道定植有超过500种的细菌，在结肠中的数量为1011-1012/g。因此，这些控制机制必需能够从对宿主引起明显伤害的侵袭性病原体中区别出非致病性的附着细菌。事实上，通过与新摄入的潜在致病性微生物竞争，肠道菌群对宿主的防御大有裨益。
存在于人类胃肠道中的细菌能够引起炎症。对固有微生物菌群的异常免疫应答可涉及到某些疾病状态，例如炎性肠病。与正常菌群相关的抗原通常会导致免疫耐受，而不能达到这样的耐受是粘膜发炎的主要机制(6)。在患有炎性肠病(IBD)的患者中，其耐受被破坏的证据包括针对于所述肠道菌群的抗体水平升高。
本发明涉及双歧杆菌菌株，其可通过调制细胞因子水平或通过抗拮以及排除来自胃肠道的促炎症微生物从而表现出具有免疫调节的作用。
发明内容
本发明提供了双歧杆菌菌株AH1205(NCIMB41387)或其突变株或变异株。
所述突变株是遗传修饰的突变株。所述变异株是天然存在的双歧杆菌变异株。
所述菌株是益生菌。其是生物学纯培养物的形式。
本发明还提供了双歧杆菌NCIMB41387的分离株。
在本发明的一个实施方案中，双歧杆菌菌株是活性细胞的形式。或者双歧杆菌菌株是以非活性细胞形式存在的
在本发明的一个实施方案中，所述双歧杆菌菌株是从婴儿粪便中分离的，所述双歧杆菌菌株在口服之后在人中具有明显的免疫调节性。
本发明还提供了包含本发明所述双歧杆菌菌株的制剂。
在本发明的一个实施方案中，所述制剂包括其他的益生性物质。
在本发明的一个实施方案中，所述制剂包括有益生元物质。
优选地，所述制剂包括可摄取的载体。所述可摄取的载体可以是药用的可接受载体，例如胶囊、片剂或粉末。优选地，所述可摄取的载体可以是食物制品，例如酸化乳、酸奶、冷冻酸奶、奶粉、浓缩奶、软干酪、调料或饮料。
在本发明的一个实施方案中，本发明所述制机还包含有蛋白和/或肽，特别是富含谷氨酰胺/谷氨酸的蛋白和/或肽、脂类、碳水化合物、维生素、矿物质和/或痕量元素。
在本发明的一个实施方案中，双歧杆菌菌株在每克递送系统中以大于106cfu的量存在于所述制剂中。优选地，所述制剂包括一种或多种佐剂、细菌成分、药物实体或生物学化合物。
在本发明的一个实施方案中，所述制剂可用于免疫和接种方案。
本发明还提供了本发明的双歧杆菌菌株或制剂，其可用作食物，用作药物，用于预防和/或治疗不良炎性活性，用于预防和/或治疗不良呼吸道炎性活性(例如哮喘)，用于预防和/或治疗不良胃肠道炎性活性(例如炎性肠病如克罗恩氏病或溃疡性结肠炎、肠易激综合征、慢性肠炎、或感染后结肠炎)，用于预防和/或治疗胃肠道癌症，用于预防和/或治疗系统性疾病例如类风湿性关节炎，用于预防和/或治疗由不良炎性活性所引起的自身免疫失调，用于预防和/或治疗由不良炎性活性所引起的癌症，用于预防癌症，用于预防和/或治疗由不良炎性活性所引起的腹泻疾病(例如与艰难梭菌(Clostridium difficile)相关的腹泻、与轮状病毒相关的腹泻或感染后腹泻)，用于预防和/或治疗由感染性因子例如大肠杆菌所引起的腹泻疾病。
本发明还提供了用于制备一种抗炎生物治疗剂以预防和/或治疗不良炎性活性，或用于制备多种抗炎生物治疗剂以预防和/或治疗不良炎性活性的本发明所述双歧杆菌菌株或制剂。
在本发明的一个实施方案中，本发明所述菌株可通过抗拮以及从胃肠道中排除促炎症反应的微生物来发挥作用。
本发明还提供了用于制备抗炎生物治疗剂从而降低促炎症细胞因子水平的本发明所述双歧杆菌菌株或制剂。
本发明还提供了用于制备抗炎生物治疗剂从而调节IL-10水平的本发明所述双歧杆菌菌株。
由于双歧杆菌菌株具有拮抗致病物种生长的能力，本发明还提供了将双歧杆菌菌株作为抗感染益生菌的用途。
发明人还发现特定的双歧杆菌菌株能够在体外引起免疫调节的效果。
本发明因此在预防或治疗失调免疫应答，例如不良炎症反应(如哮喘)时具有极大的潜在治疗价值。
双歧杆菌是共生性微生物。其是从人体胃肠道内的微生物菌群中分离得到的。由于其导致的炎性活性同样会破坏宿主细胞及组织的功能，所以胃肠道内的免疫系统并不会对这类菌群的成员产生明显的反应。因此，存在一些机制，凭借着所述的机制免疫系统能够识别与致病性生物体所不同的胃肠道菌群中的共生性非致病成员。这确保了对宿主组织的损伤是被限制的并依然保留了防御性的屏障。
长双歧杆菌(Bifidobacterium longum)菌株AH1205在2006年5月11日被保藏于NCIMB，其记录的保藏号码为NCIMB41387。
所述长双歧杆菌可以是遗传修饰的突变株，或者可以是天然存在的变异株。
优选地，所述长双歧杆菌是活性细胞的形式。
或者，所述长双歧杆菌可以是非活性细胞的形式。
应该理解，本发明的特定双歧杆菌菌株可以口服摄入的形式以常规的制剂例如胶囊、微胶囊、片剂、颗粒、粉末、锭剂、丸剂、栓剂、悬液和糖浆对动物(包括人类)进行给药。适合的制剂可通过使用常规的有机和无机添加剂采用常规方法来制备。药物组合物中的活性成分量可根据所需要的治疗效果来进行操作。
所述制剂还可包含细菌成分、药物实体或生物学化合物。
此外，还可使用任意适合的公知方法，并可包含药物可接受的载体或佐剂来制备含有本发明所述菌株的疫苗。
在本说明书中，术语突变株，变异株以及遗传修饰的突变株包括与亲本菌株相比，其基因型和/或表现型性质都发生改变的双歧杆菌菌株。天然存在的长双歧杆菌变异株包括对所分离到所选定靶向性质的自发改变。对亲本菌株性质的故意改变是通过常规(体外)遗传操作技术，例如基因破坏，接合转移等来实现的。遗传修饰包括例如通过载体(包括质粒DNA或噬菌体)向细菌菌株的基因组进行插入而将外源和/或内源DNA序列导入双歧杆菌菌株的基因组。
天然或诱导的突变包括至少单个碱基的改变，例如缺失、插入、转换或其他DNA修饰，其可导致由所述DNA序列所编码氨基酸序列的改变。
术语突变株，变异株以及遗传修饰的突变株还包括这样的双歧杆菌菌株，其经历了遗传改变，所述遗传改变以对于自然界中的所有微生物一致的速率在基因组中累积，和/或所述遗传改变通过自发突变和/或基因的获取和/或基因的丢失而发生，其不是通过对基因组进行故意(体外)操作实现的，而是通过当暴露于环境压力例如抗生素时能够提供选择性优势从而支持细菌生存的对变异株和/或突变株的自然选择来实现的。可以通过向基因组中故意(体外)插入特定基因来产生突变株，其并没有在根本上改变所述生物体生物体的生物化学功能，但其产物可用来对细菌的例如抗生素抗性进行鉴定或筛选。
本领域所属技术人员应该理解双歧杆菌的突变株或变异株可通过与亲本菌株的DNA序列同源性分析进行鉴定。与亲本菌株具有接近序列一致性的双歧杆菌菌株被认为是突变株或变异株。与亲本菌株具有96％或更高序列一致性(同源性)，例如97％或更高，或98％或更高，或99％或更高的双歧杆菌菌株被认为是突变株或变异株。可使用在线同源性算法“BLAST”程序，公开于http://www.ncbi.nlm.nih.gov/BLAST/，来确定序列的同源性。
亲本菌株的突变株还包括得自与所述亲本菌株的16s-23s基因间间隔子多核苷酸序列具有至少85％序列同源性，例如至少90％序列同源性，或至少95％序列同源性的双歧杆菌菌株。这些突变株还包含在细菌基因组中其他DNA序列的DNA突变。
附图简述
图1为长双歧杆菌AH1205的BOX PCR(生物分析仪)条形码图。使用Agilent2100软件确定碱基对大小。
图2图示了在8天饲喂阶段中长双歧杆菌AH1205的粪便回收，并证实了AH1205能够在鼠胃肠道中转移的能力。
图3为条线图，显示长双歧杆菌AH1205对于人PBMC的IL-10细胞因子产生的影响。结果表示为平均值+/-SE(n＝6)。
图4A和B图示了益生菌株AH1205(A)和安慰剂(B)对于经卵清蛋白(OVA)攻击之后的致敏动物的支气管肺泡灌洗液中总细胞数的影响(n＝10/组，相对于单独的OVA*＝p＜0.05)。
图5A和B图示了益生菌株AH1205(A)和安慰剂(B)对醋甲胆碱气道反应性的影响，其通过在使用OVA或盐水鼻内攻击24小时之后卵清蛋白(OVA)致敏的小鼠中增加的停顿(Penh)的改变来进行评估。每个数据点都代表平均值±SEM(n＝10/组，相对于单独的OVA*＝p＜0.05)。
图6A至B为来自卵清蛋白(OVA)敏化的小鼠的支气管肺泡灌洗液(BAL)中IL-10(A)，INFγ(B)，TNF(C)，IL-6(D)和CCL2(E)细胞因子水平的示意图。每个柱代表平均值±SEM(n＝10，相对于OVA攻击的盐水出的对照*p＜0.05)。
图7图示了来自AH1205饲喂小鼠的CD4+CD25+细胞明显降低了响应CD4T细胞的增殖(n＝7)。
图8为在CD4+群(同样为CD25+)中，通过流式细胞术评估的派伊尔淋巴集结细胞的百分数。
图9A与B所示为在摄取AH1205的无菌小鼠中，表达转录因子Foxp3的CD4/CD25+细胞百分数明显上调。(A)＝脾细胞，(B)＝MLNC细胞(对脾分析而言n＝4/组，对MLNC分析而言n＝2/3)。
图10为当无菌小鼠摄取了长双歧杆菌AH1205之后，在CD3/CD28刺激的MLNC培养物中所分泌的细胞因子IL-6，MCP-1和INF-γ水平降低。结果表示为每组平均值+/-标准差(n＝4/组)。
图11为当无菌小鼠摄取了长双歧杆菌AH1205之后，在CD3/CD28刺激的脾细胞培养物中所分泌的细胞因子IL-6和INF-α水平降低。结果表示为每组平均值/-标准差(n＝4/组)。
图13所示为与乳杆菌(Lactobacillus)GG相比较，3个月后益生菌株AH1205的稳定性。
发明详述
本发明人发现长双歧杆菌菌株AH1205不仅是酸和胆汁耐受性的并可在胃肠道中转移(transit)，还可通过调节细胞因子水平或通过抗拮并排除来自胃肠道的促炎症或免疫调节微生物，从而另人吃惊的具有免疫调节作用。
益生菌一般是以活性细胞的形式。然而其还可扩展至非活性细胞，例如杀死的培养物或含有由益生菌所表达有益因子的组合物。这可包括热杀死的微生物或通过暴露于改变的pH或施加压力而被杀死的微生物。考虑到非活性细胞产品制剂要更简单一些，可将这样的细胞轻松地整合入药品中且储藏要求也比活性细胞要宽松的多。干酪乳杆菌(Lactobacillus casei)YIT9018提供了有效使用热杀死细胞作为治疗和/或预防肿瘤生长的方法的一个示例，参见美国专利第4,347,240号。
尚不清楚是否实施免疫调节作用需要完整的细菌，或者是否本发明的个体活性成分能够被单独的利用。某些细菌菌株的促炎成分已被鉴定出来。革兰氏阴性细菌的促炎症作用是通过脂多糖(LPS)介导的。LPS单独可诱导促炎网络，部分是由于LPS可结合于单核细胞上的CD14受体。由于整个细胞的作用，一般都认为益生菌的成分拥有免疫调节活性。直到对这些成分进行了分离，才能够期待制药级别的操作。
IL-10是由T细胞，B细胞，单核细胞和巨噬细胞产生的。这种细胞因子能够增强B细胞向抗体分泌细胞的增殖与分化。IL-10具有最主要的抗炎性活性。其可通过单核细胞上调IL-1RA的表达，并抑制大多数单核细胞的炎性活性。通过反馈机制IL-10能够抑制单核细胞产生细胞因子，具有反应活性氧和氮中间体，II类MHC的表达，寄生虫杀死，以及IL-10产生(7)。这种细胞因子还表现出可通过干扰PGE2-cAMP依赖的代谢途径从而封闭单核细胞产生肠胶原酶和IV型胶原酶，因此可作为慢性炎症疾病中可见的结缔组织破坏的一种重要调节物。
宿主对感染的反应可被描述为先天和获得性细胞和体液免疫反应，旨在限制冒犯性生物体的散布以及重建器官的内环境稳定。然而，为了限制对宿主组织继发伤害的攻击性，可激活一系列调节限制。调节性T细胞(Tregs)就可实现一个这样的机制。这些细胞可来自胸腺但也可在外周器官，包括在消化道粘膜中进行诱导。Treg细胞的故意给药能够在较广范围的小鼠模型中抑制炎症疾病，包括试验性自身免疫脑脊髓炎，炎性肠病，细菌诱导的结肠炎，胶原诱导的关节炎，I型糖尿病，气道嗜酸性炎症，移植物-宿主疾病以及器官移植。叉头转录因子Foxp3(叉头盒P3)可在Treg细胞中选择性表达，其是Treg发育及功能所必需的，并足以在常规CD4细胞中诱导Treg表现型(19)。在Foxp3中的突变可在人和小鼠中引起严重的多器官自身免疫。发明人了描述能够在体内产生CD25阳性/Foxp3阳性T调节细胞的双歧杆菌菌株。
本发明可从以下实施例中获得更明确的理解。
实施例1：对从婴儿粪便中分离的细菌进行表征。益生性状的证明。
益生菌的分离
从母乳喂养的3日龄男婴获得新鲜粪便并进行连续稀释，接种于添加有0.05％半胱氨酸和莫匹罗星(mupirocin)的TPY(酪蛋白胰酶水解物，蛋白胨和酵母汁)和MRS(deMann，Rogosa和Sharpe)培养基中。使用CO2产生试剂盒(Anaerocult A，Merck)将平板保温于厌氧罐(BBL，Oxoid)中37℃培养2-5天。将革兰氏阳性，过氧化氢酶阴性的杆状形状或分叉/多态细菌分离物在复合非选择性培养基(MRS和TPY)上进行划线纯化。除非另有声明，将分离物常规培养于MRS或TPY培养基中，在37℃在厌氧条件下。将假定的双歧杆菌保存于40％甘油并储存于-20℃和-80℃。
在分离到纯双歧杆菌菌株之后，指定其名称为AH1205，对其微生物学特征进行评价并总结于下表1。AH1205是革兰氏阳性，过氧化氢酶阴性的多态型细菌，其是果糖-6-磷酸磷酸酮酶阳性的，确证了其为双歧杆菌。使用加入单一碳源的基本培养基时，AH1205能够生长于所检测的全部碳源(葡萄糖、乳糖、核糖、阿拉伯糖、半乳糖、棉子糖、果糖、麦芽膏、甘露糖、麦芽糖、蔗糖)中。
表1
*是指果糖-6-磷酸磷酸酮酶分析
品种鉴定
进行了16s基因间间隔子(IGS)序列测定从而鉴定了所分离到的双歧杆菌。简言之，使用100μl提取液和25μl组织制备液(Sigma，XNAT2试剂盒)从AH1205中提取DNA。将样本于95℃保温5分钟，然后加入100μl中和液(XNAT2试剂盒)。使用Nanodrop分光光度计对基因组DNA溶液进行定量并储存于4℃。使用基于SEQ ID NO.1的IGS L：5’-GCTGGATCACCTCCTTTC-3’(SEQ ID NO.3)，和基于SEQ ID NO.2的IGS R：5’-CTGGTGCCAAGGCATCCA-3’(SEQ ID NO.4)的IGS引物进行PCR。循环条件为94℃3分钟(1个循环)，94℃30秒，53℃30秒，72℃30秒(28个循环)。所述PCR反应含有4μl(50ng)DNA，PCR混合物(XNAT2试剂盒)，0.4μM IGS L和R引物(MWGBiotech，德国)。PCR反应在Eppendorf热循环仪上进行。PCR产物(10μl)与分子量标记(100bp梯度标记，Roche)一起在2％染有EtBr的琼脂糖凝胶中电泳，从而确定IGS图谱。使用PromegaWizard PCR纯化试剂盒对双歧杆菌的PCR产物(单条带)进行纯化。使用针对于基因间间隔子区域的引物序列(如上所述)对纯化的PCR产物进行测序。随后将序列数据在NCBI核苷酸数据库中进行检索从而根据核苷酸同源性确定所述菌株。将所得DNA序列数据提交NCBI标准核苷酸-核苷酸同源性BLAST搜索引擎(http://www.ncbi.nlm.nih.gov/BLAST/)。鉴定出与所述序列最接近的匹配，然后使用DNASTAR MegAlign软件将所述序列进行比较比对。在序列表中可见到所得序列(SEQ ID NO.1[IGS正向序列]和SEQ IDNO.2[IGS反向序列])。检索NCIMB数据库可发现AH1205具有独特的IGS(SEQ ID NO.1[正向序列]和SEQ ID NO.2[反向序列])序列，其具有与长双歧杆菌的最接近的序列同源性。
为了开发AH1205的条码PCR图谱，使用了BOX引物进行PCR(8)。循环条件为94℃ 7分钟(1个循环)，94℃ 1分钟，65℃ 8分钟(30个循环)，以及65℃ 16分钟。所述PCR反应含有50ng DNA，PCR混合物(XNAT2试剂盒)，0.3μM BOXA1R引物(5’-CTACGGCAAGGCGACGCTGACG-3’)(SEQ ID NO.5)(MWG Biotech，德国)。PCR反应在Eppendorf热循环仪上进行。使用DNA 7500
在Agilent 2100生物分析仪(Agilent，德国)对PCR产物(1μl)与分子量标记(7500bp梯度标记，Agilent，德国)一起进行操作。使用Agilent生物分析仪软件确定条码图(PCR产物图谱、)，并确定峰数量(PCR产物)和大小(图1)。
抗生素敏感性图谱
使用“纸片敏感性”分析方法确定长双歧杆菌的抗生素敏感性图谱。将生长于适当肉汤培养基中24-48小时的培养物(100μl)倾倒铺板于琼脂培养基上，并将含有已知浓度抗生素的纸片放置于琼脂上。在厌氧条件下在37℃保温1-2天之后检测菌株的抗生素敏感性。如果可见到1mm或更大的抑菌圈则考虑所述菌株是敏感的。独立的评估每种抗生素的最低抑制浓度(MIC)。克林霉素、万古霉素和甲硝唑的MIC分别为0.032、0.75和＞256。
肠道转移
为确定长双歧杆菌能否在相当于胃中发现的低pH值条件下存活，从新鲜的过夜培养物中收集细菌细胞，用磷酸缓冲液(pH6.5)洗涤2次并重悬于(采用1M HCl)将pH调节至2.5的TPY肉汤培养基中。将细胞保温于37℃并使用平板计数法在5，30，60和120分钟测定存活情况。AH1205在pH2.5的条件下可在5分钟内存活良好，但在30分钟之后则不能回收到具有活性的细胞。
从胃排出之后，推定的益生菌将暴露于小肠中的胆汁盐。为了确定长双歧杆菌暴露于胆汁条件下的存活能力，将培养物划线于添加有0.3％(w/v)、0.5％、1％、2％、5％、7.5％或10％猪胆汁的TPY琼脂平板上。在含有高至0.5％胆汁的平板上都观察到了长双歧杆菌的生长。
在鼠模型中，对长双歧杆菌AH1205在胃肠道中的转移能力进行了评估。对每日摄入1×109AH1205的小鼠以及粪便颗粒进行了饲喂微生物存在的检测。对AH1205的检测是通过分离自发形成的双歧杆菌利福平抗性变异株来辅助的-将利福平加入用于评价转移的TPY平板，确保仅有所饲喂的利福平抗性双歧杆菌得以培养。每日收集粪便样本并确认长双歧杆菌转移通过胃肠道(图2)。
抗微生物活性
将用于本研究中的指示性致病微生物在以下生长条件下在下述培养基中进行扩增：鼠伤寒沙门氏菌(Salmonella typhimurium)(37℃，需氧)在添加有0.6％酵母汁(TSAYE，Oxoid)的胰蛋白胨大豆肉汤/琼脂培养基中，空肠弯曲杆菌(Campylobacter jejuni)(37℃，厌氧)和大肠杆菌O157：H7(37℃，厌氧)在血琼脂培养基中，艰难梭菌(Clostridium difficile)(37℃，厌氧)在加强梭菌培养基(RCM，Oxiod)中。所有菌株都接种于新鲜的生长培养基并于实验之前进行过夜生长。
使用延迟的方法(9)来检测抗微生物活性。简言之，将长双歧杆菌AH1205保温36-48小时。将10倍连续稀释液涂平板(100μl)于TPY琼脂培养基上。在过夜保温之后，将指示细菌覆盖于具有完全分开菌落的平板上。指示菌苔是通过向已接种TPY平板的表面倾倒接种有2％(v/v)过夜指示培养物的融化覆盖物来制备的。所述平板在适合指示细菌(indicator bacterium)生长的条件下再次保温过夜。抑菌圈半径大于1mm的指示培养物可被考虑为对所述检测细菌敏感。长双歧杆菌AH1205能够抑制所有检测的致病性生物体的生长，所测定的透明圈对鼠沙门氏菌，空肠弯曲杆菌，大肠杆菌O157：H7和艰难梭菌分别为8.67、＞80、4.33和11.67mm。
实施例2：PBMC对长双歧杆菌反应产生细胞因子
通过密度梯度离心从健康供体分离外周血单核细胞(PBMC)。用益生菌菌株在37℃对PBMC刺激72小时。在此时，收集培养物上清液，离心，分装并保存于-70℃直到使用流式微珠阵列(BD BioSciences)来对IL-10的水平进行分析。AH1205诱导人PBMC显著分泌IL-10，提示这一益生菌株能够在体内诱导抗炎症应答(图3)。
实施例3：在鼠哮喘模型中长双歧杆菌AH1205能够减轻呼吸道疾病
本研究调查了是否益生菌长双歧杆菌AH1205能否抑制过敏性气道炎症的卵清蛋白(OVA)致敏小鼠模型中的过敏反应。简言之，通过在0天和6天腹腔注射OVA致敏成年雄性BALB/c小鼠。在12天和14天用OVA进行鼻内攻击。在最后一次攻击(第15天)的24小时之后，测定小鼠的气道反应性之后进行BAL程序。OVA/alum致敏的、盐水攻击的小鼠用作对照。整个试验期间动物都接受益生菌或安慰剂。采用支气管肺泡(BAL)灌洗液中的炎症细胞计数来对气道炎症(细胞因子和细胞计数)进行分析。还采用Buxco整体体积描记图测定气道反应性。还从OVA致敏的小鼠中分离脾细胞，并在存在抗CD-3和抗CD-28抗体的条件下进行保温，之后通过流式细胞术测定上清液中的细胞因子水平。
与肉汤饲喂的动物相比，在OVA攻击之后，长双歧杆菌AH1205并未导致从BAL液中回收的细胞数明显降低(图4)。测定气道反应性，且与盐水刺激的小鼠相比时，用OVA对致敏小鼠进行的攻击增加了对醋甲胆碱的AHR。正如通过变长的停顿的变化所测定的那样，AH1205并不能调节对于醋甲胆碱的这种增高的气道反应性(图5)。
通过细胞珠阵列测定了BAL细胞因子水平，并且证明了与OVA对照相比，饲喂AH1205的动物具有明显降低的TNF-α水平(图6C)。IL-10、INF-γ、IL-6和CCL2水平没有明显的差异(图6)。
实施例4：Treg效应物模型
本研究调查了在健康小鼠中益生菌摄取对于调节性T细胞数量和活性的影响。将BALB/c小鼠(10只/组)饲喂长双歧杆菌AH1205或安慰剂3周。在益生菌/安慰剂摄取之后，分离CD4+CD25+T调节细胞，并通过使用流式细胞术测定抗CD3/CD28刺激的CFSE-标记的CD4+应答T细胞的增殖来确定其体外抑制活性。将CD4+应答T细胞与CD4+CD25+T细胞共保温作为对照。在益生菌或安慰剂饲喂小鼠的脾脏中，确定小鼠脾细胞中同样是FoxP3阳性的CD4+CD25+细胞(调节性T细胞)的百分数。
将与来自益生菌/安慰剂饲喂小鼠的CD4+CD25+细胞共保温时增殖的CD4+细胞的百分数与来自相同处理小鼠的CD4+CD25-细胞共保温时增殖的CD4+细胞的百分数进行比较。在每种情况下，与含有单独的CD4细胞以及耗尽CD25+细胞的培养物相比，在含有CD4+CD25+细胞的培养物中，T细胞的增殖有所下降(图7)。
确定了在CD4+类群中同样是CD25+的细胞百分数(图8)。与其安慰剂饲喂的对应物相比，长双歧杆菌AH1205饲喂组具有明显更多的CD25+的CD4+T细胞(即T-调节细胞)。这说明通过饲喂AH1205，在CD4+类群中的T-调节细胞的百分数明显增加。
还测定了益生菌或安慰剂饲喂小鼠的全部脾细胞类群中的CD4+CD25+FoxP3+细胞的数量。与饲喂安慰剂或未饲喂小鼠相比，在益生菌饲喂的小鼠的脾脏中表达FoxP3的CD4+CD25+T调节细胞数量未发生改变。
实施例5：无菌模型
购买6周龄的无菌小鼠，并保持在UCC生物服务中心的无菌单位中。动物摄取益生菌长双歧杆菌AH12059天或保持无菌状态。通过流式细胞术分析T调节细胞的诱导，并通过CBA定量细胞因子的水平。
通过在研究过程中测定选择性琼脂上的双歧杆菌计数来分析AH1205的转移。即使每天给药约1×109生物体，AH1205也并未以可检测的数量在无菌小鼠的消化道中转移。结果提示双歧杆菌在消化道内的成活需要其他的微生物或宿主因子。
尽管AH1205并未以可检测的数量在消化道内转移，但所述细菌确实与宿主的免疫系统相互作用。在9天饲喂之后，在AH1205饲喂的无菌动物肠系膜淋巴结和脾脏中的CD4+CD25+FoxP3+细胞数量都有明显增加(图9)。总CD3/CD4或CD3/CD8计数保持不变。
使用抗CD3/CD28抗体或LPS在体外刺激分离的肠系膜淋巴结细胞(MLNC)及脾细胞，或保持未刺激的状态作为阴性对照。对小鼠预饲喂AH1205时，在CD3/CD28刺激之后，培养物上清液中MLNC的IL-6和INF-γ的分泌都实质上(substantially)降低，而MCP-1水平也明显抑制(图10)。在各组之间的IL-10水平保持类似。预饲喂AH1205时，IL-6和TNF-α的脾细胞释放都为实质上但不显著的降低(图11)。在未刺激或LPS刺激的培养物中未注意到明显的差异，但总的说来发明人从双歧杆菌AH1205饲喂动物中观察到了较低的促炎症细胞因子产生。
实施例6：稳定性结果
益生菌菌株AH1205的稳定性在30℃条件下在3个月发生了改变(图12)。
乳杆菌GG在所述检测阶段的表现不好，在3个月的时间段中有两个log单位的下降，而菌株AH1205在相同检测阶段中存活力下降了高达约1个log单位。
免疫调节
人类免疫系统在多种人类疾病的病源学和病理学中起重要作用。高免疫反应和低免疫反应可导致大部分疾病状态，或是其组成部分。一种生物学实体家族，称为细胞因子，对免疫过程的控制尤其重要。这些微妙细胞因子网络的扰动越来越多地与多种疾病的相关。这些疾病包括但不限于，炎性疾病、免疫缺陷、炎性肠病、肠易激综合征、癌症(尤其是那些胃肠和免疫系统的癌症)、腹泻性疾病、抗生素相关的腹泻、儿科腹泻、阑尾炎、自身免疫紊乱、多发性硬化、阿尔茨海默氏病、类风湿性关节炎、乳糜泄(coeliac disease)、糖尿病、器官移植、细菌感染、病毒感染、真菌感染、牙周病、泌尿生殖器疾病、性传播疾病、HIV感染、HIV复制、HIV相关腹泻、手术相关创伤、手术诱导的转移性疾病、败血症、体重下降、厌食症、发烧控制、恶病质(cachexia)、创伤愈合、溃疡、消化道屏蔽功能、过敏、哮喘、呼吸疾病、循环疾病、冠心病、贫血、血凝系统疾病、肾病、中枢神经系统疾病、肝病、局部缺血、营养不良、骨质疏松症、内分泌紊乱、表皮疾病、银屑病和寻常痤疮。对每一种所检测益生菌株而言，其对于细胞因子产生的效果都是特异性的。因此，可根据针对具体疾病类型的专门性细胞因子失调来选择具体的益生菌株。可使用单独的AH1205菌株或其突变株或变异株或选定的这些菌株来实现对疾病特异性治疗的定制。
免疫教育
肠道菌群对于肠道免疫系统的发育和适当功能具有重要的作用。在肠道菌群缺乏的时候，肠道免疫系统是发育不全的，正如在无菌动物模型中所证明的那样，而且某些功能性参数也降低了，例如巨噬细胞吞噬能力和免疫球蛋白生成(10)。消化道菌群在刺激性非伤害性免疫反应中的重要性也变得愈发明显。在西方世界中过敏发生及严重性的增加与卫生保健和公共卫生的改善以及宿主收到的感染刺激的数量和范围的降低有关。这种免疫刺激的缺乏可允许宿主与非致病性，但具有抗原性的因子反应，从而导致过敏或自身免疫。一系列非致病性免疫调节细菌的故意摄取可以为宿主提供必需和适当的教育性刺激从而提供免疫功能的适当发育和控制。
炎症
炎症是用来描述在承受物理伤害，感染或正在发生免疫反应的位点上液体，血浆蛋白和白细胞局部聚集的术语。对炎症反应的控制可在多个水平中实施(11)。控制因素包括细胞因子，激素(例如氢化可的松)，前列腺素，反应中间体和白细胞三烯。细胞因子是低分子量的具有生物活性的蛋白，其涉及免疫学和炎症反应的产生与控制，同时还可调控发育，组织修复和造血作用。其为白细胞自身以及与其他细胞类型之间提供了交流的渠道。大多数细胞因子都是多效性的并可表达多种生物学重叠的活性。控制炎症反应的是细胞因子级联反应和网络，而并非是特定细胞因子对特定细胞类型的作用(12)。炎症反应的减弱导致了较低浓度的适当激活信号，而其他的炎症介导物则导致了炎症反应的停止。TNFα是一种关键的促炎症细胞因子，由于其启动了一些列细胞因子和生物学作用，导致了炎症状态。因此，能够抑制TNFα的制剂目前均被用于治疗炎症疾病，例如，英利昔单抗(infliximab)。
促炎症细胞因子被认为在许多炎症疾病，包括炎性肠病(IBD)中起到重要的作用。目前针对于治疗IBD的疗法都旨在降低这些促炎症细胞因子，包括IL-8和TNFα的水平。这样的疗法在治疗系统性炎症疾病例如类风湿性关节炎时也能够具有重要的作用。
本发明所述菌株在一系列炎症疾病的治疗中都具有潜在的应用，尤其是与其他抗炎症疗法，例如非类固醇抗感染药物(NSAID)或英利昔单抗组合使用时。
细胞因子与癌症
跨广谱肿瘤类型的多功能细胞因子的产生提示在患有癌症的患者中正在进行明显的炎症反应。目前尚不清楚何种这类应答的保护性效果会对体内肿瘤细胞的生长于发育有不利作用。然而，这些炎症反应都能够不利地影响到带有肿瘤的宿主。复杂的细胞因子相互作用都参与在肿瘤与正常组织中细胞因子产生与细胞增殖的调控(13，14)。长期以来都认为体重下降(恶病质)是在癌症患者中的单一最常见死亡原因，且初始的营养不良也指出不良的预后。对肿瘤的生长于扩散而言，其必需诱导新生血管的形成并分解细胞外基质。炎症反应对以上机制的实施具有重要的作用，因此对宿主的衰弱以及肿瘤的发展有一定作用。由于婴儿长双歧杆菌具有的抗炎症性质，这些细菌菌株能够降低恶性细胞转化的比率。此外，肠道细菌能够从膳食化合物中产生具有遗传毒性，致癌性以及肿瘤促进活性的物质，而消化道细菌则能够活化促致癌物为DNA反应活性制剂(15)。一般地，与消化道内的其他类群，例如拟杆菌属，真细菌属和梭菌纲的微生物相比，双歧杆菌的种类都具有较低的异型生物质代谢酶。因此，消化道内双歧杆菌属细菌数量的增加也能够有益地调节这些酶的水平。
疫苗/药物递送
大多数致病生物体都是通过粘膜表面进入的。可通过特定的传染性制剂对这些位点进行有效接种来保护免受侵染。迄今为止，口服疫苗策略都集中于在对活致病性生物体的减毒或纯化的胶囊化抗原的使用中(16)。经工程化能够从感染性制剂中产生抗原的益生菌，在体内，提供了极具前景的替代品，因为对人类的摄取而言，这些细菌被认为是安全的(GRAS状态)。
小鼠的研究证明摄取表达外源抗原的益生菌能够提高保护性的免疫应答。可在乳酸杆菌中表达编码破伤风毒素片段C(TTFC)的基因，并通过口服途径免疫小鼠。这样的系统能够诱导抗体滴度明显高至足以保护小鼠免受致死性毒素的刺激。除抗原提呈外，活细菌载体也能够在体内产生具有生物活性的化合物，例如具有免疫刺激作用的细胞因子。在鼻内免疫的小鼠中，乳酸杆菌分泌的具有生物活性的人IL-2或IL-6和TTFC能够诱导10-15倍以上的血清IgG滴度(17)。然而，采用这一特定的细菌菌株，通过与这些细胞因子的共表达，总IgA水平并未升高。也对其他的细菌菌株，例如格氏链球菌(Streptococcus gordonii)，进行了其作为粘膜疫苗有用性的检测。定植于鼠口腔与鞘膜腔的重组格氏链球菌可诱导对于该细菌所表达抗原的粘膜与系统性抗体反应(18)。因此，使用益生菌作为载体进行的口服免疫不仅可以保护宿主免受感染，还能够取代病原体正常引起的免疫刺激，从而有益于宿主的免疫教育。
益生元
益生性生物体的引入是通过以适当的载体摄入微生物来实现的。其益处在于提供了能够在大肠中促进这些益生菌株生长的介质。一种或多种寡糖，多糖或其他益生菌的加入都能够促进在胃肠道中乳酸细菌的生长。益生元是指任意非活性的食物成分，其是由被认为是具有阳性价值的内源性细菌，例如双歧杆菌，乳酸杆菌在结肠中特异性的发酵而成的。益生元的类型可包括果糖，木糖，大豆，半乳糖，葡萄糖和甘露糖。益生菌株与一种或多种益生元化合物的组合给药可增强体内所述给药益生菌的生长，从而导致更有力的健康受益，且被称为合益作用(synbiotic)。
其他活性成分
应该理解益生菌株可预防性给药或以其本身或与上述的其他益生菌和/或益生元物质一起作为治疗方法。此外，所述细菌可作为使用其他活性物质的预防或治疗方案的一部分，例如那些用于治疗炎症或其他病症特别是免疫相关病症的方案。这样的组合可作为单一制剂给药或在相同或不同时间且使用相同或不同的给药途径作为分离的制剂给药。
本发明并不局限于本说明书中所述的实施方案，其可在细节中有所改变。
参考文献
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aacactaaaa atagagttng attngaaatt aacagcaaga acgaggaatn aaaggnaacc 180
ccgtnttgnt tgngtccact atncagtttt naagccacca cgcaccacca cgccgtncgg 240
acgggaccag cccgccatna ggnacgatgg gcatngaatc gcgccaggnc aaancctggg 300
gtggcgatnc gggagcccaa aagcgcatnc acaccactnc cgcggaacat nccacgacgg 360
acgcaccgna agnccatgat tttttncaca ccancagccc caagncgccg cgactgncgc 420
gacgccnggg ctcgcaccgc cngacgaaca tncggncgtn ttntncgtan aaaggaggtt 480
cccancnann ncng 494
<210>2
<211>479
<212>DNA
<213>Bifidobacterium longum
<400>2
aananaaacg ccgcngttct ccgcggtgcg tgccccgtcg tcncggcagt cgcggcggcc 60
tggggctgct ggtgtggaag agatcatggg ctttcggtgc gtccgtcntg ggatgttccg 120
cgggagtggt gtgnatgcgc ttttggnctc ccggatcgcc accncaggct ttggcctggc 180
gcgattcgat gcccatcgtg cctgatggcg ggctggtccc gtccggacgg cntggtggtg 240
cgtggtggct tgagaactgg atagtggacg cgagcaagac ngggtttcct ttgattcctc 300
ttcttgctgt tgatttcgaa tcgaactcta tttttantgt ttgnttccat cgttttgtga 360
ncattttaat gtgangantt gtcctctggg aatttgctan gaangancct tgnngccang 420
cncaccntgn ngnncctgtt gcctgcaang gcgnanggng gaagcccttg canccagaa 479
<210>3
<211>18
<212>DNA
<213>Unknown
<400>3
gctggatcac ctcctttc
<210>4
<211>18
<212>DNA
<213>Unknown
<400>4
ctggtgccaa ggcatcca
<210>5
<211>22
<212>DNA
<213>Unknown
<400>5
ctacggcaag gcgacgctga cg
1
Claims (39)
1.保藏号为NCIMB41387的长双歧杆菌(Bifidobacterium longum)菌株AH1205或其突变株或变异株。
2.权利要求1的双歧杆菌菌株，其中所述突变株是遗传修饰的突变株。
3.权利要求1的双歧杆菌菌株，其中所述变异株是天然存在的双歧杆菌变异株。
4.权利要求1的双歧杆菌菌株，其是益生菌。
5.权利要求1或4的双歧杆菌菌株，其中所述菌株是生物学纯培养物的形式。
6.双歧杆菌NCIMB41387的分离株。
7.活性细胞形式的权利要求1-6中任一权利要求所述的双歧杆菌菌株。
8.非活性细胞形式的权利要求1-6中任一权利要求所述的双歧杆菌菌株。
9.权利要求1-8中任一权利要求所述的双歧杆菌菌株，其中所述双歧杆菌是从婴儿粪便中分离的。
10.权利要求1-9中任一权利要求所述的双歧杆菌菌株，其中所述菌株在口服之后在人中具有明显的免疫调节性。
11.包含权利要求1-10中任一权利要求所述双歧杆菌菌株的制剂。
12.权利要求11的制剂，其还含有益生性物质(probiotic material)。
13.权利要求11或12中任一权利要求所述的制剂，其还含有益生元物质(prebiotic material)。
14.权利要求11-13中任一权利要求所述的制剂，其还含有可摄取的载体。
15.权利要求14所述的制剂，其中所述可摄取的载体是药用的可接受载体，例如胶囊、片剂或粉末。
16.权利要求14所述的制剂，其中所述可摄取的载体是食物制品，例如酸化乳、酸奶、冷冻酸奶、奶粉、浓缩奶、软干酪、调料或饮料。
17.权利要求11-16中任一权利要求所述的制剂，其还含有蛋白质和/或肽，特别是富含谷氨酰胺/谷氨酸的蛋白质和/或肽、脂质、碳水化合物、维生素、矿物质和/或痕量元素。
18.权利要求11-17中任一权利要求所述的制剂，其中双歧杆菌菌株在每克所述制剂中以大于106cfu的量存在。
19.权利要求11-18中任一权利要求所述的制剂，其还含有佐剂。
20.权利要求11-19中任一权利要求所述的制剂，其还含有细菌成分。
21.权利要求11-20中任一权利要求所述的制剂，其还含有药物实体。
22.权利要求11-21中任一权利要求所述的制剂，其还含有生物学化合物。
23.权利要求11-22中任一权利要求所述的制剂，其用于免疫和接种方案。
24.权利要求1-10中任一权利要求所述的双歧杆菌菌株或权利要求11-23中任一权利要求所述的制剂，其用于食物中。
25.权利要求1-10中任一权利要求所述的双歧杆菌菌株或权利要求11-23中任一权利要求所述的制剂，其用作药物。
26.权利要求1-10中任一权利要求所述的双歧杆菌菌株或权利要求11-23中任一权利要求所述的制剂，其用于预防和/或治疗不良炎性活性。
27.权利要求1-10中任一权利要求所述的双歧杆菌菌株或权利要求11-23中任一权利要求所述的制剂，其用于预防和/或治疗不良胃肠道炎性活性，例如炎性肠病如克罗恩氏病或溃疡性结肠炎、肠易激综合征、慢性肠炎、或感染后结肠炎。
28.权利要求1-10中任一权利要求所述的双歧杆菌菌株或权利要求11-23中任一权利要求所述的制剂，其用于预防和/或治疗胃肠道癌症。
29.权利要求1-10中任一权利要求所述的双歧杆菌菌株或权利要求11-23中任一权利要求所述的制剂，其用于预防和/或治疗系统性疾病例如类风湿性关节炎。
30.权利要求1-10中任一权利要求所述的双歧杆菌菌株或权利要求11-23中任一权利要求所述的制剂，其用于预防和/或治疗由不良炎性活性所引起的自身免疫失调。
31.权利要求1-10中任一权利要求所述的双歧杆菌菌株或权利要求11-23中任一权利要求所述的制剂，其用于预防和/或治疗由不良炎性活性所引起的癌症。
32.权利要求1-10中任一权利要求所述的双歧杆菌菌株或权利要求11-23中任一权利要求所述的制剂，其用于预防癌症。
33.权利要求1-10中任一权利要求所述的双歧杆菌菌株或权利要求11-23中任一权利要求所述的制剂，其用于预防和/或治疗由不良炎性活性所引起的腹泻疾病，例如与艰难梭菌(Clostridium difficile)相关的腹泻、与轮状病毒相关的腹泻、或由感染性因子例如大肠杆菌所引起的感染后腹泻或腹泻疾病。
34.权利要求1-10中任一权利要求所述的双歧杆菌菌株或权利要求11-23中任一权利要求所述的制剂，其用于制备用于预防和/或治疗不良炎性活性的抗炎生物治疗剂。
35.权利要求34所述的双歧杆菌菌株，其用于制备用于调节IL-10水平的一组生物治疗剂。
36.权利要求1-10中任一权利要求的双歧杆菌菌株或其具活性衍生片段或突变株在预防和/或治疗炎性疾病、免疫缺陷、炎性肠病、肠易激综合征、癌症(尤其是那些胃肠和免疫系统的癌症)、腹泻性疾病、抗生素相关的腹泻、儿科腹泻、阑尾炎、自身免疫紊乱、多发性硬化、阿尔茨海默氏病、类风湿性关节炎、乳糜泄(coeliac disease)、糖尿病、器官移植、细菌感染、病毒感染、真菌感染、牙周病、泌尿生殖器疾病、性传播疾病、HIV感染、HIV复制、HIV相关腹泻、手术相关创伤、手术诱导的转移性疾病、败血症、体重下降、厌食症、发烧控制(fever control)、恶病质(cachexia)、创伤愈合、溃疡、消化道屏蔽功能、过敏、哮喘、呼吸疾病、循环疾病、冠心病、贫血、血凝系统疾病、肾病、中枢神经系统疾病、肝病、局部缺血、营养不良、骨质疏松症、内分泌紊乱、表皮疾病、银屑病和/或寻常痤疮中的用途。
37.权利要求1-10中任一权利要求的双歧杆菌菌株，其中所述菌株可通过抗拮以及排除来自胃肠道中的促炎微生物来发挥作用。
38.权利要求1-10中任一权利要求所述的双歧杆菌菌株或权利要求11-23中任一权利要求所述的制剂，其用于制备用于降低促炎细胞因子水平的抗炎生物治疗剂。
39.权利要求1-10中任一权利要求所述双歧杆菌菌株由于其具有拮抗致病物种生长的能力从而用作抗感染益生菌株的用途。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| US90731207P | 2007-03-28 | 2007-03-28 | |
| US60/907,312 | 2007-03-28 | ||
| PCT/IE2008/000034 WO2008117267A2 (en) | 2007-03-28 | 2008-03-28 | Probiotic bifidobacterium strains |
Publications (2)
| Publication Number | Publication Date |
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| CN101679938A true CN101679938A (zh) | 2010-03-24 |
| CN101679938B CN101679938B (zh) | 2014-03-19 |
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| CN200880017881.0A Expired - Fee Related CN101679938B (zh) | 2007-03-28 | 2008-03-28 | 益生双歧杆菌菌株 |
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| Country | Link |
|---|---|
| US (2) | US8709398B2 (zh) |
| EP (1) | EP2134835B1 (zh) |
| JP (1) | JP2010522553A (zh) |
| KR (1) | KR20090127180A (zh) |
| CN (1) | CN101679938B (zh) |
| AU (1) | AU2008231467A1 (zh) |
| BR (1) | BRPI0809448A2 (zh) |
| CA (1) | CA2682327A1 (zh) |
| GB (1) | GB2460781B (zh) |
| HK (1) | HK1141554A1 (zh) |
| MX (1) | MX2009010418A (zh) |
| MY (1) | MY146595A (zh) |
| NZ (1) | NZ580006A (zh) |
| RU (1) | RU2466185C2 (zh) |
| WO (1) | WO2008117267A2 (zh) |
| ZA (1) | ZA200906803B (zh) |
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| US9259019B2 (en) * | 2010-11-11 | 2016-02-16 | Mars, Incorporated | Bifidobacteriumstrain |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103327989A (zh) * | 2010-04-23 | 2013-09-25 | 营养生理学有限责任公司 | 哺乳动物胃肠感染的预防和治疗 |
| CN103327989B (zh) * | 2010-04-23 | 2016-03-02 | 营养生理学有限责任公司 | 哺乳动物胃肠感染的预防和治疗 |
| CN105112333A (zh) * | 2015-08-31 | 2015-12-02 | 江南大学 | 一种具有良好肠道定殖能力的长双歧杆菌及筛选方法和应用 |
| CN110352237A (zh) * | 2017-02-28 | 2019-10-18 | 营养健康有限公司 | 可以有益地调节针对呼吸道病毒感染的免疫应答的长双歧杆菌 |
| CN110352237B (zh) * | 2017-02-28 | 2023-01-10 | 精密生物集团有限公司 | 可以有益地调节针对呼吸道病毒感染的免疫应答的长双歧杆菌 |
| CN115428954A (zh) * | 2022-09-15 | 2022-12-06 | 北京三元食品股份有限公司 | 复合益生菌及发酵乳在制备用于辅助治疗hiv患者产品中的应用 |
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| WO2008117267A2 (en) | 2008-10-02 |
| MX2009010418A (es) | 2010-02-18 |
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| RU2009136394A (ru) | 2011-05-10 |
| GB0916991D0 (en) | 2009-11-11 |
| EP2134835B1 (en) | 2014-10-15 |
| NZ580006A (en) | 2012-03-30 |
| GB2460781B (en) | 2012-01-25 |
| WO2008117267A3 (en) | 2008-11-27 |
| EP2134835A2 (en) | 2009-12-23 |
| CN101679938B (zh) | 2014-03-19 |
| ZA200906803B (en) | 2010-05-26 |
| RU2466185C2 (ru) | 2012-11-10 |
| CA2682327A1 (en) | 2008-10-02 |
| US20110020400A1 (en) | 2011-01-27 |
| BRPI0809448A2 (pt) | 2014-09-09 |
| US8709398B2 (en) | 2014-04-29 |
| US20140328879A1 (en) | 2014-11-06 |
| GB2460781A (en) | 2009-12-16 |
| KR20090127180A (ko) | 2009-12-09 |
| HK1141554A1 (zh) | 2010-11-12 |
| AU2008231467A1 (en) | 2008-10-02 |
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