CN1430518A - 干酪乳杆菌在免疫刺激肽中的应用 - Google Patents
干酪乳杆菌在免疫刺激肽中的应用 Download PDFInfo
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Abstract
本发明涉及干酪乳杆菌在口服给药来加强特异性针对病原微生物的免疫的组合物中的应用。所述组合物可以特别是食品或食品添加物。
Description
本发明涉及乳酸菌加强抗传染性物质的特异免疫反应的用途。
乳酸菌(LABs)通常用于生产发酵食品,尤其是乳制品。
Metchnikoff的研究(The prolongation of life.第1版,NewYork:GP Putman’s Sons,1908)最初提示了乳酸菌对健康的作用,并从此成为许多研究的主题。
现在通常承认各种乳酸菌可发挥有益于健康的作用。这些细菌也称作“益生菌”-表示当它们被足量摄取时,除了常规的营养作用外,还对健康发挥积极作用的活微生物的名称。在属于乳杆菌属、双歧杆菌属、链球菌属和乳球菌属的种中已特别描述了益生菌,一般用于乳品工业。
认为益生菌通过妨碍病原微生物的发展,和/或更直接作用于免疫***来特别干预肠道菌群的水平。例如,已经观察到益生菌或含这些细菌的发酵食品如酸乳酪的摄入导致病原细菌减少;在免疫***方面,已经报道了各种作用:活化参与特异性或非特异性免疫反应的细胞,如淋巴细胞和巨噬细胞,免疫球蛋白,尤其是IgA水平增加;免疫***活化细胞因子水平增加等。(综述,参见例如MEYDANI和HA(Am JClin Nutr,71,861-7217,2000)。
总之,对各种益生乳酸菌进行的研究趋向总结出有些种,或至少这些种的有些株具有免疫刺激性能。另一方面,这些性能所基于的机制,和潜在参与的免疫***成分仍未确定。因此看来有必要阐明这些方面,尤其是为了提出益生菌各种种或株的更好的目标应用。
在人和动物中实施的几个研究提示,干酪乳杆菌(Lactobacilluscasei)种的细菌对健康具有有益作用,特别是对免疫***有积极作用。
已经表明在小鼠中,摄入含干酪乳杆菌株DN-114 001的发酵牛奶可增加抵抗鼠伤寒杆菌的感染[PAUBERT-BRAQUET等.Int JImmunother,4:153,(1995)];同时观察到巨噬细胞活化和循环IgAs增加。
菌株DN-114 001已于1994年12月30日保藏在巴黎,25 rue duDocteur Roux,Institut Pasteur的CNCM(Collection Nationale deCultures de Microorganismes)[国立微生物保藏中心],保藏号为I-1518;在PCT申请WO 96/20607(申请人为COMPAGNIE GERVAISDANONE)中描述了这个株,和其酸乳酪发酵组合用于制备发酵乳制品。
在人中进行的最近研究也报道了含干酪乳杆菌株DN-114 001的发酵牛奶的摄入促使加强抵抗鼠伤寒杆菌。这个作用归功于对非特异性先天免疫的作用[YOON等,Iht J Immunother;15,79-89(1999)]。
发明人研究了干酪乳杆菌是否也对适应性免疫有作用,它与先天免疫不同,引起对抗给定病原物的特异性免疫反应。
为了这个目的,发明人研究了体内口服给予干酪乳杆菌对响应各种普通病原物的代表性抗原:细菌抗原(破伤风);真菌抗原(念珠菌)和病毒抗原(流感)的T细胞增殖离体刺激的作用。
他们观察到对于每个测试的抗原,干酪乳杆菌摄入导致T细胞,特别是CD3+亚群响应所述抗原活化的增殖能力增加。这个作用尤其表现在流感抗原的情况下。
本发明的主题是干酪乳杆菌物种的菌株在制备可口服给药来加强抗病原微生物的特异性全身免疫反应的组合物中的应用。
这种免疫反应的加强是由对所述病原微生物抗原特异性的T细胞增殖能力增加而产生的。
根据本发明的优选实施方案,所述微生物是空气传播病原体,特别是呼吸道病原体。
有关的病原体特别是细菌或病毒;在后者中,将提到,例如,鼻病毒、呼吸道合胞病毒(RSV)和粘液病毒(正粘病毒如流感病毒)(甲、乙、或丙型流感),或副粘病毒,尤其是副流感病毒)。
本发明的实施方案中,所述干酪乳杆菌可单独或与干酪乳杆菌物种或其它物种的其它乳酸菌联合使用。有利地,它可与酸乳酪酵素,即保加利亚乳杆菌(Lactobacillus bulgaricus)和唾液链球菌嗜热亚种(Streptococcus thermophilus)组合使用。
它也可以以完整细菌的形式使用,可以是或可以不是活的,也可以以细菌溶菌产物的形式,或以细菌级分的形式使用。
优选,在根据本发明的应用中制备的组合物中每毫升含有至少105,优选至少106,通常在1×108和1.5×109之间的干酪乳杆菌细胞。
当干酪乳杆菌与酸乳酪酵素组合使用时,所述组合物中每毫升也有利地含至少107,优选2×108和1×109之间的唾液链球菌嗜热亚种细胞,和每毫升至少5×105,优选4×106和2×107之间的保加利亚乳杆菌细胞。
尤其最适合用于本发明的干酪乳杆菌株是CNCM株I-1518。
根据本发明制备的组合物可以以食品或食品添加物的形式给予。它们可以是例如,乳制品,特别是发酵乳制品,它们至少含所述干酪乳杆菌株,任选与其它乳酸菌组合,例如与酸乳酪酵素组合。
根据本发明制备的组合物可用于传染起源,特别是病毒起源,尤其是流感起源的病理情况的预防和治疗。优选,为了获得最佳的效果,它们将以相当于吸收至少107,优选至少108,通常在109和1012之间的干酪乳杆菌细胞的量给药至少一周,优选至少10天。
在随后的进一步描述的帮助下,将更清楚地理解本发明,该描述是指阐明干酪乳杆菌株加强对微生物抗原的特异性反应的性质的非限制性实施例。
实施例1:干酪乳杆菌对响应抗原刺激的T细胞增殖的作用
为了检测摄入含干酪乳杆菌菌株DN-114 001(CNCM I-1518)的发酵乳制品对响应抗原刺激的T细胞增殖的作用,实施与安慰剂相比的双盲实验。
该研究的条件如下:
个体
募集华盛顿医院中心传染病科(华盛顿特区)的88个健康个体,18至50岁。有肝炎或肾病,心血管功能紊乱,免疫或胃肠道疾病,严重哮喘或糖尿病病史的个体,在开始研究前少于3个月,用抗生素或免疫抑制剂治疗的个体,有酗酒或酒精依赖性病史的个体,已知对乳制品不耐受或过敏的个体,低卡路里饮食的个体,前季期间已接种抗流感疫苗的个体,和孕妇或哺乳妇女从本研究中排除。
WHC研究委员会批准了本研究的方案和条件,管理对人实施研究的机构审查部也批准。
所选个体随机分成2组:
-47个个体的一组(26个女性和21个男性)接受每天100ml含2%脂肪的发酵乳制品,包括酸乳酪酵素(保加利亚乳杆菌和唾液链球菌嗜热亚种)和干酪乳杆菌菌株DN-114 001,由DANONE以ACTIMEL商标销售。
-41个个体的一组(22个女性和19个男性)接受28天安慰剂:每天100ml用水稀释(1/5,v/v)的补充糖以给予与ACTIMEL等同卡路里值的牛奶。
要求2个组的个体在研究期间避免食用酸乳酪或其它发酵乳制品。
ACTIMEL组和安慰剂组的个体平均(圆括号中指出标准差)年龄分别是36(7.3)和32.7(7.4)。
为了确定基础值,在ACTIMEL或安慰剂开始摄入前,从2个组的每个个体抽取血液样品(55ml)。在9、18和28天给予个体控制随访,完成有关他们健康、可能的副作用以及任何可能干扰结果解释的疾病发展的短调查表。为了免疫学实验,每次随访期间抽取血液样品。
对于每个个体的血液样品,进行完整血细胞计数和血液化学分析。此外,用流式细胞术进行白细胞及其亚群(T细胞和亚群,B细胞,单核细胞和NK细胞)的表型分析。
细胞增殖的测定
通过如下所述测定3HTdR掺入来离体确定ACTIMEL组个体和安慰剂组个体,有关三个微生物抗原:念珠菌、破伤风和流感的T细胞增殖反应。
细胞制备:
所取的每个样品的30ml肝素化血液处理如下:将管以1500rpm离心10分钟。小心地将血浆转移到标记的冷冻管中并在70℃保存[原文如此]。血液转移到15ml离心管中并用PBS稀释到1∶3。将10mlFicoll-hypaque加入到50ml离心管中并覆盖30ml稀释的血液。管以2000rpm在室温下离心2分钟。弃去PBS上层,混合单个核细胞并转移到15ml离心管中。加入10ml HBSS,涡旋并以1500rpm离心10分钟;弃去上清,沉淀重悬于2-3ml HBSS。加入8ml HBSS,将管以1500rpm离心6分钟。这个方案重复两次,回收的细胞重悬于1-2mlPBS然后涡旋。计数细胞,台盼蓝排除法检查它们的活力,其浓度调整到2×108/ml。
制备抗原:
破伤风抗原:实验当天制备。PBS中将破伤风类毒素(CONNAUGHTLABORATORY,Willowdale,加拿大)稀释到1∶1000制备原液。
白色念珠菌(Candida albicans)抗原:PBS中将白色念珠菌抗原(BAYER CO,ELKERT,IN)稀释到1∶1000制备原液。
流感抗原:PBS中将流感病毒抗原(NIBSC,Herts,英国)稀释到1∶125制备原液。
使用微滴定板(96孔)。每个孔接受100μl抗原原液和100μl细胞,每孔2×105个细胞的终浓度。对照孔接受100μl PBS代替抗原原液。板在37℃,5%CO2下温育5天;温育结束前18小时,加入20μl的50μCi/ml3HTdR(NEW ENGLAND NUCLEAR,Boston,MA)。在滤器上收获每个板的孔的细胞,为了测定3HTdR掺入,滤器直接在MATRIX 9600 beta-计数器(PACKARD INSTRUMENTS)中计数,以CPM(每分钟计数)表示。
对于已接受ACTIMEL的组的每个个体和已接受安慰剂的组的每个个体,根据下列公式测定刺激指数(SI)估计增殖:
统计学分析
描述性统计学(平均数、标准差、中值)用于总结在每个测定时间,本研究的每个组中T细胞接触每个抗原的增殖反应。由于增殖反应的分布偏差,对增殖数据进行自然对数转换。
与基础值比较增殖反应的变异用于统计学建模[LITTELL等.SASSystem for Mixed Model.North Carolina:SAS Institute Inc,(1996)]。使用DIGGLE等[Analysis of Longitudinal Data.NewYork:University Press Inc,1994]描述的曲线平滑技术表现增殖反应与基础值相比较随时间的变化。
开发了混合线性模型以研究增殖反应的轨迹(trajectory)。这个模型允许将研究的每组的增殖数据调整为二次曲线。
这个模型由下列等式定义:Yijt=αij+β1jT+β2jT2+εijt,i=1,….n,j=1,2,t=1,2,3,4
其中:
Yijt表示个体i在产品组j在时间t时,与基础值相比的增殖反应的差异;对每个变量已经进行自然对数转换,Yijt=Log(在时间t的增殖)-Log(基础值)。
αij表示在产品组j中个体i的截距(interception)。它反应在模型中的随机作用。αij~MVN(O,G),G含有对角线结构(djagonalstructure)中方差的分量(MVN:多项式变量分布(multinomalvariable distribution))。
β1j和β2j是产品组j的T和T2的回归系数;
T是测定的时刻(第0,9,18或28天),T2是T的二次方。
εijt是误差系数:
εijt~MVN(O,R)和R=σ2In,其中In表示单位矩阵n×n。
实施了下列假说的统计学检验:
a)检测估计的回归系数是否是0.H0:β1j=0对H1:β1j≠0 (对于线性项)和H0:β2j=0对H1:β2j≠0 (对于二次项)如果β1j和β2j不同于0,则没有轨迹。如果β2j与0有显著差异,则有二次轨迹。如果只有β1j与0有显著差异,则有线性轨迹。
b) 比较两组的轨迹是否相同。H0:β11=E12对H1:β11≠β12 (对于线性项)和H0:β21=E22对H1:β21≠β22(对于二次项)用SAS统计包进行分析。结果下表I给出了有关个体的人数统计数据和增殖的基础值的估计。
表I
SD=标准差
人数统计数据和基础值 | 安慰剂 | ACTIMEL | 安慰剂与ACTIMEL比较 |
性别 女性男性 | 2219 | 2621 | 卡方检验p=0.826 |
年龄 平均数(SD)中值 | 32.7(7.4)31 | 36.0±7.337 | T检验P=0.038 |
人种 白色黑色其他 | 26123 | 25175 | 卡方检验精确p=0.652 |
白细胞 平均数(SD)中值 | 5997(1451)5992 | 5810(1399)5990 | T检验P=0.540 |
淋巴细胞 平均数(SD)中值 | 1932(567)1812 | 2009(554)1993 | T检验P=0.519 |
CD3+CD4+ 平均数(SD)中值 | 865(327)740 | 907(325)818 | T检验P=0.546 |
CD3+CD8+ 平均数(SD)中值 | 469(205)417 | 431(181)403 | T检验P=0.360 |
CD3+CD25+ 平均数(SD)中值 | 380(200)349 | 408(182)392 | T检验P=0.489 |
CD3+CD45+ 平均数(SD)中值 | 1384(488)1354 | 1411(434)1382 | T检验P=0.783 |
T细胞对特异性微生物抗原的增殖反应
下表2给出了每组(ACTINEL和安慰剂)在各个采样时间的外周血液单个核细胞(PBMCs)的离体增殖的平均数、标准差和中值。
表2
SD=标准差
抗原 | 安慰剂 | ACTIMEL | ||||||
0天 | 9天 | 18天 | 28天 | 0天 | 9天 | 18天 | 28天 | |
念珠菌平均数SD中值 | 2.32.01.5 | 2.73.11.7 | 2.94.11.6 | 1.91.21.6 | 3.03.41.7 | 3.23.51.7 | 4.35.62.0 | 2.32.61.4 |
破伤风平均数SD中值 | 7.37.85.2 | 11.812.36.3 | 7.98.05.1 | 8.78.16.7 | 8.415.83.5 | 8.710.45.2 | 10.311.85.0 | 7.88.25.1 |
流感平均数SD中值 | 14.211.411.1 | 21.719.116.5 | 17.019.69.8 | 17.315.712.0 | 13.012.69.6 | 19.717.116.9 | 20.316.617.0 | 13.912.711.0 |
本研究对于三个微生物抗原的增殖反应的基础值(0天),两组之间没有显著性差异。
图1图解了本研究的两组对于每个抗原在时间上的增殖反应的变化:ACTIMEL组:连续线;安慰剂组:虚线。
下表3提供了统计学建模结果。
表3
念珠菌:
抗原 | 变量 | 参数估计 | 标准误 | H0检验:参数=0 | 2条曲线的比较 |
念珠菌 | 安慰剂 TT2 | 0.017-0.0007 | 0.0140.0005 | P=0.232P=0.208 | H0:β11=β12P=0.540H0:β21=β22P=0.458 |
ACTIMEL TT2 | 0.028-0.0012 | 0.0130.0005 | P=0.030P=0.013 | ||
破伤风 | 安慰剂 TT2 | 0.034-0.0008 | 0.0140.0005 | P=0.022P=0.141 | H0:β11=β12P=0.630H0:β21=β22P=0.626 |
ACTIMEL TT2 | 0.043-0.0011 | 0.0130.0005 | P=0.001P=0.020 | ||
流感 | 安慰剂 TT2 | 0.022-0.0004 | 0.0170.0006 | P=0.181P=0.475 | H0:β11=β12P=0.045H0:β21=β22P=0.027 |
ACTIMEL TT2 | 0.068-0.0023 | 0.0150.0006 | P=0.0001P=0.0001 |
在ACTIMEL组中,0天的基础反应3.0±3.4增加到第9天的3.2±3.5,和第18天的4.3±5.6,然后在28天降到2.3±2.6(表2)。估计的线性项T和二次项T2的系数分别是0.028和0.0012(表3)。两个值与0有统计学显著差异(分别是p=0.030和0.013)。这些观察结果暗示对念珠菌抗原的增殖反应的变化具有显著的正趋向。增殖反应首先增加然后降低,如图1a所示。
安慰剂组显示本研究期间的小改变。估计的T和T2的回归系数是0.017和0.0007。这些值与0没有显著差异(分别是p=0.232和0.208)。这些观察结果显示对照组增殖反应在本研究期间没有显著改变。如图1a所示,安慰剂组曲线比ACTIMEL组的曲线平坦。尽管ACTIMEL组与安慰剂组相比,显示出明显的轨迹,两条曲线间的差异没有达到统计学显著性的水平(T的p=0.540和T2的p=0.458,表3)。
破伤风:
对于ACTIMEL组,反应从基础水平逐渐增加到第18天,然后下降。估计的T和T2的回归系数分别是0.043和0.0011(表3)。这两个值与0有显著差异(分别是p=0.001和0.020)。如念珠菌的情况,ACTIMEL组在本研究期间增殖反应的正变化有显著性。在安慰剂组,平均值从0天的7.3增加到9天的11.8,然后18天降至7.9,在28天再次增加到8.7(图1b)。即使二次项T2具有非显著系数(-0.0008,p=0.141,表3),T的显著估计系数(0.034,p=0.022,表3)显示出轨迹作用。然而,如果ACTIMEL组与安慰剂组比较,统计学检验在两条曲线间未显示任何显著差异(T和T2分别是p=0.630和0.626)。
流感:
ACTIMEL组比安慰剂组显示更清晰的改变。平均值从0天的13±12.6增加到9天的19.7±17.1,保持这个水平到18天,然后在28天降至13.9±12.7(图1c)。估计的T和T2的两个系数与零有显著差异(p=0.001)。这些统计显示本研究期间增殖反应的正改变是显著性的(表2)。
安慰剂组显示与破伤风观察到的那些相似的变化。如图1c图示,平均值到9天增加,到18天降低,到28天再次增加。两个估计的回归系数与0没有显著差异(T和T2的p值分别是0.181和0.475),表明对流感抗原的增殖反应变异没有显著轨迹。
当比较ACTIMEL组和安慰剂组估计的参数时,观察到线性参数和二次方参数都有显著差异(T的p=0.045和T2的p=0.027)(表3)。这些结论表明本研究的两组间增殖反应的变化具有显著差异。
实施例2:干酪乳杆菌对响应流感抗原刺激的T淋巴细胞亚群增殖的作用。
体外对微生物抗原应答的T亚群的确切性质未知。T淋巴细胞特定亚群的任何一个,如表型CD3+CD4+,CD3+CH8+,CD3+CH25+和CD3+CD45+代表的那些,可以认为是初级应答者,或这些组合亚群可能有助于对激发抗原的总体增殖反应。
假设特定淋巴细胞亚群是激发抗原的主要应答者,为了确定ACTIMEL组和安慰剂组之间4个亚群得到的增殖反应是否有显著差异,使用上面实施例1所述的统计模型对T细胞亚群CD3+CD4+,CD3+CH8+,CD3+CH25+和CD3+CD45+进行分析。
在这些分析中,对于每个亚群,最初基于总PBMCs的增殖反应的值转换为根据每个血液样品中CD3+CD4+,CD3+CH8+,CD3+CH25+和CD3+CD45+ T细胞总频率计算的新值。下一步,对每个亚群进行统计学分析,如上面实施例1所述。
对于四个淋巴细胞亚群,每个安慰剂和ACTIMEL组的平均数、标准差和中值在下表4给出。
表4
SD=标准差
淋巴细胞亚群 | 安慰剂 | ACTIMEL | ||||||
0天 | 9天 | 18天 | 28天 | 0天 | 9天 | 18天 | 28天 | |
CD3+CD4+平均数SD中值 | 10184.072.8 | 149130111 | 11311774.5 | 12512791.0 | 87.410463.0 | 13190.2103 | 13311292.0 | 10712764.5 |
CD3+CD8+平均数SD中值 | 192155167 | 268250218 | 251289140.5 | 251336168 | 230375105 | 301286180 | 365554214 | 244302126 |
CD3+CD25+平均数SD中值 | 250219185 | 377374263 | 260208228 | 354462247 | 177139159 | 267163262 | 310210251 | 270305177 |
CD3+CD45+平均数SD中值 | 63.554.147.5 | 87.670.966.6 | 73.081.343.1 | 76.279.751.4 | 52.172.234.0 | 78.756.364.0 | 87.179.267.8 | 69.195.241.0 |
本研究的两组之间基础值的差异无统计学显著性。
使用上面实施例1所述的统计学模型,在对流感抗原应答中,分析四个淋巴细胞亚群中每一个的增殖相对于这些基础值的变异。图2以对数级图示了这些亚群中的每一个和本研究两组中的每个组的增殖的变异。
下表5给出了统计学建模的结果。
表5
SE=标准误
淋巴细胞亚群 | 变量 | 参数估计(SE) | H0检验:参数=0 | 2条曲线的比较 |
CD3+CD45+ | 安慰剂 TT2 | 0.015(0.016)-0.0003(0.0006) | P=0.352P=0.597 | H0:β11=β12P=0.015H0:β21=β22P=0.016 |
ACTIMEL TT2 | 0.071(0.015)-0.0024(0.0006) | P<0.001P<0.001 | ||
CD3+CD25+ | 安慰剂 TT2 | 0.024(0.016)-0.0004(0.0006) | P=0.144P=0.463 | H0:β11=β12P=0.031H0:β21=β22P=0.030 |
ACTIMEL TT2 | 0.071(0.015)-0.0022(0.0006) | P<0.001P<0.001 | ||
CD3+CD8+ | 安慰剂 TT2 | 0.0142(0.017)-0.0003(0.0006) | P=0.410P=0.671 | H0:β11=β12P=0.013H0:β21=β22P=0.012 |
ACTIMEL TT2 | 0.070(0.015)-0.0024(0.0006) | P<0.001P<0.001 | ||
CD3+CD4+ | 安慰剂 TT2 | 0.022(0.017)-0.0005(0.0006) | P=0.203P=0.436 | H0:β11=β12P=0.028H0:β21=β22P=0.024 |
ACTIMEL TT2 | 0.072(0.015)-0.0025(0.0006) | P<0.001P<0.001 |
四个淋巴细胞亚群中每一个的增殖反应与总PBMCs观察到的反应一致。接触流感抗原过程中,观察到ACTIMEL组的四个淋巴细胞亚群有显著变化。这些变化可以以时间的二次函数来表示。
观察到安慰剂组的四个亚群有小的变化。
此外,两组间的所有淋巴细胞亚群具有显著性差异。
结论
这些结果表明,对于检测的3个抗原,抗原激发者诱导的增殖反应增加,该增加在ACTIMEL组高于安慰剂组。在流感抗原的情况下,对于总PBMCs和T细胞亚群CD3+CD4+,CD3+CH8+,CD3+CH25+和CD3+CD45+的每一个来说,ACTIMEL组的增加与安慰剂组观察到的相比,具有统计学显著性。
因此看来在有关的个体中,ACTIMEL摄入诱导体内免疫引发,引起它们的T细胞对微生物抗原尤其是流感抗原的离体反应,这种反应比安慰剂组观察到的好。
该反应的增加与ACTIMEL组个体中CD3+T细胞及其亚群的活化频率和状态有关。
此外,与CD25活化标记的存在正相关提示表达CD25 IL-2受体和能够对流感抗原更有效地应答的流感特异性T细胞体内活化的参与。T细胞亚群的分析也提示增殖反应可能包括与流感抗原对应的CD4+和CD8+亚群。CD3+/CD8+T亚群在分析增殖中的重要性提示流感特异性CD8+细胞毒性细胞库体内引发的可能性。
Claims (7)
1.干酪乳杆菌物种的菌株在制备可口服给药来加强抗病原微生物的特异性全身免疫反应的组合物中的应用。
2.权利要求1的应用,其特征在于所述的病原微生物是呼吸道的病原体。
3.权利要求1和2任一项的应用,其特征在于所述的病原微生物是选自鼻病毒、呼吸道合胞病毒和粘液病毒的病毒。
4.权利要求3的应用,其特征在于所述的病毒是流感病毒。
5.权利要求1至4任一项的应用,其特征在于所述的干酪乳杆菌菌株是CNCM株I-1518。
6.权利要求1至5任一项的应用,其特征在于所述的组合物是食品或食品添加物的形式。
7.权利要求1至6任一项的应用,其特征在于所述的组合物是发酵乳制品的形式。
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FR00/06679 | 2000-05-25 | ||
FR0006679A FR2809312B1 (fr) | 2000-05-25 | 2000-05-25 | Utilisation de l. casei dans des compositions immunostimulantes |
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CN1430518A true CN1430518A (zh) | 2003-07-16 |
CN1194707C CN1194707C (zh) | 2005-03-30 |
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ES (1) | ES2267763T3 (zh) |
FR (1) | FR2809312B1 (zh) |
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PL (1) | PL201801B1 (zh) |
PT (1) | PT1283714E (zh) |
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CN103097513A (zh) * | 2010-03-12 | 2013-05-08 | 热尔韦·达诺尼公司 | 用于乳糜泻的乳酸菌 |
CN102186486B (zh) * | 2008-10-17 | 2013-07-24 | 皮埃尔法布雷医药公司 | 包括接骨木萃取液和副干酪乳杆菌、干酪乳杆菌、保加利亚乳杆菌或嗜热链球菌的菌株的结合物的组合物 |
CN103220921A (zh) * | 2010-10-15 | 2013-07-24 | 科.汉森有限公司 | 免疫佐剂 |
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BRPI0611492B1 (pt) | 2005-05-31 | 2021-10-13 | Mars, Incorporated | Bifidobactéria probiótica felina |
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CN103097513A (zh) * | 2010-03-12 | 2013-05-08 | 热尔韦·达诺尼公司 | 用于乳糜泻的乳酸菌 |
CN103097513B (zh) * | 2010-03-12 | 2018-01-30 | 热尔韦·达诺尼公司 | 用于乳糜泻的乳酸菌 |
CN103220921A (zh) * | 2010-10-15 | 2013-07-24 | 科.汉森有限公司 | 免疫佐剂 |
CN103220921B (zh) * | 2010-10-15 | 2015-12-16 | 科.汉森有限公司 | 免疫佐剂 |
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