CN113018308A - 用于调节免疫平衡的组合物 - Google Patents
用于调节免疫平衡的组合物 Download PDFInfo
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- CN113018308A CN113018308A CN202011542027.5A CN202011542027A CN113018308A CN 113018308 A CN113018308 A CN 113018308A CN 202011542027 A CN202011542027 A CN 202011542027A CN 113018308 A CN113018308 A CN 113018308A
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- lactic acid
- composition
- acid bacteria
- eps
- immune balance
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Abstract
本发明为用于调节免疫平衡的组合物。提供以具有食用经验的物质为有效成分、且能够调节免疫平衡的组合物。提供包含乳酸菌的胞外多糖作为有效成分、且用于调节免疫平衡的组合物。调节免疫平衡详细而言包括维持IL‑17的产生,更详细而言,调节免疫平衡包括增加选自由IFN‑γ、IL‑4和IL‑10组成的组中的任意者的产生、维持IL‑17的产生。
Description
技术领域
本发明涉及用于调节免疫平衡的、含有乳酸菌的培养物的组合物。
背景技术
识别抗原的辅助T细胞(Th)具有通过向细胞外大量分泌某些细胞因子而将周围的免疫反应引导至特定方向的作用。这些Th存在几种类型。
例如,Th1通过主要分泌IFN-γ而将免疫反应引导至增强细胞性免疫的方向。具体而言,被IFN-γ刺激的巨噬细胞活跃地吞噬病原体、并激活细胞毒性T细胞、NK细胞等而提高细胞毒活性。Th2细胞通过释放IL-4等并增强提高抗体产生的体液性免疫而有助于防御感染。通过激活Treg而阻止会引起炎症性疾病、变态反应等的过度的免疫反应。Th17是新近发现的一种Th,分泌IL-17等细胞因子。IL-17是一种炎症性细胞因子,一般认为其的增强与自身免疫疾病的病症发生有关。已经明确,由Th17引起的免疫反应作为防御细胞外细菌和真菌的机制发挥作用,另一方面,其的过度增强与类风湿性关节炎、炎症性肠病、多发性硬化、银屑病等自身免疫疾病密切相关。
因此,各Th具有通过各自产生的细胞因子而抑制彼此的功能、在正常状态下特定Th的功能不会亢进的机制。维持这种免疫的激活/抑制的适当的平衡(免疫平衡)对于天然免疫和获得性免疫系统的生理功能是非常重要的。若该平衡崩溃,则导致自身免疫疾病、过敏症、免疫缺陷等免疫系统疾病。
关于使免疫控制机制恢复正常以克服变态反应疾病、自身免疫疾病这一点,已经有一些报道(专利文献1~3)。另外,作为与乳酸菌相关的报道,专利文献4中,通过经口摄取副干酪乳杆菌KW3110株和两歧双歧杆菌YIT4007株的培养物的加热后冷冻干燥物的组合,从而使变态反应疾病模型小鼠中嗜酸性粒细胞向肺泡中的浸润比例显著降低且penh(对于吸入乙酰甲胆碱的气道阻力(气道过敏性))降低,以及胶原诱发关节炎模型小鼠中抗胶原抗体效价降低且观察到抑制关节炎的倾向,基于这些结果提出特征在于含有(A)副干酪乳杆菌(Lactobacillus paracasei)的菌体和/或其处理物及(B)双歧杆菌(Bifidobacterium)属的细菌的菌体和/或其处理物的免疫平衡调节用组合物。专利文献5中,在使用了用TGF-β和IL-6刺激后的小鼠脾脏细胞的试验中,通过添加乳酸菌中的嗜热链球菌(Streptococcus thermophilus)的特定菌株的培养物的杀菌后冷冻干燥物,从而促进IFN-γ的产生且抑制了IL-17的产生,基于该实验结果提出含有特定的乳酸菌中的嗜热链球菌作为抑制IL-17的产生的有效成分的药物或饮食品。专利文献6中,通过在培养基中加入经加热杀菌的双歧杆菌CFB1株,在用TGF-β和IL-6刺激后的小鼠脾脏细胞中,IL-17的产生得到抑制,IFN-γ产生上调且IL-4的产生减少,基于上述实验结果提出含有特定的双歧杆菌属微生物、抑制IL-17的产生、优选促进IFN-γ的产生、并且抑制IL-4的产生的饮食品。
另一方面,乳酸菌在其发酵过程中会产生各种物质,其中一种为胞外多糖(Exopolysaccharides;EPS)。申请人基于通过经口给予德氏乳杆菌保加利亚亚种(Lactobacillus delbrueckii subsp.bulgaricus)OLL 1073R-1株的培养物的冷冻干燥粉末、从而在慢性类风湿性关节炎的动物实验模型中胶原诱发关节炎(CIA;Collagen-Induced Arthritis)发病率和炎症严重程度这两者均减少至约1/5的实验结果,提出了一种自身免疫疾病预防组合物,其特征在于,含有具有产生以半乳糖和葡萄糖作为结构糖且含有磷的多糖类的性质的乳酸菌、含有该乳酸菌的物质、其处理物中的至少一种(专利文献7)。
现有技术文献
专利文献
专利文献1:国际公开WO2015/156339(日本专利第6307153号)
专利文献2:国际公开WO2017/089795(日本特表2018-501188号公报)
专利文献3:日本特开2018-002714号公报
专利文献4:日本特开2009-057346号公报
专利文献5:日本特开2010-115126号公报
专利文献6:日本特开2010-246523号公报
专利文献7:日本特开2000-247895号公报
发明内容
发明要解决的问题
从充分地调节免疫平衡这样的观点出发,期望的是增强选自由Th1、Th2和Treg组成的组中的任意者的功能,但不增强Th17的功能。另外,自不用说,期望的是以具有食用经验的物质作为有效成分、且能够调节免疫平衡的组合物。
用于解决问题的方案
本发明人等对利用德氏乳杆菌保加利亚亚种(Lactobacillus delbrueckiisubsp.Bulgaricus)OLL1073R-1发酵的酸奶、或由该乳酸菌产生的胞外多糖(Exopolysaccharide:EPS)的功能进行了研究。其中,这次发现EPS具有新的功能,基于该功能,发现EPS能够有效地用于调节免疫平衡,完成了本发明。
本发明提供以下方案。
[1]一种用于调节免疫平衡的组合物,其包含乳酸菌的胞外多糖作为有效成分。
[2]根据1所述的组合物,其中,调节免疫平衡包括维持IL-17的产生。
[3]根据1或2所述的组合物,其中,调节免疫平衡包括增加选自由IFN-γ、IL-4和IL-10组成的组中的任意者的产生、维持IL-17的产生。
[4]根据1~3中任一项所述的组合物,其中,调节免疫平衡包括维持Th17的功能。
[5]根据1~4中任一项所述的组合物,其中,调节免疫平衡包括增强选自由Th1、Th2和Treg组成的组中的任意者的功能、维持Th17的功能。
[6]根据1~5中任一项所述的组合物,其中,乳酸菌是被分类为乳杆菌属的乳酸菌。
[7]根据1~6中任一项所述的组合物,其中,乳酸菌是被分类为德氏乳杆菌保加利亚亚种的乳酸菌。
[8]根据1~7中任一项所述的组合物,其以发酵乳形式包含胞外多糖。
[9]一种调节对象中的免疫平衡的方法,其包括向对象给予乳酸菌的胞外多糖(针对人的医疗行为或治疗方法除外。)。
另外,本发明还提供以下方案。
[10]一种乳酸菌的胞外多糖在制造用于调节免疫平衡的组合物中的应用。
[11]一种乳酸菌的胞外多糖在制造用于增加选自由IFN-γ、IL-4和IL-10组成的组中的任意者的产生、维持IL-17的产生的组合物中的应用。
[12]一种乳酸菌的胞外多糖或包含乳酸菌的胞外多糖的组合物,其用于调节免疫平衡的方法中。
[13]一种乳酸菌的胞外多糖或包含乳酸菌的胞外多糖的组合物,其用于增加选自由IFN-γ、IL-4和IL-10组成的组中的任意者的产生、维持IL-17的产生的方法中。
[14]一种调节对象中的免疫平衡的方法,其包括向对象给予乳酸菌的胞外多糖或包含乳酸菌的胞外多糖的组合物。
[15]一种用于增加对象中的选自由IFN-γ、IL-4和IL-10组成的组中的任意者的产生、维持IL-17的产生的方法,其包括向对象给予乳酸菌的胞外多糖或包含乳酸菌的胞外多糖的组合物。
发明的效果
根据本发明,能够在不增强Th17的功能的情况下增强选自由Th1、Th2和Treg组成的组中的任意者的功能,由此,能够在对象中调节免疫平衡。
另外,根据本发明,能够在不增加IL-17的分泌的情况下促进选自由IFN-γ、IL-4和IL-10组成的组中的任意者的分泌,由此,能够在对象中调节免疫平衡。
附图说明
图1是抗原肽刺激时的由抗原特异性Th分泌的细胞因子分泌量。平均±SEM,n=8,在抗原肽刺激时有EPS和无EPS之间,通过学生t检验计算出P值。
具体实施方式
以下对本发明进行详细地说明。
本发明涉及以乳酸菌所产生的胞外多糖(EPS)为有效成分的组合物。更详细而言,涉及以EPS为有效成分、用于调节免疫平衡的组合物。
[有效成分]
本发明的组合物包含乳酸菌的EPS作为有效成分。乳酸菌是同化葡萄糖并产生以相对于糖的收率计为50%以上的乳酸的微生物的总称,作为生理学性质,具有如下特征:为革兰氏阳性菌中的球菌或杆菌,不具有运动性,大多数情况无孢子形成能力(也有如凝结芽孢杆菌那样具有孢子形成能力的乳酸菌。),过氧化氢酶阴性等。自古以来,乳酸菌就已通过发酵乳等在世界各地被食用,可以说是安全性极高的微生物。乳酸菌分为多个属。本发明的组合物中包含的乳酸菌的EPS优选由被分类为乳杆菌(Lactobacillus)属的乳杆菌属乳酸菌产生。
本发明的组合物中使用的EPS只要具有目标效果就没有特别限定。乳酸菌所产生的EPS在结构上分为作为同多醣的EPS和作为杂多糖的EPS(例如,由半乳糖和葡萄糖构成的EPS),还有时进行了磷酸化、硫酸化等修饰,任意者均可以作为本发明的组合物的有效成分使用。优选的EPS的一个例子是,包含中性多糖体和在中性多糖体上添加有磷酸基的酸性多糖体中的至少一者的EPS。已知德氏乳杆菌保加利亚亚种(Lactobacillus delbrueckiisubsp.bulgaricus)、乳酸乳球菌乳脂亚种(Lactococcus lactis subsp.cremoris)等会产生这样的EPS。本发明中使用的EPS可以是一种,还可以是两种以上的组合。
本发明的组合物中使用的特别优选的产生EPS的乳酸菌的例子是乳杆菌属乳酸菌。作为乳杆菌属乳酸菌,例如可列举出保加利亚种、干酪种、嗜酸种、植物种等。这些乳杆菌属乳酸菌当中,本发明中更优选分类为德氏乳杆菌保加利亚亚种(Lactobacillusdelbrueckii subsp.bulgaricus)(也称为保加利亚菌)的乳酸菌。特别优选的方式中,乳酸菌为德氏乳杆菌保加利亚亚种OLL1073 R-1菌(保藏编号:FERM BP-10741)(有时称为“保加利亚菌R-1株”。)。即,本发明的组合物中使用的EPS的特别优选的一个例子是保加利亚菌R-1株所产生的EPS。
保加利亚菌R-1株在国家高级工业科学技术学院,国际专利生物保藏中心(IPOD,NITE)(日本千叶县木更津市上总镰足2-5-8 120号室)进行了基于布达佩斯条约的国际保藏(保藏者:株式会社明治、保藏日:2006年11月29日、保藏编号:FERM BP-10741)。
本发明的组合物中包含的乳酸菌的EPS可以以乳酸菌发酵物形式而包含。乳酸菌发酵物除了包括由乳酸菌得到的发酵物本身之外,还包括其处理物。乳酸菌发酵物本身包括例如发酵乳(具体而言,酸奶等)。处理物包括例如:通过过滤、离心分离或膜分离对粗纯化物、纯化物、发酵物进行除菌而得到的培养滤液、培养上清液;将培养滤液、培养上清液浓缩而得到的浓缩物;浓缩物的干燥物。
乳酸菌的EPS的制备方法可以利用现有技术,在需要更详细的条件时,可以参照本说明书的实施例等。另外,在以乳酸菌发酵物形式制备乳酸菌的EPS时,可以将产生EPS的乳酸菌作为起子添加至原料乳中进行发酵,在发酵物中产生EPS,从而制造包含EPS的发酵乳。关于发酵时的条件,例如原料乳、发酵温度、发酵时间,只要所使用的乳酸菌能够产生EPS就没有特别限制,本领域技术人员可以进行适宜设定。
[用途]
本发明的组合物能够用于调节免疫平衡。
本发明中所谓的调节免疫平衡包括维持IL-17的产生、或增加选自由IFN-γ、IL-4和IL-10组成的组中的任意者的产生。调节免疫平衡优选包括维持IL-17的产生、且增加选自由IFN-γ、IL-4和IL-10组成的组中的至少一者的产生,更优选包括维持IL-17的产生、且增加IFN-γ、IL-4和IL-10的产生。
关于细胞因子的产生,“维持”是指既不增加也不减少。本领域技术人员可以适宜判断是否能称为维持、另外是否能称为增加。
例如,可以如下进行判断:
对于给予和未给予要评价的成分的组,分别测定目标细胞因子的产生量。然后在是否给予之间进行差异显著性检验,P值低于显著性水平(典型的是0.05)时可以判断为存在差异(“增加”等)。
另外,对于两组,求出平均值,平均值之差较小时,例如为20%以下、优选为10%以下时,可以判断为“维持”。或者在是否给予之间进行差异显著性检验,P值较大时,例如为0.5以上、优选为0.6以上,更优选为0.7以上、进一步优选为0.8以上时,可以判断为“维持”。
本发明中所谓的调节免疫平衡还包括:维持Th17的功能或增强选自由Th1、Th2和Treg组成的组中的任意者的功能。免疫平衡的调节优选包括维持Th17的功能、且增强选自由Th1、Th2和Treg组成的组中的至少一者的功能,更优选包括维持Th17的功能、且增强Th1、Th2和Treg的功能。
关于辅助T细胞的功能,“维持”是指不增强。对于是否能称为维持、另外是否能称为增强,可以通过对作为目标的T细胞所产生的细胞因子的产生量进行分析来加以判断。
由本发明的组合物引起的IFN-γ、IL-4和IL-10的产生的增加、以及IL-17的产生的维持可以在脾脏中加以确认。IFN-γ、IL-4、IL-10和IL-17的产生量例如可以在外周血中进行分析,另外,可以通过分析利用适合的方法刺激从外周血得到的T细胞而增加的程度,由此进行评价。在分析IFN-γ、IL-4、IL-10和IL-17时,可以使用市售的试剂盒进行分析。
分析是指:对是否存在分析对象分子、及存在时其程度(量)中的任意者进行测定。
与用于治疗感染性疾病、癌症的其它疗法一起进行免疫平衡的调节的情况下,也可以使用本发明的组合物。这样的其它疗法有:利用药物的疗法、手术、辐射线治疗、其它免疫疗法(例如,细胞因子疗法、免疫激活剂的给予、免疫细胞移植等)、健康食品或营养强化剂的摄取、运动疗法等。
通过利用本发明的组合物来调节免疫平衡,从而降低各种免疫疾病的发病风险、而且能够期待对其进行治疗。免疫疾病的例子有:类风湿性关节炎及与其类似疾病(例如,类风湿性关节炎、恶性类风湿性关节炎/类风湿性血管炎、风湿性多肌痛、RS3PE综合征、手部骨性关节炎)、脊柱关节炎(例如,强直性脊柱炎、银屑病性关节炎、SAPHO综合征、反应性关节炎)、(自身免疫疾病(例如,系统性红斑狼疮、系统性硬皮病、多肌炎/皮肌炎、无肌病性皮肌炎、混合性结缔组织病、干燥综合征、抗磷脂抗体综合征)、白塞病、成人斯蒂尔病、复发性多软骨炎、卡斯尔门病、TAFRO综合征、血管炎综合征(例如,高安动脉炎、巨细胞动脉炎、结节性多发性动脉炎、ANCA相关性血管炎、显微镜下多血管炎、肉芽肿性多血管炎、嗜酸性肉芽肿性多血管炎、变态反应疾病(支气管哮喘、嗜酸性粒细胞增多症、IgG4相关性疾病、血管性水肿)、肺动脉高压、不明原因的发热、骨质疏松、感染性疾病(肺孢子菌肺炎、带状疱疹)等。
本发明的组合物的一个方式是除了自身免疫疾病预防组合物以外的、用于调节免疫平衡的组合物以及用于增加选自由IFN-γ、IL-4和IL-10组成的组中的任意者的产生、维持IL-17的产生的组合物。
[组合物]
(食品组合物等)
本发明的组合物可以为食品组合物或药物组合物。除非特别声明,否则食品和药物不仅包括用于人类的食品和药物,还包括用于人以外的动物的食品和药物。除非特别声明,否则食品包括常规食品、功能性食品、营养组合物,另外包括治疗食品(发挥治疗目的的食品。医生开出的膳食处方,营养师等依据其制作菜单,基于该菜单烹调出的食品。)、饮食疗法食品、配方食品、护理食品、治疗辅助用食品。除非特别声明,否则食品不仅包括固态物,还包括液态的食品,例如饮料、保健饮料、流食和汤。功能性食品是指能对生物体赋予规定的功能性的食品,例如包括:特定保健用食品(包括附加条件的特保[特定保健用食品])、功能性标示食品、包括营养功能食品在内的保健功能食品、特殊用途食品、营养辅助食品、健康辅助食品、营养强化剂(例如,片剂、包衣片剂、糖衣片剂、胶囊、液剂等各种剂型的食品)、美容食品(例如,减肥食品)等全部健康食品。另外,本发明中“功能性食品”包括应用了食品法典委员会(FAO/WHO联合食品标准委员会)的食品标准的健康声明(Health claim)的健康食品。
(对象)
本发明的组合物适于给予优选调节免疫平衡的对象、或使其进行摄取。这样的对象包括:婴幼儿、儿童、成人(15岁以上)、中老年人、老年人(65岁以上)、生病期间和病后的人、孕妇、产妇、男性、女性。
(给予途径)
本发明的组合物可以以各种途径进行给予。给予途径的例子是:经口给予(PO)、经管营养(胃瘘、肠瘘)、灌肠给予、经皮给予、经粘膜给予、吸入给予、皮肤上给予(日语:皮膚上投与)、吸入给予、灌肠给予、腹腔内给予(IP)、滴眼、滴耳、经鼻给予、阴道内给予、经静脉给予(IV)、经动脉给予(IA)、肌肉给予(IM)、皮下给予(SC、sub-Q)、皮内给予(ID)等。本发明的组合物优选进行经肠给予(经口给予、经管营养或灌肠给予),由于本发明的组合物的有效成分为EPS,因此与将乳酸菌或发酵物作为有效成分的情况相比,可以更广泛地选择给予途径,而且更容易制成适于给予途径的剂型。
(有效成分的含量/用量)
本发明的组合物中的乳酸菌的EPS的含量为可发挥目标效果的量即可。可以考虑接受者的年龄、体重、症状等各种因素来适宜设定组合物的给予量或摄取量,每一天的乳酸菌的EPS的量例如可以设为0.1mg以上,优选设为0.6mg以上,更优选设为1mg以上,特别优选设为3mg以上。在下限值为任何值时,每一天的EPS的量的上限值均可以设为500mg以下,优选设为300mg以下,特别优选设为250mg以下。
每一次给予或每一次食用、即每一次的乳酸菌的EPS的量例如可以设为0.03mg以上,优选设为0.2mg以上,更优选设为1mg以上。在下限值为任何值时,每一次的EPS的量的上限值均可以设为200mg以下,优选设为100mg以下,更优选设为70mg以下,特别优选设为30mg以下。
以发酵乳那样的组合物的方式使用本发明的组合物中的乳酸菌的EPS时,以组合物计的一天量例如可以设为30g以上,优选设为50g以上,更优选设为60g以上,特别优选设为100g以上。在下限值为任何值时,以发酵乳计的一天量的上限值均可以设为例如1500g以下,优选设为1200g以下,更优选设为900g以下,更优选设为600g以下。
以组合物计的一次量例如可以设为10g以上,优选设为20g以上,更优选设为30g以上。在下限值为任何值时,以组合物计的一次量的上限值均可以设为例如500g以下,优选设为400g以下,更优选设为200g以下,特别优选设为125g以下。
组合物可以一天给予/摄取1次,还可以一天给予多次,例如在每次吃饭时,即给予3次。组合物以食用经验丰富的乳酸菌的EPS作为有效成分。因此,本发明的组合物的有效成分是食用经验较久的EPS,因此适于长期摄取。因此可以重复或长期摄取,例如可以持续给予/摄取3天以上,优选1周以上,更优选4周以上,特别优选1个月以上。需要说明的是,认为即使增加EPS的给予/摄取量也几乎不对IL-17的产生造成影响。
(其它成分、添加剂)
本发明的组合物可以包含容许作为食品或药物的其它有效成分、营养成分。这样的成分的例子是氨基酸类(例如,赖氨酸、精氨酸、甘氨酸、丙氨酸、谷氨酸、亮氨酸、异亮氨酸、缬氨酸)、糖类(葡萄糖、蔗糖、果糖、麦芽糖、海藻糖、赤藓糖醇、麦芽糖醇、帕拉金糖、木糖醇、糊精)、电解质(例如,钠、钾、钙、镁)、维生素(例如,维生素A、维生素B1、维生素B2、维生素B6、维生素B12、维生素C、维生素D、维生素E、维生素K、生物素、叶酸、泛酸和烟酸类)、矿物质(例如,铜、锌、铁、钴、锰)、抗生素、食物纤维、蛋白质、脂质等。
另外组合物可以进一步包含容许作为食品或药物的添加物。这样的添加物的例子是非活性载体(固体载体、液体载体)、赋形剂、表面活性剂、结合剂、崩解剂、润滑剂、助溶剂、悬浮剂、涂布剂、着色剂、保存剂、缓冲剂、pH调节剂、乳化剂、稳定剂、甜味剂、抗氧化剂、香料、酸味剂、天然物质。更具体而言,为水、其它水性溶剂、制药上可接受的有机溶剂、胶原蛋白、聚乙烯醇、聚乙烯基吡咯烷酮、羧基乙烯基聚合物、藻酸钠、水溶性葡聚糖、水溶性糊精、羧甲基淀粉钠、果胶、黄原胶、阿拉伯胶、酪蛋白、明胶、琼脂、甘油、丙二醇、聚乙二醇、凡士林、石蜡、硬脂醇、硬脂酸、人血清白蛋白、甘露糖醇、山梨糖醇、乳糖、三氯蔗糖、甜菊糖、阿斯巴甜、安赛蜜、柠檬酸、乳酸、苹果酸、酒石酸、磷酸、醋酸、果汁、蔬菜汁等。
(剂型/形态)
本发明的药物组合物根据给予途径可以制成下述任意剂型:气溶胶剂、液剂、浸膏(软浸膏、干燥浸膏)、酏剂、胶囊剂(硬胶囊剂、软胶囊剂、颗粒剂、丸剂、眼软膏剂、经皮吸收型制剂悬浮剂/乳剂、栓剂、散剂、酒精剂、片剂(口腔崩解片、咀嚼片、泡腾片、速释片(素片、裸片)、糖衣片)、糖浆剂、浸泡剂/汤剂、注射剂、贴剂、酊剂、滴眼剂、锭剂、软膏剂、巴布剂、芳香水剂、擦剂、柠檬水剂、流浸剂、露剂等。
作为适于经口给予的剂型,可列举出片剂、颗粒剂、散剂、丸剂、胶囊剂等固体制剂、液剂、悬浮剂、糖浆剂等液体制剂、凝胶剂、气溶胶剂等。
本发明的食品组合物可以制成固体、液体、混合物、悬浮液、粉末、颗粒、糊剂、啫喱、凝胶、胶囊等任意的形态。另外,本发明的食品组合物可以制成乳制品、营养强化剂、点心、饮料、保健饮料、调味剂、加工食品、配菜、汤等任意的形态。更具体而言,本发明的组合物可以制成乳饮料、清凉饮料、乳酸菌饮料、乳性饮料、发酵乳、酸奶、冰淇淋、压片、巧克力、乳酪、面包、饼干(biscuits)、咸饼干(cracker)、比萨饼、配方奶粉、液态奶、流食、病人用食品、营养食品、冷冻食品、加工食品等形态,另外可以制成用于混合于饮料、食品中进行摄取的颗粒、粉末、糊剂、浓厚液体等形态。
(其它)
在本发明的组合物的制造中,可以适宜选择配混乳酸菌的EPS的阶段。只要不显著损害乳酸菌的EPS的特性,配混的阶段就没有特别限制。例如,可以在制造工序的各阶段在原材料中混合并配混培养产生EPS的乳酸菌而得到的包含EPS的培养物、其粗纯化物、纯化物。或者,将本发明的组合物以发酵乳的方式加以实施时,在原材料、发酵后的发酵乳中混合并配混包含EPS的培养物、其粗纯化物、纯化物,或者可以通过在原料乳中添加产生EPS的乳酸菌作为起子并进行发酵而产生EPS,由此制造包含EPS的发酵乳。
本发明的组合物中可以标示能够用于调节免疫平衡的内容,另外可以标示推荐向特定的对象进行摄取的内容。可以直接或间接标示,直接标示的例子是在制品本身、包装、容器、标签、标志等有形物体上记载,间接标示的例子包括通过网页、店铺、小册子、展览会、媒体研讨会等研讨会、书籍、报纸、杂志、电视、广播、邮件、电子邮件、音频等场所或手段进行的广告/宣传活动。
以下使用实施例对本发明进行进一步具体地说明。但本发明的保护范围不限定于这些实施例。
[实施例]
<EPS(胞外多糖)的制备>
实施例1中,对用10质量%脱脂奶粉培养基培养德氏乳杆菌保加利亚亚种OLL1073R-1而得到的培养物中的EPS进行了纯化。即,在以37℃培养18小时的培养物中以最终浓度达到10质量%的方式加入三氯乙酸,去除变性蛋白质,加入冷乙醇并在4℃下静置2小时,得到包含EPS的沉淀物。将其用透析膜(截留分子量6000-8000)相对于MilliQ水进行透析,用酶将核酸和蛋白质消化后,再次进行乙醇沉淀而得到沉淀物。将其溶解于MilliQ水中,再次进行透析后冷冻干燥,由此将EPS纯化。
<实施例1>
使用人乙型肝炎病毒抗原肽(I-Ad HBc辅助肽TPPAYRPPNAPIL,MBL)50μg对4只C57BL/6J小鼠、雌性、8周龄(CHARLES RIVER LABORATORIES JAPAN,INC.)进行免疫。将弗氏完全佐剂(和光纯药)50μL、上述抗原肽溶液5μL、PBS 45μL共计100μL充分乳化后,作为免疫组合物注射至每一只小鼠的腹腔内。免疫后,人乙型肝炎病毒抗原(以下记作HBc)特异性的各Th在小鼠体内增殖,并且在体内循环。
免疫1周后,让小鼠安乐死。采集包含HBc抗原特异性的Th1、Th2、Th17、Treg的脾脏,合并4只的脾细胞并以一定的细胞数(5×106细胞/ml)进行培养。在培养时加入HBc肽(10μg/ml)来刺激各Th,48小时后使用BD OptEIA小鼠ELISA套装(Becton,Dickinson andCompany)测定了HBc抗原肽特异性的、所产生的IFN-γ、IL-4、IL-17、IL-10的上清液浓度(IFN-γ、IL-4、IL-10)。使用IL-17A Mouse Uncoated ELISA Kit(Invitrogen)测定了IL-17。对于任一将EPS添加至培养基中(150μg/mL)的情况也同样地进行测定,与未加入EPS的情况进行比较。各情况下,平均±SEM,n=8,在HBc肽刺激时有EPS和无EPS之间,通过学生t检验计算出P值。
结果确认了抗原特异性的IFN-γ、IL-4、IL-17、IL-10。认为这些分别由Th1、Th2、Th17、Treg产生。将EPS添加至培养基中时,除IL-17以外的细胞因子分泌显著增加。然而,IL-17未发生变化。(图1)
由这些结果发现:EPS在不激活Th17的情况下(也不抑制,一直维持适量的表达)激活Th1、Th2、Treg,促进IFN-γ、IL-4、IL-10的产生。
Claims (13)
1.一种乳酸菌的胞外多糖在制造用于调节免疫平衡的组合物中的应用。
2.根据权利要求1所述的应用,其中,调节免疫平衡包括维持IL-17的产生。
3.根据权利要求2所述的应用,其中,调节免疫平衡包括增加选自由IFN-γ、IL-4和IL-10组成的组中的任意者的产生、维持IL-17的产生。
4.根据权利要求1至3中任一项所述的应用,其中,调节免疫平衡包括维持Th17的功能。
5.根据权利要求4所述的应用,其中,调节免疫平衡包括增强选自由Th1、Th2和Treg组成的组中的任意者的功能、维持Th17的功能。
6.根据权利要求1~3和5中任一项所述的应用,其中,乳酸菌是被分类为乳杆菌属的乳酸菌。
7.根据权利要求4所述的应用,其中,乳酸菌是被分类为乳杆菌属的乳酸菌。
8.根据权利要求6所述的应用,其中,乳酸菌是被分类为德氏乳杆菌保加利亚亚种的乳酸菌。
9.根据权利要求7所述的应用,其中,乳酸菌是被分类为德氏乳杆菌保加利亚亚种的乳酸菌。
10.根据权利要求8所述的应用,其中,乳酸菌为德氏乳杆菌保加利亚亚种FERM BP-10741。
11.根据权利要求9所述的应用,其中,乳酸菌为德氏乳杆菌保加利亚亚种FERM BP-10741。
12.根据权利要求1~3、5和7~11中任一项所述的应用,其中,以发酵乳形式包含胞外多糖。
13.一种调节对象中的免疫平衡的方法,其不包括治疗方法,所述方法包括向对象给予乳酸菌的胞外多糖。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2019234183A JP2021101645A (ja) | 2019-12-25 | 2019-12-25 | 免疫バランスの調節のための組成物 |
JP2019-234183 | 2019-12-25 |
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