KR101644593B1 - Anti-Allergic Compositions Comprising Bacillus amyloliquefaciens 26N As Active Ingredients - Google Patents
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Abstract
본 발명은 바실러스 아밀로리퀴페시언스 26N 균주(기탁번호 KCCM 11287P)를 유효성분으로 포함하는 항알레르기성 조성물를 제공한다. 본 발명은 항알레르기 활성을 갖는 바실러스 아밀로리퀴페시언스 26N 균주를 제공한다. 본 발명의 바실러스 아밀로리퀴페시언스 26N 균주는 조절 T 세포를 활성화 시키고 항염증 사이토카인인 IL10을 증가시킴으로써 알레르기를 효과적으로 제어할 수 있다. The present invention provides an antiallergic composition comprising as an active ingredient a Bacillus amyloliquefaciens strain 26N (Accession No. KCCM 11287P). The present invention provides a Bacillus amyloliquefaciens strain 26N having an anti-allergic activity. The Bacillus amyloliquefaciens strain 26N of the present invention can effectively control allergies by activating regulatory T cells and increasing IL10, an anti-inflammatory cytokine.
Description
본 발명은 바실러스 아밀로리퀴페시언스 26N 균주 또는 상기 균주의 배양물을 유효성분으로 포함하는 항알레르기성 조성물에 관한 것이다.
The present invention relates to an antiallergic composition comprising as an active ingredient a Bacillus amyloliquefaciens strain 26N or a culture of said strain.
우리나라에서 천식의 발생이 계속해서 증가되고 있으며 2007년 통계에 의하면 천식으로 사망한 환자수가 2,023명으로 보고되었다. 또한, 우리나라 소아 알레르기 천식의 유병률은 80년대 초에 비해 2배 이상 증가했고 소아 100명 중 10명이 천식을 앓고 있으며 이중 50%가 평생 천식을 앓는다. 따라서 알레르기 질환의 발병 예방 및 효과적인 제어 기술이 절실히 필요한 상태이다. The incidence of asthma continues to increase in Korea. According to 2007 statistics, 2,023 patients were reported to die from asthma. In addition, the prevalence of pediatric allergic asthma in Korea has more than doubled from the early 1980s, and 10 out of 100 children have asthma, of which 50% have lifelong asthma. Therefore, the prevention of the onset of allergic diseases and effective control technology are urgently needed.
기존 알레르기 천식 치료방법은 근본치료가 되지 않고 있으며, 여러 약제 중 2 가지 이상을 병용하여 질환의 완화 내지 감소시키는 것에 지나지 않으며 이러한 약들은 대부분 심각한 부작용을 나타내어 문제점을 가지고 있다. 또한, Omalizumab과 같은 항체제제들은 개발 및 치료 시 아주 많은 비용이 들어가는 문제를 안고 있다.Existing allergic asthma treatment is not a fundamental treatment, and it is merely to alleviate or reduce the disease by using two or more of several medicines, and most of these medicines have serious side effects and have problems. In addition, antibody preparations such as Omalizumab have a problem of costly development and treatment.
최근 미국을 중심으로 장내 세균의 균총을 규명하는 메타지놈 프로젝트 진행결과 장내균총의 분포와 알레르기를 포함하는 다양한 면역계 질환과 상관관계가 밝혀지고 있다. 따라서, 장내 세균의 분포와 다양성 그리고 장 면역과 면역계가 밀접히 연관되어 지고 있음이 규명되고 있는 단계이다. Recently, Metagenome project to identify intestinal microflora in the US has been linked to various immune system diseases including distribution of intestinal microflora and allergy. Therefore, the distribution and diversity of intestinal bacteria and intestinal immunity are closely related to each other.
프로바이오틱스 관련 시장은 2003년을 기준으로 미국의 시장규모는 1억 4430만불로 시장규모액의 증가는 11.2%이었으며 2010년까지 연평균 성장률은 13.0%로 예상되었으며 2010년 시장 규모는 약 3억 9400만 달러였다. 유럽의 시장 규모는 2003년 기준, 유럽의 시장규모는 4천만 30만불로 15.8% 증가하였으며, 2010년까지의 연평균 성장률은 16.7%로 예상되고 있다. 예상되는 2010년 예상 시장 규모는 1억 3790만 달러이며 국내 프로바이오틱스 시장 규모는 1000억원을 넘는 것으로 추정되고 있다. The market size of the probiotics market was US $ 144.3 million as of 2003. The market size was 11.2%, and the annual average growth rate was estimated at 13.0% by 2010. The market size in 2010 was about 394 million dollars Respectively. The market size of Europe increased 15.8% in 2003 to 40 million US dollars, and the average annual growth rate until 2010 is expected to be 16.7%. The expected 2010 market size is estimated at $ 137.9 million, and the domestic probiotic market is estimated to exceed 100 billion won.
알레르기억제와 같은 면역제어용 프로바이오틱스 발굴 및 평가 기술은 아직 확립되지 않은 상태임으로, 체계적인 인 비트로 또는 인 비보 모방 스크리닝 시스템을 개발하고 그 기술을 잘 활용한다면 경제적인 효용가치도 막대할 것으로 예상된다. The technology for detecting and evaluating immunity control probiotics such as allergy suppression has not yet been established. Therefore, it is expected that if the systematic in-vitro or in-vivo mimic screening system is developed and utilized well, the economic utility value will also be enormous.
근본적 작용기작에 대한 연구의 미비한 상태이며 및 대부분의 연구가 인 비트로에서 행해지고 있다. 즉 프로바이오틱스의 섭취는 구강을 통해 이루어짐에도 불구하고 지금까지의 연구는 대부분 세포주를 이용한 인 비트로 실험이 주를 이루었으며 이러한 실험 방법은 사람이 프로바이오틱스의 섭취 시 나타낼 수 있는 기능에 대한 연구를 대체할 수 없는 큰 단점이 있다. 또한, 프로바이오틱스에 노출되는 장내 면역계(GALT)는 다양한 면역세포가 동시에 존재하여 상호작용을 일으켜 프로바이오틱스의 면역작용을 나타내나 인 비트로 실험은 생체 내 환경과는 차이가 많다.There is a lack of research on the fundamental mechanisms and most of the work is done in vitro . Although the ingestion of probiotics is carried out through the oral cavity, most of the research to date has been focused on in vitro experiments using cell lines, and these experimental methods can be replaced by studies on the functions that people may experience when ingesting probiotics There is a major drawback. In addition, the intestinal immune system (GALT) exposed to probiotics exhibits immune functions of probiotics due to the simultaneous presence of various immune cells, and in vitro experiments are different from the in vivo environment.
이에 본 발명에서는 한국형 전통식품에서 분리한 균주의 항알레르기 활성을 평가하기 위해 다양한 면역세포를 생쥐에서 직접 분리한 후 이들에 대한 Bacillus amyloliquefaciens 26N 의 영향을 평가함으로써 인 비보 시스템에 가까운 연구결과를 도출하였다.In the present invention, deriving the results close to the in vivo system by evaluating the effects of Bacillus amyloliquefaciens 26N for these were directly separating the different immune cells in mice to evaluate anti-allergic activity of the bacterial strains isolated from Korean traditional food .
현재 해외의 프로바이오틱스에 대한 면역조절 능력의 평가는 다양한 질환 동물모델에 적용되고 있으며, 그 성과 역시 해마다 가파른 속도로 증가하고 있는 단계이다. 1형 당뇨병, 류마티스 관절염, 퇴행성 관절염, 궤양성 대장염과 같은 염증성 질환들의 염증 반응 억제를 타겟팅하는 분야만이 아니라 독감 바이러스나 암과 같은 질병에 대항할 수 있도록 면역 반응을 증대시킬 수 있는 프로바이오틱스의 기능에 대해서도 연구가 활발히 진행 중이다. 이외에도 알레르기, 천식, 아토피와 같은 질병의 치료 목적으로도 프로바이오틱스의 역할 및 그 기능이 많은 주목을 받고 있다.Currently, the evaluation of immunity control for overseas probiotics is applied to various disease animal models, and the results are also increasing at a rapid pace every year. The ability of probiotics to increase the immune response to fight against diseases such as influenza virus or cancer, as well as areas that target inflammatory responses to inflammatory diseases such as type 1 diabetes, rheumatoid arthritis, degenerative arthritis, and ulcerative colitis Research is also actively underway. In addition, the role of probiotics and their functions are attracting much attention for the treatment of diseases such as allergy, asthma, and atopy.
대부분의 프로바이오틱스는 유래가 인간의 장 또는 식품이기 때문에 동물모델을 이용한 효능이 입증되면 다른 화학적 약제와 안정성의 입증에 큰 문제가 없다는 장점이 있다. 또한 최근 들어 면역조절제로서 프로바이오틱스의 질병 치료 효능이 다양한 임상실험을 통해 검증되고 있다. 천식, 궤양성 대장염, 관절염 등의 질병이 많이 시도되어지고 있으며 최근 들어 아토피에 대한 임상시도 및 연구가 가속화 되고 있는 실정이다.Because most probiotics are derived from human intestines or foods, there is an advantage in that there is no major problem in proving the stability of other chemical agents when proven efficacy using animal models. Recently, the efficacy of probiotics as an immunomodulator has been verified through various clinical trials. Asthma, ulcerative colitis, and arthritis. Recently, clinical trials and studies on atopy have been accelerated.
산업화 동향 분석에 따르면 전통적으로 강세인 유럽에서 프로바이오틱스 개발을 주도하고 있으며 미국, 일본 등지에서도 최근에 기능성 프로바이오틱스 개발 및 사업화가 활발히 진행되고 있는 상태이다. 대표적인 상품으로 VSL3#는 캐나다의 VSL Phamaceutical company에 의해서 개발되었으며, 현재 전세계 시장을 대상으로 활발한 판매활동을 벌이고 있으며 최근에 국내시장에도 면역조절 개별인정형으로 판매되고 있다.
According to industrialization trend analysis, it is leading the development of probiotics in Europe, which is traditionally strong, and the development and commercialization of functional probiotics is being actively carried out in the US and Japan recently. VSL3 # was developed by the VSL Phamaceutical company in Canada. It is currently active in the global market, and recently it has been marketed as an immunity regulator in the domestic market.
본 명세서 전체에 걸쳐 다수의 논문 및 특허문헌이 참조되고 그 인용이 표시되어 있다. 인용된 논문 및 특허문헌의 개시 내용은 그 전체로서 본 명세서에 참조로 삽입되어 본 발명이 속하는 기술 분야의 수준 및 본 발명의 내용이 보다 명확하게 설명된다.
Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.
본 발명자들은 조절 T 세포를 활성화시키고 면역반응을 조절함으로써 인체 내의 알레르기 반응을 억제시킬 수 있는 균주를 선별하고자 예의 연구 노력하였다. 그 결과, 항알레르기 활성을 가지는 신규한 바실러스 아밀로리퀴페시언스(Bacillus amyloliquefaciens) 26N 균주(기탁번호 KCCM 11287P)를 선별하고 상기 균주가 조절 T 세포를 활성화 시키고, 항염증 활성을 갖는 IL-10을 증가시킴으로써 알레르기를 효과적으로 제어할 수 있다는 것을 규명함으로써 본 발명을 완성하게 되었다. The present inventors have made extensive efforts to select strains capable of inhibiting allergic reactions in the human body by activating regulatory T cells and regulating immune responses. As a result, a novel strain of Bacillus amyloliquefaciens strain 26N (accession number KCCM 11287P) having antiallergic activity was selected and the strain activated regulatory T cells, and IL-10 having anti-inflammatory activity To thereby effectively control the allergy, thereby completing the present invention.
따라서, 본 발명의 목적은 바실러스 아밀로리퀴페시언스 26N(Bacillus amyloliquefaciens 26N) 균주(기탁번호 KCCM 11287P) 또는 상기 균주의 배양물을 유효성분으로 포함하는 항알레르기성 조성물을 제공하는데 있다. Accordingly, an object of the present invention is to provide an antiallergic composition comprising as an active ingredient a Bacillus amyloliquefaciens 26N strain (Accession No. KCCM 11287P) or a culture of the strain.
본 발명의 다른 목적은 항알레르기 활성을 갖는 바실러스 아밀로리퀴페시언스 26N 균주(기탁번호 KCCM 11287P)를 제공하는데 있다.
Another object of the present invention is to provide a Bacillus amyloliquefaciens strain 26N (accession number KCCM 11287P) having an antiallergic activity.
본 발명의 다른 목적 및 이점은 하기의 발명의 상세한 설명 및 청구범위에 의해 보다 명확하게 된다.
Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention and claims.
본 발명의 일 양태에 따르면, 본 발명은 바실러스 아밀로리퀴페시언스 26N(Bacillus amyloliquefaciens 26N) 균주(기탁번호 KCCM 11287P) 또는 상기 균주의 배양물을 유효성분으로 포함하는 항알레르기성 조성물을 제공한다.
According to one aspect of the present invention, there is provided an antiallergic composition comprising a strain of Bacillus amyloliquefaciens 26N (accession number KCCM 11287P) or a culture of said strain as an active ingredient.
본 발명자들은 조절 T 세포를 활성화시키고 면역반응을 조절함으로써 인체 내의 알레르기 반응을 억제시킬 수 있는 균주를 선별하고자 예의 연구 노력하였다. 그 결과, 항알레르기 활성을 가지는 신규한 바실러스 아밀로리퀴페시언스(Bacillus amyloliquefaciens) 26N 균주(기탁번호 KCCM 11287P)를 선별하고 상기 균주가 조절 T 세포를 활성화 시키고, 항염증 활성을 갖는 IL-10을 증가시킴으로써 알레르기를 효과적으로 제어할 수 있다는 것을 규명하였다. The present inventors have made extensive efforts to select strains capable of inhibiting allergic reactions in the human body by activating regulatory T cells and regulating immune responses. As a result, a novel strain of Bacillus amyloliquefaciens strain 26N (accession number KCCM 11287P) having antiallergic activity was selected and the strain activated regulatory T cells, and IL-10 having anti-inflammatory activity To control allergies effectively.
본 명세서에서, 용어 “알레르기”는 인체의 어떤 물질에 대한 과민증, 즉 외부로부터 들어온 물질에 대한 신체 면역계의 과도한 반응으로 유발되는 다양한 질환, 질병 또는 이상 상태를 의미한다. 본 발명의 조성물에 적용되는 알레르기 질환으로는, 바람직하게는, 제 Ⅰ 형 즉시형 과민반응 및 제 Ⅳ 형 지연형 과민반응이다. 제 Ⅰ 형 즉시형 과민반응은 기관지 천식, 알레르기성 비염, 아토피성 피부염, 알레르기성 결막염, 알레르기성 중이염, 두드러기 및 아나필락시스 쇼크(anaphylatic shock)이고, 제 Ⅳ 형 지연형 과민반응은 접촉성 과민증, 알레르기성 접촉성 피부염, 세균 알레르기, 진균 알레르기, 바이러스 알레르기, 약물 알레르기, 갑상선염 및 알레르기성 뇌염이다. As used herein, the term " allergy " refers to a variety of diseases, conditions, or abnormal conditions caused by hypersensitivity to certain substances in the body, i.e., excessive response of the body's immune system to substances introduced from the outside. The allergic diseases to be applied to the composition of the present invention are preferably Type I immediate hypersensitivity reaction and Type IV delayed hypersensitivity reaction. Type I immediate hypersensitivity reactions are bronchial asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, allergic otitis media, urticaria and anaphylatic shock, Type IV delayed hypersensitivity reactions include contact hypersensitivity, allergy Sexually-transmitted dermatitis, bacterial allergy, fungal allergy, viral allergy, drug allergy, thyroiditis and allergic encephalitis.
제 Ⅰ 형 즉시형 과민반응은 2 단계로 나뉘는데 제 1 단계는 알레르겐의 체내 침입에 의하여 IgE 및 IgG1의 분비를 억제하고, IgG2a의 분비를 증가시키는 IL-12 및 IFN-γ를 생산하는 Th1 세포반응과 IL-4, IL-5 및 IL-13 등을 생산하는 Th2 세포반응의 균형이 Th2 쪽으로 기울어지게 되면 Th2의 과도한 면역반응으로 IL-4 및 IL-13 등이 분비되고 그 영향으로 B 세포가 생산한 IgE 특이항체들이 비만세포(mast cell) 및 호염기구(basophil)의 표면에 부착됨으로써 알레르기 발증이 준비된 단계이다. 이를 알레르겐에 감작되었다고 한다. 알레르기 발증의 제 2 단계는 초기반응과 후기반응으로 나뉘며, 초기반응은 알레르겐이 체내에 재침입하여 비만세포를 자극하고 탈과립 반응을 유발하여 이때 방출된, 히스타민, 지질대사물, 사이토카인 등에 의한 혈관확장 등이 일어나는 것이고, 후기반응은 해당 조직에 호중구, 호산구, 대식세포, Th2 세포, 호염기구 등이 침윤하여 활성화됨으로써 염증이 유발되어 아토피피부염, 비염, 천식 등을 일으키는 것이다. The type I immediate-type hypersensitivity reaction is divided into two stages. The first step is to suppress the secretion of IgE and IgG1 by the invasion of the allergen and the Th1 cell reaction to produce IL-12 and IFN-γ which increase secretion of IgG2a And IL-4, IL-5, and IL-13, the IL-4 and IL-13 are secreted by the excessive immune response of Th2, The IgE-specific antibodies produced are attached to the surface of mast cells and basophils, so that allergic inflammation is prepared. It has been sensitized to allergens. The second stage of the allergic manifestation is divided into an initial reaction and a late reaction. The initial reaction is to re-enter the body to stimulate mast cells and induce a degranulation reaction, which causes release of histamine, lipid metabolites, cytokines, And eosinophil, eosinophil, macrophage, Th2 cell, and basophil are infiltrated into the affected tissue to induce inflammation, resulting in atopic dermatitis, rhinitis, asthma, and the like.
바람직하게는, 상기 알레르기는 천식, 알레르기성 비염, 알레르기성 피부염, 알레르기성 아토피 피부염 또는 식품 알레르기이다.Preferably, the allergy is asthma, allergic rhinitis, allergic dermatitis, allergic atopic dermatitis or food allergy.
본 명세서에서 용어 “유효성분으로 포함하는”이란 하기의 바실러스 아밀로리퀴페시언스 26N 균주(기탁번호 KCCM 11287P) 또는 상기 균주의 배양물의 항알레르기 효능 또는 활성을 달성하는 데 충분한 양을 포함하는 것을 의미한다. 본 발명의 조성물에 포함된 양적 상한은 당업자가 적절한 범위 내에서 선택하여 실시할 수 있다.As used herein, the term " comprising as an active ingredient " means containing the following Bacillus amyloliquefaciens strain 26N (accession number KCCM 11287P) or an amount sufficient to achieve the antiallergic potency or activity of the culture of the strain do. The quantitative upper limit included in the composition of the present invention can be selected by a person skilled in the art within a suitable range.
본 발명의 일 구현예에 따르면, 본 발명의 조성물은 조절 T 세포를 활성화시킨다. 조절 T 세포는 면역계가 활성화되는 것을 억제하는 기능을 하며, 그로 인해 면역계의 자기면역관용(self-tolerance)을 통제한다. 그 결과, 건강한 개체에서 자가면역 질환의 발병을 예방한다. According to one embodiment of the invention, the composition of the invention activates regulatory T cells. Regulatory T cells function to inhibit the activation of the immune system, thereby controlling the self-tolerance of the immune system. As a result, it prevents the onset of autoimmune diseases in healthy individuals.
본 발명에 따르면, 본 발명의 조성물에 의한 조절 T 세포의 활성화는 Foxp3 발현 증가에 의한 것이다. According to the present invention, activation of regulatory T cells by the composition of the invention is due to increased Foxp3 expression.
본 발명의 일 구현예에 따르면, 본 발명의 조성물은 Foxp3의 발현을 5 내지 30% 증가시킨다. 본 발명의 다른 구현예에 따르면, 본 발명의 조성물은 Foxp3의 발현을 8 내지 20% 증가시킨다. 본 발명의 특정 구현예에 따르면, 본 발명은 Foxp3의 발현을 10 내지 15% 증가시킨다. According to one embodiment of the present invention, the composition of the present invention increases the expression of Foxp3 by 5 to 30%. According to another embodiment of the present invention, the composition of the present invention increases the expression of Foxp3 by 8 to 20%. According to certain embodiments of the present invention, the present invention increases the expression of Foxp3 by 10 to 15%.
본 발명의 일 구현예에 따르면, 본 발명의 조성물은 IL10의 생성을 증가시킨다. IL10은 대식세포와 모노사이트 및 T-세포 림프구 복제와 염증성 사이토카인 (IL1, TNF-α, TGF-β, IL6, IL8 및 IL12)의 분비를 억제하는 림프계 세포에 의해 생성되는 강력한 Th-2 사이토카인이다. IL10은 항염증성 사이토카인으로서 IL10이 증가되면 염증반응이 억제된다. According to one embodiment of the present invention, the composition of the present invention increases the production of IL10. IL10 is a potent Th-2 cytokine produced by lymphoid cells that inhibits macrophage and monocyte and T-cell lymphocyte replication and the secretion of inflammatory cytokines (IL1, TNF-alpha, TGF-beta, IL6, IL8 and IL12) It's Cain. IL10 is an anti-inflammatory cytokine, and the inflammatory response is suppressed when IL10 is increased.
본 발명의 다른 구현예에 따르면, 본 발명의 조성물에 의해 생성된 IL-10 수치에 대한 IL-12 생성 수치의 비율은 60 내지 100이다. According to another embodiment of the present invention, the ratio of the IL-12 producing level to the IL-10 level produced by the composition of the invention is 60-100.
본 발명의 특정 구현예에 따르면, 본 발명의 조성물에 의해 생성된 IL-10 수치에 대한 IL-12 생성 수치의 비율은 75 내지 85이다. According to certain embodiments of the invention, the ratio of IL-12 producing levels to IL-10 levels produced by the compositions of the invention is 75-85.
본 발명의 항알레르기 조성물 중 바실러스 아밀로리퀴페시언스 26N 균주(기탁번호 KCCM 11287P) 또는 상기 균주의 배양물 이외의 성분은 항알레르기 활성 및 항염증 작용을 촉진하는 성분으로써 당업계에 공지된 다양한 성분이 포함될 수 있다.Among the anti-allergic compositions of the present invention, the components other than the Bacillus amyloliquefaciens strain 26N (accession No. KCCM 11287P) or the culture of the strain are components that promote anti-allergic activity and anti-inflammatory action, May be included.
본 발명의 조성물은 약제학적 조성물로 제조될 수 있다.The compositions of the present invention may be prepared with pharmaceutical compositions.
본 발명의 바람직한 구현예에 따르면, 본 발명의 조성물은 (a) 상술한 본 발명의 바실러스 아밀로리퀴페시언스 26N 균주(기탁번호 KCCM 11287P) 또는 상기 균주의 배양물의 약제학적 유효량; 및 (b) 약제학적으로 허용되는 담체를 포함하는 약제학적 조성물이다. 본 명세서에서 용어 “약제학적 유효량”은 상술한 바실러스 아밀로리퀴페시언스 26N 균주의 효능 또는 활성을 달성하는 데 충분한 양을 의미한다.According to a preferred embodiment of the present invention, the composition of the present invention comprises (a) a pharmaceutically effective amount of the Bacillus amyloliquefaciens strain 26N of the present invention (accession number KCCM 11287P) or a culture of the strain; And (b) a pharmaceutically acceptable carrier. As used herein, the term " pharmaceutically effective amount " means an amount sufficient to achieve efficacy or activity of the Bacillus amyloliquefaciens strain 26N described above.
본 발명의 조성물이 약제학적 조성물로 제조되는 경우, 본 발명의 약제학적 조성물은 약제학적으로 허용되는 담체를 포함한다. 본 발명의 약제학적 조성물에 포함되는 약제학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 약제학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다. 적합한 약제학적으로 허용되는 담체 및 제제는 Remington's Pharmaceutical Sciences (19th ed., 1995)에 상세히 기재되어 있다.When the composition of the present invention is manufactured from a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).
본 발명의 약제학적 조성물은 경구 또는 비경구 투여할 수 있으며, 바람직하게는 경구 투여 방식으로 적용된다.The pharmaceutical composition of the present invention can be administered orally or parenterally, and is preferably administered orally.
본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 본 발명의 약제학적 조성물에 포함된 생리활성물질인 콩 발효물의 투여량은 성인 기준으로 0.001-100 ㎎/kg 범위 내이다.The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . The dose of the fermented soybean, which is a physiologically active substance contained in the pharmaceutical composition of the present invention, is within the range of 0.001-100 mg / kg on an adult basis.
본 발명의 약제학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액, 시럽제 또는 유화액 형태이거나 엑스제, 산제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or in the form of excipients, powders, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.
본 발명의 조성물은 식품 조성물로 제공될 수 있다.The composition of the present invention can be provided as a food composition.
본 발명의 조성물이 식품 조성물로 제조되는 경우, 유효성분으로서 바실러스 아밀로리퀴페시언스 26N 균주 또는 그 배양물 뿐만 아니라, 식품 제조 시에 통상적으로 첨가되는 성분을 포함하며, 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함한다. 상술한 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스, 올리고당 등; 및 폴리사카라이드, 예를 들어 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 향미제로서 천연 향미제 [타우마틴, 스테비아 추출물 (예를 들어 레바우디오시드 A, 글리시르히진 등]) 및 합성 향미제(사카린, 아스파르탐 등)를 사용할 수 있다.When the composition of the present invention is prepared as a food composition, it contains not only the Bacillus amyloliquefaciens strain 26N as an active ingredient or a culture thereof, but also a component ordinarily added in food production, for example, a protein, a carbohydrate , Fats, nutrients, flavoring agents, and flavoring agents. Examples of the above-mentioned carbohydrates are monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, oligosaccharides and the like; And polysaccharides such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavorings such as tau martin and stevia extract (e.g., rebaudioside A and glycyrrhizin) and synthetic flavorings (saccharine, aspartame, etc.) can be used as flavorings.
예컨대, 본 발명의 식품 조성물이 드링크제로 제조되는 경우에는 본 발명의 콩 발효물 이외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙, 두충 추출액, 대추 추출액, 감초 추출액 등을 추가로 포함시킬 수 있다. For example, when the food composition of the present invention is prepared as a drink, it may further contain citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, juice, mulberry extract, jujube extract, licorice extract, .
본 발명의 조성물은 화장료 조성물로 제조될 수 있다.The composition of the present invention can be prepared with a cosmetic composition.
본 발명의 바실러스 아밀로리퀴페시언스 26N 균주(기탁번호 KCCM 11287P) 또는 상기 균주의 배양물을 유효성분 포함하는 항알레르기용 조성물이 화장료 조성물로 제조되는 경우, 유효 성분으로서의 바실러스 아밀로리퀴페시언스 26N 균주(기탁번호 KCCM 11287P) 또는 그 배양물 이외에 화장료 조성물에 통상적으로 이용되는 성분들을 포함하며, 예컨대 안정화제, 용해화제, 비타민, 안료 및 향료와 같은 통상적인 보조제, 그리고 담체를 포함한다.When the antiallergic composition comprising the active ingredient of the Bacillus amyloliquefaciens strain 26N of the present invention (accession number KCCM 11287P) or the culture of the strain is prepared from a cosmetic composition, the active ingredient Bacillus amyloliquefaciens 26N (Accession no. KCCM 11287P) or cultures thereof, and includes customary adjuvants such as stabilizers, solubilizers, vitamins, pigments and flavoring agents, and carriers.
본 발명의 화장료 조성물은 당업계에서 통상적으로 제조되는 어떠한 제형으로도 제조될 수 있으며, 예를 들어, 용액, 현탁액, 유탁액, 페이스트, 겔, 크림, 로션, 파우더, 비누, 계면활성제-함유 클린싱, 오일, 분말 파운데이션, 유탁액 파운데이션, 왁스 파운데이션 및 스프레이 등으로 제형화될 수 있으나, 이에 한정되는 것은 아니다. 보다 상세하게는, 유연 화장수, 영양 화장수, 영양 크림, 마사지 크림, 에센스, 아이 크림, 클렌징 크림, 클렌징 포옴, 클렌징 워터, 팩, 스프레이 또는 파우더의 제형으로 제조될 수 있다.The cosmetic composition of the present invention can be prepared into any of the formulations conventionally produced in the art and can be used as a solution, a suspension, an emulsion, a paste, a gel, a cream, a lotion, a powder, a soap, , Oil, powder foundation, emulsion foundation, wax foundation and spray, but is not limited thereto. More specifically, it can be manufactured in the form of a soft lotion, a nutritional lotion, a nutritional cream, a massage cream, an essence, an eye cream, a cleansing cream, a cleansing foam, a cleansing water, a pack, a spray or a powder.
본 발명의 제형이 페이스트, 크림 또는 겔인 경우에는 담체 성분으로서 동물성유, 식물성유, 왁스, 파라핀, 전분, 트라칸트, 셀룰로오스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크 또는 산화아연 등이 이용될 수 있다.When the formulation of the present invention is a paste, cream or gel, an animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as the carrier component .
본 발명의 제형이 페이스트, 크림 또는 겔인 경우에는 담체 성분으로서 동물성유, 식물성유, 왁스, 파라핀, 전분, 트라칸트, 셀룰로오스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크 또는 산화아연 등이 이용될수 있다.When the formulation of the present invention is a paste, cream or gel, an animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as the carrier component have.
본 발명의 제형이 파우더 또는 스프레이인 경우에는 담체 성분으로서 락토스, 탈크, 실리카, 알루미늄 히드록시드, 칼슘 실리케이트 또는 폴리아미드 파우더가 이용될 수 있고, 특히 스프레이인 경우에는 추가적으로 클로로플루오로히드로카본, 프로판/부탄 또는 디메틸 에테르와 같은 추진체를 포함할 수 있다.When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. In the case of a spray, in particular, / Propane or dimethyl ether.
본 발명의 제형이 용액 또는 유탁액인 경우에는 담체 성분으로서 용매, 용해화제 또는 유탁화제가 이용되고, 예컨대 물, 에탄올, 이소프로판올, 에틸카보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸글리콜 오일, 글리세롤 지방족 에스테르, 폴리에틸렌 글리콜 또는 소르비탄의 지방산 에스테르가 있다.When the formulation of the present invention is a solution or an emulsion, a solvent, a dissolving agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, , 3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan fatty acid esters.
본 발명의 제형이 현탁액인 경우에는 담체 성분으로서 물, 에탄올 또는 프로필렌 글리콜과 같은 액상의 희석제, 에톡실화 이소스테아릴 알코올, 폴리옥시에틸렌 소르비톨 에스테르 및 폴리옥시에틸렌 소르비탄 에스테르와 같은 현탁제, 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가 또는 트라칸트 등이 이용될 수 있다.In the case where the formulation of the present invention is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.
본 발명의 제형이 계면-활성제 함유 클린징인 경우에는 담체 성분으로서 지방족 알코올 설페이트, 지방족 알코올 에테르 설페이트, 설포숙신산 모노에스테르, 이세티오네이트, 이미다졸리늄 유도체, 메틸타우레이트, 사르코시네이트, 지방산 아미드 에테르 설페이트, 알킬아미도베타인, 지방족 알코올, 지방산 글리세리드, 지방산 디에탄올아미드, 식물성 유, 라놀린 유도체 또는 에톡실화 글리세롤 지방산 에스테르 등이 이용될 수 있다.When the formulation of the present invention is an interfacial active agent-containing cleansing, the carrier component may include aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid amide Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives, or ethoxylated glycerol fatty acid esters.
본 발명의 조성물은 사료 조성물로 제조될 수 있다.The composition of the present invention may be prepared from a feed composition.
본 발명의 바실러스 아밀로리퀴페시언스 26N 균주(기탁번호 KCCM 11287P) 또는 상기 균주의 배양물을 유효성분 포함하는 항알레르기용 조성물이 사료 조성물로 제조되는 경우, 바실러스 아밀로리퀴페시언스 26N 균주(기탁번호 KCCM 11287P)의 배양물, 또는 사료 제조시 통상적으로 첨가되는 첨가제 등을 가하여 제조할 수 있다. 예컨대, 비타민, 아미노산류, 미네랄 등의 각종 양분, 항산화제, 항생물질, 항균제 및 기타의 첨가제이다. 그 형상에는 분체, 과립, 펠릿 또는 현탁액 등이 포함된다.When the antiallergic composition comprising the active ingredient of the Bacillus amyloliquefaciens strain 26N of the present invention (accession number KCCM 11287P) or the culture of the strain is prepared from the feed composition, the Bacillus amyloliquefaciens strain 26N No. KCCM 11287P), or an additive usually added in the production of feeds. For example, various nutrients such as vitamins, amino acids and minerals, antioxidants, antibiotics, antibacterial agents and other additives. The shape includes powders, granules, pellets or suspensions, and the like.
본 발명의 조성물이 사료 조성물로 제조되는 경우, 육상 또는 수상 동물에 대하여 단독으로 또는 사료에 혼합하여 공급할 수 있다. 본 발명의 사료에는 분말사료, 고형사료, 모이스트 펠릿사료, 드라이 펠릿사료, EP(Extruder Pellet) 사료, 날먹이 등이 포함되며, 이에 한정되는 것은 아니다.
When the composition of the present invention is prepared from a feed composition, it may be supplied to the land or aquatic animals singly or in a feed mixture. The feed of the present invention includes, but is not limited to, powdered feed, solid feed, moist pellet feed, dry pellet feed, extruder pellet (EP) feed,
본 발명의 다른 일 양태에 따르면, 본 발명은 항알레르기 활성을 갖는 바실러스 아밀로리퀴페시언스 26N 균주(기탁번호 KCCM 11287P)를 제공한다.
According to another aspect of the present invention, the present invention provides a Bacillus amyloliquefaciens strain 26N (accession number KCCM 11287P) having antiallergic activity.
본 발명의 특징 및 이점을 요약하면 다음과 같다: The features and advantages of the present invention are summarized as follows:
(a) 본 발명은 바실러스 아밀로리퀴페시언스 26N 균주(기탁번호 KCCM 11287P)를 유효성분으로 포함하는 항알레르기성 조성물을 제공한다.(a) The present invention provides an antiallergic composition comprising as an active ingredient a Bacillus amyloliquefaciens strain 26N (Accession No. KCCM 11287P).
(b) 본 발명은 항알레르기 활성을 갖는 바실러스 아밀로리퀴페시언스 26N 균주(기탁번호 KCCM 11287P)를 제공한다. (b) The present invention provides a strain of Bacillus amyloliquefaciens strain 26N having antiallergic activity (Accession No. KCCM 11287P).
(c) 본 발명의 바실러스 아밀로리퀴페시언스 26N 균주(기탁번호 KCCM 11287P)는 조절 T 세포를 활성화 시키고 항염증 사이토카인인 IL10을 증가시킴으로써 알레르기를 효과적으로 제어할 수 있다.
(c) The Bacillus amyloliquefaciens strain 26N of the present invention (Accession No. KCCM 11287P) can effectively control allergies by activating regulatory T cells and increasing IL10, an anti-inflammatory cytokine.
도 1은 바실러스 아밀로리퀴페시언스 아종 플랜타룸 F1275, 바실러스 아밀로리퀴페시언스 26N 및 양성대조군인 ICR5의 공동배양에 따른 Foxp3의 발현 정도를 측정한 결과이다. FIG. 1 shows the results of measurement of the expression level of Foxp3 according to co-culture of Bacillus amyloliquefaciens subsp. Plantarum F1275, Bacillus amyloliquefaciens 26N and positive control group ICR5.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .
실시예Example
실험 재료 및 방법Materials and Methods
균주의 분리 및 동정Isolation and Identification of Strain
균주는 트립티케이스 대두 한천(디프코社, 미국) 배지를 이용하여 재래식으로 제조된 메주로부터 분리하였으며, 16S rDNA 시퀀싱을 통해 균주를 동정하였다. 동정 결과, 상기 분리된 균주의 16s rDNA 염기서열은 기존의 바실러스 아밀로리퀴페시언스 FZB42(T) 균주와 100%의 상동성을 보였다. 상기 분리 균주에 대하여 유전체(genome) 분석을 수행한 결과, 상기 균주의 유전체 사이즈는 3.95M로 일반적인 바실러스 균주의 유전체 사이즈와 유사한 정도를 보였지만, 상기 균주가 가지고 있는 ORF의 개수는 4760개로 상당히 많은 수의 유전자를 가지고 있는 것으로 나타났다. The strain was isolated from conventionally prepared meju using the medium of tryptic case soybean agar (Difco, USA), and strain was identified through 16S rDNA sequencing. As a result of the identification, the 16s rDNA sequence of the isolated strain showed 100% homology with the conventional Bacillus amyloliquefaciens FZB42 (T) strain. As a result of genome analysis of the isolate, the genome size of the strain was 3.95 M, which was similar to that of a general Bacillus strain. However, the number of ORFs contained in the strain was 4760, which was considerably large Of the genes.
본 균주의 배양을 위한 배지 조성은 트립티케이스 대두 배지(BD236950) 이며, 배양조건은 pH 7.3 ± 0.2, 온도 37℃, 24 시간 진탕 또는 고체 정치배양이며, 산소요구성은 호기성이고 동결건조보존 또는 세포현탁액 동결을 통해 균주 보존이 가능하다. 이 균주를 바실러스 아밀로리퀴페시언스 26N 균주로 명명하고, 국제미생물기탁기관인 한국미생물보존센터(KCCM)에 2012년 6월 14일자로 기탁하였으며, 기탁번호 KCCM 11287P를 부여받았다.
The culture medium for the cultivation of this strain was as follows: tryptic case soybean medium (BD236950) . The culture conditions are pH 7.3 ± 0.2, 37 ° C, 24 hours shaking or solid state culture. The oxygen requirement is aerobic and the strain can be preserved by lyophilization preservation or cell suspension freezing. This strain was designated as Bacillus amyloliquefaciens strain 26N and deposited on June 14, 2012 at the Korean Microorganism Conservation Center (KCCM), an international microorganism depository, and received the deposit number KCCM 11287P.
실험동물Experimental animal
본 연구를 위해 유전적으로 어떠한 변형도 일어나지 않은 야생형의 생쥐(계통 번호-C57BL/6, 스탁 번호-000664, the Jackson laboratory)를 사용하였다. 또한, Foxp3의 발현 정도를 비교적 쉽게 확인하기 위해 유전적으로 변형된 생쥐(Foxp3-GFP 넉 인 마우스, 계통 이름-B6.Cg-Foxp3 tm2Tch /J, 스탁 번호-006772, Jackson laboratory)를 이용하였다. 이 생쥐의 경우 야생형의 종을 기반으로 만들어졌기 때문에 전반적인 유전 정보는 동일하나, Foxp3가 발현할 때 형광 신호를 낼 수 있는 분자인 EGFP(enhanced green fluorescence protein)가 함께 발현하여 이러한 형광 신호가 Foxp3 발현 정도를 대변해 주기 때문에 이 생쥐를 통해 감지가 어려운 Foxp3의 발현 정도를 항체의 사용 없이도 비교적 용이하게 확인할 수 있다.
For this study, wild-type mice (strain No. -C57BL / 6, STOCK No. -000664, the Jackson laboratory), which had no genetic modification, were used. Genetically modified mice (Foxp3-GFP knock-in mice, strain name-B6.Cg- Foxp3 tm2Tch / J, STOCK No. -006772, Jackson laboratory) were used to comparatively easily detect the expression level of Foxp3 . These mice were made based on wild-type species, so the overall genetic information is the same, but when Foxp3 is expressed, EGFP (enhanced green fluorescence protein), which is a molecule capable of emitting fluorescence signal, is expressed together with the Foxp3 expression The expression level of Foxp3, which is difficult to detect through this mouse, can be comparatively easily detected without the use of antibodies.
면역 세포 분리Immune cell isolation
생쥐의 장간막 림프절(mesenteric lymph node)을 적출한 후, 림프절에 존재하는 면역 세포(대부분 림프구)를 단일 세포 부유하여 실험에 이용하였다. 장내에 존재하는 프로바이오틱스는 장 내 면역계에 존재하는 면역 세포들에 의해 인지되기 때문에 프로바이오틱스의 특성을 분석하기 위해 적절한 면역 세포는 장간막 림프절에 존재하는 면역 세포이다. 따라서, 이 림프절에서 분리한 면역 세포로 바실러스 아밀로리퀴페시언스 26N(Bacillus amyloliquefaciens 26N)의 특성을 분석하였다.
After the mesenteric lymph node of the mouse was removed, the immune cells (mostly lymphocytes) present in the lymph nodes were suspended in a single cell and used for the experiment. Because the probiotics present in the intestine are recognized by immune cells present in the intestinal immune system, appropriate immune cells are immune cells present in the mesenteric lymph nodes to characterize the probiotics. Therefore, the characteristics of Bacillus amyloliquefaciens 26N ( Bacillus amyloliquefaciens 26N) were analyzed as immunocytes isolated from the lymph nodes.
공동 배양(co-culture) Co-culture
분리한 면역 세포와 바실러스 아밀로리퀴페시언스 26N은 1:10 비율 즉, 면역 세포 3x106과 균주 3x107 cfu를 72시간 동안 37℃ 배양기에서 배양하였다. 이 때 항생제인 젠타마이신(11811-031, 15 μg/mL, GIBCO)을 함께 처리하여 시험균주의 과잉성장을 방지하였다.
The isolated immune cells and Bacillus amyloliquefaciens 26N was cultured in a 1: 10 ratio, i.e., 3x10 < 6 > cells of the immune cells and 3x10 < 7 > cfu of the strain for 72 hours in a 37 DEG C incubator. At that time, the antibiotic gentamycin (11811-031, 15 μg / mL, GIBCO) was treated together to prevent the overgrowth of the test strain.
효소면역측정법(Enzyme-linked immunosorbent assay, ELISA) Enzyme-linked immunosorbent assay (ELISA)
ELISA는 효소를 표식자로 하여 항원항체반응을 이용한 항원 또는 항체의 양을 측정하는 방법 중 하나이다. 면역 세포와 유산균을 공동 배양 후 상등액에 존재하는 사이토카인의 양을 측정하기 위해 IL-10(Mouse IL-10 ELISA Ready-SET-Go, eBioscience) 및 IL-12p70(Mouse IL-12p70 ELISA Ready-SET-Go, eBioscience) ELISA를 실시하였다. 각각의 사이토카인을 감지하는 코팅용 항체를 96웰에 처리한 후, 상층액을 넣고 일정 시간 동안 반응이 진행되도록 놓아둔 후, 각각의 사이토카인을 감지하는 또 다른 검출용 항체를 처리하였다. 이 때 처리하는 검출용 항체는 효소(HRP)와 결합하고 있는데, 이 때 효소의 기질(Tetramethylbenzidine Substrate Solution, eBioscience)을 첨가하여 효소-기질 반응에 의한 결과물로 색의 변화가 일어난다. 이러한 간접적인 방법을 통해 사이토카인의 절대량을 측정할 수 있다.
ELISA is a method of measuring the amount of an antigen or an antibody using an antigen-antibody reaction using an enzyme as a marker. (Mouse IL-10 ELISA Ready-SET-Go, eBioscience) and IL-12p70 (Mouse IL-12p70 ELISA Ready-SET) were used to measure the amount of cytokine present in the supernatant after co- -Go, eBioscience) ELISA. The coating antibody for detecting each cytokine was treated in 96 wells, and the supernatant was added thereto. After allowing the reaction to proceed for a predetermined period of time, another detection antibody for detecting each cytokine was treated. At this time, the antibody for detection is bound to the enzyme (HRP), and a color change occurs as a result of an enzyme-substrate reaction by adding an enzyme substrate (Tetramethylbenzidine Substrate Solution, eBioscience). The absolute amount of cytokine can be measured by this indirect method.
유세포 분석기(Flow cytometry)를 통한 표면 분자(surface molecule) 발현 측정 Measurement of Surface Molecule Expression by Flow Cytometry
유세포 분석기는 레이저를 기반으로 하여 세포의 특정 신호를 감지해 내는 기술로, 분석기에 내재되어 있는 전기 장치에 의해 이러한 신호가 감지되며 이를 통해 살아있는 세포의 생체 분자 발현 정도를 확인할 수 있다. 세포의 표면 분자 발현 정도를 비교하기 위해 바실러스 아밀로리퀴페시언스 26N과 공동 배양한 면역 세포들을 이 유세포 분석기(COULTER Epics XL, BECKMAN)를 통해 Foxp3가 발현할 때 함께 발현하는 GFP 시그널을 측정함으로써 Foxp3의 발현양을 측정ㆍ비교하였다.
A flow cytometer is a laser-based technology that detects specific signals of cells. Such signals are detected by an electrical device embedded in the analyzer, and thus the degree of biomolecular expression of living cells can be checked. In order to compare the degree of expression of surface molecules of cells, Bacillus amyloliquefaciens 26N were coexpressed with Foxp3, and the amount of Foxp3 expression was measured and compared by measuring the GFP signals that were expressed when Foxp3 was expressed through this flow cytometer (COULTER Epics XL, BECKMAN).
실험결과Experiment result
항알레르기 활성 측정 - Foxp3 발현량 증가Measuring antiallergic activity - Increasing the expression of Foxp3
조절 T 세포는 T세포의 부분 집합 중 하나로 다른 T 세포와 다르게 과도한 면역 반응을 억제하는 역할을 수행한다. 이러한 조절 T 세포가 알레르기 질환을 억제한다는 것이 다양한 연구 결과를 통해 뒷받침 되고 있다. 시험균주와 장간막 림프절 세포를 공동배양 시, 조절 T 세포의 분포를 늘릴 수 있는 균주가 항 알레르기 효능을 띠는 프로바이오틱스가 될 가능성이 높다. Foxp3는 조절 T 세포의 대표적인 조절인자로 Foxp3 넉 인(Knock-in) 실험용 생쥐를 이용하면, 효율적으로 조절 T 세포(regulatory T cell)의 분포를 평가할 수 있다. 따라서, 시험균주들과 조절 T 세포 간의 상호작용을 알아보기 위해 Foxp3 넉 인 실험용 생쥐의 장간막 림프절 세포를 분리하여 각각의 시험균주와 1:10 비율 혼합한 후 3일간 공동 배양을 진행하였다. 3일 후, 시험균주와 공동 배양한 세포를 걷어 낸 후, Foxp3와 함께 발현하는 GFP의 발현 정도를 유세포 분석기를 통해 확인하였다. 형광 단백질인 GFP의 발현 정도는 Foxp3 발현의 발현 정도를 간접적으로 보여주는 지표이므로 이를 통해 조절 T 세포의 분포를 확인할 수 있다.Regulatory T cells are one of a subset of T cells that, unlike other T cells, play a role in suppressing excessive immune responses. Various studies have shown that these regulatory T cells inhibit allergic diseases. When the test strain and mesenteric lymph node cells are co-cultured, a strain capable of increasing the distribution of regulatory T cells is likely to be a probiotic with antiallergic efficacy. Foxp3 can be used to evaluate the distribution of regulatory T cells efficiently by using Foxp3 knock-in mice as a typical regulator of regulatory T cells. Therefore, mesenteric lymph node cells of Foxp3 knock-in mice were separated and tested for 1: 10 ratio with each test strain and then co-cultured for 3 days. After 3 days, the cell co-cultured with the test strain was removed and the expression level of GFP expressed with Foxp3 was confirmed by flow cytometry. The expression level of GFP, a fluorescent protein, is an indirect indicator of the expression of Foxp3 expression, and thus the distribution of regulatory T cells can be confirmed.
실험 결과, 바실러스 아밀로리퀴페시언스 아종 플랜타룸 F1275(Bacillus amyloliquefaciens subsp. plantarum F1275), 바실러스 아밀로리퀴페시언스 26N과 공동배양 시 Foxp3의 발현 정도가 각각 17.76% 및 12.43%로 음성대조군에 비해 높게 나타났으며(도 1), 양성대조군인 IRT5와 비교 시 유사한 수준의 발현정도를 보여 Treg 조절 T 세포의 분포 증진을 통해 알레르기 질환을 억제할 수 있을 것으로 사료된다.
As a result, the expression levels of Foxp3 were 17.76% and 12.43%, respectively, when co-cultured with Bacillus amyloliquefaciens subsp. Plantarum F1275 and Bacillus amyloliquefaciens 26N, respectively, (Fig. 1). The expression levels of Treg regulatory T cells were similar to those of the positive control group IRT5, suggesting that they could suppress allergic diseases.
IL10 및 IL12 분비 억제IL10 and IL12 secretion inhibition
IL10은 대표적인 면역관용 사이토카인이며, IL-12는 대표적인 면역활성 사이토카인으로 알려져 있으므로 두 사이토카인의 절대적/상대적 양을 파악하여 항알레르기 특성을 갖은 유산균을 선별할 수 있다. 이에 본 실험에서는 Foxp3 넉 인 실험용 생쥐의 장간막 림프절 세포를 분리하여 각각의 시험균주와 1:10 비율 혼합한 후 배양하였다. 3일간 배양 후 배양 상등액을 취하여 면역 활성 사이토카인인 IL-12p70과 항염증 사이토카인인 IL-10의 절대량을 ELISA(Enzyme linked immunosorbent assay)를 통해 측정하였으며, 이 두 분자의 양을 상대적으로 수치화하여 비교하였다. 실험결과 바실러스 아밀로리퀴페시언스 아종 플랜타룸 F1275와 바실러스 아밀로리퀴페시언스 26N은 lL10/IL12의 상대적인 비율이 각각 23.53, 78.07로 높게 나타나 항염증활성을 가질 것으로 판단된다. 특히 바실러스 아밀로리퀴페시언스 26N은 양성대조군인 IRT5와 유사한 수준의 활성을 보였다.
IL10 is a representative immunocompetent cytokine, and IL-12 is known as a representative immunologically active cytokine, so that the absolute / relative amount of two cytokines can be determined and lactic acid bacteria having antiallergic properties can be selected. In this experiment, mesenteric lymph node cells of Foxp3 knockout mice were separated and cultured after mixing 1:10 ratio with each test strain. After culturing for 3 days, the culture supernatant was taken and the absolute amount of IL-12p70, an immunologically active cytokine, and IL-10, an anti-inflammatory cytokine, were measured by ELISA (enzyme linked immunosorbent assay) Respectively. As a result, the relative proportions of IL-10 / IL-12 in the Bacillus amyloliquefaciens subsp. Plantarum F1275 and Bacillus amyloliquefaciens 26N were 23.53 and 78.07, respectively, indicating that they have anti-inflammatory activity. In particular, Bacillus amyloliquefaciens 26N showed similar activity to that of the positive control group IRT5.
-
(pg/mL)IL-10
(pg / mL)
(pg/mL)IL-12p70
(pg / mL)
비율IL-10 / IL-12
ratio
*미검출(not detect), 검출 영역에서 벗어날 정도도 소량이 분비되므로 항염증활성을 기대할 수 없음.* It is not detectable, and anti-inflammatory activity can not be expected because it secretes a small amount to escape from the detection area.
*IRT5: 5개 균주로 게재된 논문과 특허를 고려할 때 항알레르기 활성이 있는 양성대조군으로 활용할 수 있음.
* IRT5: Can be used as a positive control with antiallergic activity considering 5 articles and patents published in 5 strains.
Foxp3+ 세포 분포, IL-10(interleukin 10) 및 IL-12(interleukin 12) 단백질 측정 및 두 사이토카인의 상대적 비율을 조사한 결과, 바실러스 아밀로리퀴페시언스 아종 플랜타룸 F1275와 바실러스 아밀로리퀴페시언스 26N은 조절T세포 활성화와 항염증성 사이토카인 분비를 통해 항알레르기 및 함염증 활성을 가지는 프로바이오틱스 균주임을 확인하였다.
The relative proportions of Foxp3 + cell distribution, IL-10 (interleukin 10) and IL-12 (interleukin 12) protein measurement and two cytokines were examined. As a result, Bacillus amyloliquefaciens subsp. Plantarum F1275 and Bacillus amyloliquefaciens 26N Is a probiotic strain with anti-allergic and anti-inflammatory activity through regulatory T cell activation and anti-inflammatory cytokine secretion.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.
While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
<110> KOREA FOOD RESEARCH INSTITUTE <120> Anti-Allergic Compositions Comprising Bacillus amyloliquefaciens 26N As Active Ingredients <130> PN130313 <160> 1 <170> KopatentIn 2.0 <210> 1 <211> 1458 <212> DNA <213> Bacillus amyloliquefaciens 26N 16S rDNA <400> 1 ggccatgcgg catgcctata ctgcaagtcg agcggacaga tgggagcttg ctccctgatg 60 ttagcggcgg acgggtgagt aacacgtggg taacctgcct gtaagactgg gataactccg 120 ggaaaccggg gctaataccg gatggttgtt tgaaccgcag ggttcagaca taaaaggtgg 180 cttcggctac cacttacaga tggacccgcg gcgcattagc tagttggtga ggtaacggct 240 caccaaggcg acgatgcgta gccgacctga gagggtgatc ggccacactg ggactgagac 300 acggcccaga ctcctacggg aggcagcagt agggaatctt ccgcaatgga cgaaagtctg 360 acggagcaac gccgcgtgag tgatgaaggt tttcggatcg taaagctctg ttgttaggga 420 agaacaagtg ccgttcaaat agggcggcac cttgacggta cctaaccaga aagccacggc 480 taactacgtg ccagcagccg cggtaatacg taggtggcaa gcgttgtccg gaattattgg 540 gcgtaaaggg ctcgcaggcg gtttcttaag tctgatgtga aagcccccgg ctcaaccggg 600 gagggtcatt ggaaactggg gaacttgagt gcagaagagg agagtggaat tccacgtgta 660 gcggtgaaat gcgtagagat gtggaggaac accagtggcg aaggcgactc tctggtctgt 720 aactgacgct gaggagcgaa agcgtgggga gcgaacagga ttagataccc tggtagtcca 780 cgccgtaaac gatgagtgct aagtgttagg ggggtttccg ccccttagtg ctgcagctaa 840 cgcattaagc actccgcctg ggggagtacg gtcgcaagac tgaaactcaa aggaattgac 900 gggggcccgc acaagcggtg gagcatgtgg tttaattcga agcaacgcga agaaccttac 960 caggtcttga catcctctga caatcctaga agataggacg tccccttcgg gggcagagtg 1020 acaggtggtt gcatggttgt cgtcagctcg tgtcgtgaga tgtttgggtt aagtcccgca 1080 acgagcgcaa cctttgatct tagttgccag cattcagttg ggcactctaa aggtgactgc 1140 cggtgacaaa ccgaaggaaa gggtggggga tgaagttcaa atcatcatgg ccccttattg 1200 acctgggggt aaccaccttg cttccaatgg gacagaaaaa aaaggggggc cgaaaccccc 1260 cggggttaag ccaatcccca caaatttgtt ttcttgtttc ggaaaccaaa ctttgcaatt 1320 ccaccggcgt gaagttggaa taccttttaa ttcccgggat aaccaatgcc cccggggaaa 1380 aacatttccc gggcccttgg caaacccgcc gggtcccacc ccccaagttt gtgtacccca 1440 caagtcgggg gagggacc 1458 <110> KOREA FOOD RESEARCH INSTITUTE <120> Anti-Allergic Compositions Comprising Bacillus amyloliquefaciens 26N As Active Ingredients <130> PN130313 <160> 1 <170> Kopatentin 2.0 <210> 1 <211> 1458 <212> DNA <213> Bacillus amyloliquefaciens 26N 16S rDNA <400> 1 ggccatgcgg catgcctata ctgcaagtcg agcggacaga tgggagcttg ctccctgatg 60 ttagcggcgg acgggtgagt aacacgtggg taacctgcct gtaagactgg gataactccg 120 ggaaaccggg gctaataccg gatggttgtt tgaaccgcag ggttcagaca taaaaggtgg 180 cttcggctac cacttacaga tggacccgcg gcgcattagc tagttggtga ggtaacggct 240 caccaaggcg acgatgcgta gccgacctga gagggtgatc ggccacactg ggactgagac 300 acggcccaga ctcctacggg aggcagcagt agggaatctt ccgcaatgga cgaaagtctg 360 acggagcaac gccgcgtgag tgatgaaggt tttcggatcg taaagctctg ttgttaggga 420 agaacaagtg ccgttcaaat agggcggcac cttgacggta cctaaccaga aagccacggc 480 taactacgtg ccagcagccg cggtaatacg taggtggcaa gcgttgtccg gaattattgg 540 gcgtaaaggg ctcgcaggcg gtttcttaag tctgatgtga aagcccccgg ctcaaccggg 600 gagggtcatt ggaaactggg gaacttgagt gcagaagagg agagtggaat tccacgtgta 660 gcggtgaaat gcgtagagat gtggaggaac accagtggcg aaggcgactc tctggtctgt 720 aactgacgct gaggagcgaa agcgtgggga gcgaacagga ttagataccc tggtagtcca 780 cgccgtaaac gatgagtgct aagtgttagg ggggtttccg ccccttagtg ctgcagctaa 840 cgcattaagc actccgcctg ggggagtacg gtcgcaagac tgaaactcaa aggaattgac 900 gggggcccgc acaagcggtg gagcatgtgg tttaattcga agcaacgcga agaaccttac 960 caggtcttga catcctctga caatcctaga agataggacg tccccttcgg gggcagagtg 1020 acaggtggtt gcatggttgt cgtcagctcg tgtcgtgaga tgtttgggtt aagtcccgca 1080 acgagcgcaa cctttgatct tagttgccag cattcagttg ggcactctaa aggtgactgc 1140 cggtgacaaa ccgaaggaaa gggtggggga tgaagttcaa atcatcatgg ccccttattg 1200 acctgggggt aaccaccttg cttccaatgg gacagaaaaa aaaggggggc cgaaaccccc 1260 cggggttaag ccaatcccca caaatttgtt ttcttgtttc ggaaaccaaa ctttgcaatt 1320 ccaccggcgt gaagttggaa taccttttaa ttcccgggat aaccaatgcc cccggggaaa 1380 aacatttccc gggcccttgg caaacccgcc gggtcccacc ccccaagttt gtgtacccca 1440 caagtcgggg gagggacc 1458
Claims (8)
A pharmaceutical composition for the prevention or treatment of an allergic disease comprising Bacillus amyloliquefaciens 26N (Accession No. KCCM 11287P) or a culture of the above strain as an active ingredient, ≪ / RTI >
2. The composition of claim 1, wherein said regulatory T cell activation is by increased Foxp3 expression.
2. The composition of claim 1, wherein the composition increases IL-10 production.
5. The composition of claim 4, wherein the ratio of IL-12 producing levels to IL-10 levels produced by the composition is 60-100.
A food composition for preventing or ameliorating an allergic disease comprising, as an active ingredient, a Bacillus amyloliquefaciens 26N strain (Accession No. KCCM 11287P) or a culture of the above strain as an active ingredient, ≪ / RTI >
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