KR102364723B1 - Composition for modulating immunity comprising myeloid-derived suppressor cells and regulatory T cell - Google Patents
Composition for modulating immunity comprising myeloid-derived suppressor cells and regulatory T cell Download PDFInfo
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- KR102364723B1 KR102364723B1 KR1020210034472A KR20210034472A KR102364723B1 KR 102364723 B1 KR102364723 B1 KR 102364723B1 KR 1020210034472 A KR1020210034472 A KR 1020210034472A KR 20210034472 A KR20210034472 A KR 20210034472A KR 102364723 B1 KR102364723 B1 KR 102364723B1
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Abstract
본 발명은 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)를 유효성분으로 포함하는 면역 조절용 약학적 조성물 및 이의 다양한 적용에 관한 것이다. 본 발명의 조성물은 Foxp3+Treg 세포 및IL-10 유도한 CD1d+CD5+ Breg 세포를 증가시키고, IL-17+CD4+T 세포를 억제시킴을 확인였는 바, MDSC 및 Treg의 병용 처리는 각 단독 처리보다 시너지 효과가 나타나 유의적인 면역 조절능이 존재함을 확인하였다. 또한, 상기 시너지 효과로 인하여, 쇼그렌 증후군 및 이식편대숙주병에 유의적인 치료효과가 확인되어, 관련 약학 및 식품산업에 유용하게 이용될 수 있다.The present invention relates to a pharmaceutical composition for immune regulation comprising myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) as active ingredients and various applications thereof. It was confirmed that the composition of the present invention increases Foxp3 + Treg cells and IL-10-induced CD1d + CD5 + Breg cells, and inhibits IL-17 + CD4 + T cells. Combination treatment of MDSC and Treg is each treatment alone A more synergistic effect was observed, confirming the presence of a significant immunomodulatory ability. In addition, due to the synergistic effect, a significant therapeutic effect was confirmed for Sjogren's syndrome and graft-versus-host disease, and it can be usefully used in the related pharmaceutical and food industries.
Description
골수유래억제세포 및 조절 T 세포를 포함하는 면역 조절용 조성물 및 이의 다양한 적용에 관한 것이다. To a composition for immune regulation comprising myeloid-derived suppressor cells and regulatory T cells, and to various applications thereof.
억제성 골수 세포(Suppressive myeloid cell)는 20년 전에 암을 유발시킨 동물모델에서 증가된다고 보고되었으며, 암의 진행 및 전이에 영향을 준다고 알려졌다. 최근 이들 세포들은 면역반응에서 기능적으로 중요한 역할을 한다고 평가되어져 왔다. 암세포에 의해 유도되는 면역 억제 기전 중 하나는 암에 의한 골수(myeloid) 계열의 CD11b+Gr-1+ 표현형을 갖는 세포인 골수유래억제세포(myeloid-derived suppressor cell; MDSC)의 증가이다. MDSC는 미성숙한 골수계 세포로 종양이나, 자가 면역 질환, 감염에서 과립구 등이 완전히 분화가 이루어지지 않아 미성숙한 상태로 존재한다. 이들 MDSC는 암 환자뿐만 아니라 급성 염증 질환, 외상, 패혈증, 기생충 및 진균 감염에서도 증가한다고 알려져 있다. MDSC의 기능은 활성화된 T 세포를 효과적으로 억제하는 역할을 한다. MDSC가 T 세포를 조절하는 기전은 산화질소 합성효소 (nitric oxide synthase)와 활성 산소종 (reactive oxygen species; ROS), 그리고 아르기나제(arginase)라는 효소가 필수아미노산인 L-아르기닌(L-arginine)의 대사를 극대화함으로써 T 세포 활성을 억제한다고 알려져 있다. 즉, 필수아미노산인 아르기닌(arginine)을 소비하는 효소인 아르기나제-1(arginase-1)을 높은 수준으로 발현하여 주변의 아르기닌(arginine)의 농도를 효과적으로 낮춘다. 아르기닌(Arginine)이 낮은 수준으로 존재하면 면역세포인 T 세포가 제 기능을 하지 못하게 되며, 아르기닌(arginine)에 의존하는 효소인 iNOS가 면역기능에 중요한 매개물인 산화질소 (Nitric oxide, NO)를 더 이상 만들지 못하게 될 뿐만 아니라 면역을 억제하는 강력한 독성 산화성물질인 과산화질소 (NO2)가 만들어져 대식세포와 다른 세포계에서 세포막인지 질에 산화성 손상을 야기한다. 따라서, 아르기나제(Arginase)와 NOS 활성화를 통해 T 림프구의 증식을 억제하고 ROS의 형성을 통해 T 림프구의 기능을 억제한다고 알려져 있다.Suppressive myeloid cells were reported to be increased in an animal model that caused
조절 T 세포(regulatory T cells (Tregs))는 면역계를 조절하는T 세포 들 중 한 집단으로, 자가항원에 대한 관용을 유지하고 자가면역 질병을 없앤다. 조절 T 세포는 면역계의 구성성분으로 다른 세포들의 면역 반응을 억제한다. 이는 면역계에서 과도한 반응을 막기 위해 만들어진 중요한 ‘자가-점검’ 이다. 조절 T 세포는 다양한 형태로 나타나는데 가장 널리 알려진 것은 CD4, CD25와 Foxp3 (CD4+CD25+ 조절 T 세포) 표현형이다. 이러한 조절 T 세포는 도움T세포와는 다르다. 조절 T세포의 또 다른 부분집합은 Treg17 세포이다. 조절 T 세포는 침입한 미생물을 성공적으로 없앤 후의 면역반응을 멈추는데 연관되며, 또한 자가면역 세포를 막는데도 관여한다. Regulatory T cells (Tregs) are a group of T cells that regulate the immune system, maintaining tolerance to autoantigens and eliminating autoimmune diseases. Regulatory T cells are components of the immune system that suppress the immune response of other cells. This is an important ‘self-check’ designed to prevent overreaction of the immune system. Regulatory T cells appear in various forms, the most well known being the CD4, CD25 and Foxp3 (CD4+CD25+ regulatory T cell) phenotypes. These regulatory T cells are different from helper T cells. Another subset of regulatory T cells are Treg17 cells. Regulatory T cells are involved in stopping the immune response after successful killing of invading microorganisms, and are also involved in blocking autoimmune cells.
이에 본 발명자는 효과적인 면역 조절능을 갖는 최적의 시너지 조합을 모색하던 중, 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)를 병용 처리 시, 단독 처리보다 면역 조절능이 유의적으로 증가됨을 확인하였다. 또한, MDSC 및 Treg의 시너지 효과로 인하여, 쇼그렌 증후군 또는 이식편대숙주병의 치료 효과가 나타남을 확인하여, 본 발명을 완성하였다.Accordingly, the present inventors were searching for an optimal synergistic combination with effective immunomodulatory ability, and when combined treatment with myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), single treatment It was confirmed that the immune modulatory ability was significantly increased. In addition, due to the synergistic effect of MDSC and Treg, it was confirmed that the therapeutic effect of Sjogren's syndrome or graft-versus-host disease appeared, thereby completing the present invention.
본 발명의 목적은 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)를 유효성분으로 포함하는 면역 조절용 약학적 조성물을 제공하는 것이다.It is an object of the present invention to provide a pharmaceutical composition for immune regulation comprising myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as active ingredients.
본 발명의 다른 목적은 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)를 유효성분으로 포함하는 쇼그렌 증후군의 예방 및 치료용 약학 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for the prevention and treatment of Sjogren's syndrome comprising myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as active ingredients.
본 발명의 다른 목적은 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)를 유효성분으로 포함하는 이식편대숙주병(graft-versus-host disease, GVHD) 예방 및 치료용 약학 조성물을 제공하는 것이다.Another object of the present invention is graft-versus-host disease (GVHD) comprising myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) as active ingredients. To provide a pharmaceutical composition for prevention and treatment.
본 발명의 다른 목적은 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)를 유효성분으로 포함하는 면역 조절용 건강기능식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a health functional food composition for immune regulation comprising myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as active ingredients.
본 발명의 다른 목적은 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)를 유효성분으로 포함하는 쇼그렌 증후군의 예방 및 개선용 건강기능식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a health functional food composition for the prevention and improvement of Sjogren's syndrome comprising myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) as active ingredients. will be.
본 발명의 다른 목적은 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)를 유효성분으로 포함하는 이식편대숙주병 예방 및 개선용 건강기능식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a health functional food composition for preventing and improving graft-versus-host disease, comprising myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as active ingredients will do
따라서, 본 발명은 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)를 유효성분으로 포함하는 면역 조절용 약학적 조성물을 제공한다.Accordingly, the present invention provides a pharmaceutical composition for immune regulation comprising myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as active ingredients.
또한, 본 발명은 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)를 유효성분으로 포함하는 쇼그렌 증후군의 예방 및 치료용 약학 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing and treating Sjogren's syndrome comprising myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as active ingredients.
또한, 본 발명은 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)를 유효성분으로 포함하는 이식편대숙주병(graft-versus-host disease, GVHD) 예방 및 치료용 약학 조성물을 제공한다.In addition, the present invention prevents graft-versus-host disease (GVHD) comprising myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) as active ingredients. And it provides a pharmaceutical composition for treatment.
또한, 본 발명은 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)를 유효성분으로 포함하는 면역 조절용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for immune regulation comprising myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) as active ingredients.
또한, 본 발명은 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)를 유효성분으로 포함하는 쇼그렌 증후군의 예방 및 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for preventing and improving Sjogren's syndrome, comprising myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) as active ingredients.
또한, 본 발명은 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)를 유효성분으로 포함하는 이식편대숙주병 예방 및 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for preventing and improving graft-versus-host disease, comprising myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as active ingredients. .
본 발명의 조성물은 Foxp3+Treg 세포 및IL-10 유도한 CD1d+CD5+ Breg 세포를 증가시키고, IL-17+CD4+T 세포를 억제시킴을 확인였는 바, MDSC 및 Treg의 병용 처리는 각 단독 처리보다 시너지 효과가 나타나 유의적인 면역 조절능이 존재함을 확인하였다. 또한, 상기 시너지 효과로 인하여, 쇼그렌 증후군 및 이식편대숙주병에 유의적인 치료효과가 확인되어, 관련 약학 및 식품산업에 유용하게 이용될 수 있다.It was confirmed that the composition of the present invention increases Foxp3 + Treg cells and IL-10-induced CD1d + CD5 + Breg cells, and inhibits IL-17 + CD4 + T cells. Combination treatment of MDSC and Treg is each treatment alone A more synergistic effect was observed, confirming the presence of a significant immunomodulatory ability. In addition, due to the synergistic effect, a significant therapeutic effect was confirmed for Sjogren's syndrome and graft-versus-host disease, and it can be usefully used in the related pharmaceutical and food industries.
도 1은 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 또는 조절 T 세포(regulatory T cell, Treg)의 단독 또는 병용 처리에 따른 Foxp3+Treg 세포의 조절을 확인한 도이다.
도 2는 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 또는 조절 T 세포(regulatory T cell, Treg)의 단독 또는 병용 처리에 따른 CD1d+CD5+ Breg 세포의 조절을 확인한 도이다.
도 3은 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 또는 조절 T 세포(regulatory T cell, Treg)의 단독 또는 병용 처리에 따른 IL-17+CD4+T 세포의 조절을 확인한 도이다.
도 4는 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 또는 조절 T 세포(regulatory T cell, Treg)의 단독 또는 병용 처리에 따른 이식편대숙주병 동물 모델에서 이의 치료 효과를 나타낸 도이다.
도 5는 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 또는 조절 T 세포(regulatory T cell, Treg)의 단독 또는 병용 처리에 따른 쇼그렌 증후군 동물 모델에서 이의 치료 효과를 나타낸 도이다.1 is a view confirming the regulation of Foxp3 + Treg cells according to treatment alone or in combination with bone marrow-derived suppressor cells (MDSCs, myeloid-derived suppressor cells) or regulatory T cells (regulatory T cells, Treg).
2 is a diagram confirming the regulation of CD1d+CD5+ Breg cells according to treatment alone or in combination with myeloid-derived suppressor cells (MDSCs) or regulatory T cells (Tregs).
3 is a view confirming the regulation of IL-17+CD4+T cells according to treatment alone or in combination with bone marrow-derived suppressor cells (MDSCs, myeloid-derived suppressor cells) or regulatory T cells (regulatory T cells, Treg).
4 is a view showing the therapeutic effect thereof in an animal model of graft-versus-host disease according to treatment alone or in combination with bone marrow-derived suppressor cells (MDSCs, myeloid-derived suppressor cells) or regulatory T cells (Tregs).
5 is a diagram showing the therapeutic effect thereof in an animal model of Sjogren's syndrome according to treatment alone or in combination with myeloid-derived suppressor cells (MDSCs) or regulatory T cells (Tregs).
본 발명은 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)를 유효성분으로 포함하는 면역 조절용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for immune regulation comprising myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as active ingredients.
또한 본 발명은 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)를 유효성분으로 포함하는 쇼그렌 증후군의 예방 및 치료용 약학 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing and treating Sjogren's syndrome comprising myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as active ingredients.
또한 본 발명은 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)를 유효성분으로 포함하는 이식편대숙주병(graft-versus-host disease, GVHD) 예방 및 치료용 약학 조성물을 제공한다.In addition, the present invention includes myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) as active ingredients for graft-versus-host disease (GVHD) prevention and A therapeutic pharmaceutical composition is provided.
본 발명의 약학 조성물에는 유효성분 이외에 보조제(adjuvant)를 추가로 포함할 수 있다. 상기 보조제는 당해 기술분야에 알려진 것이라면 어느 것이나 제한 없이 사용할 수 있으나, 예를 들어 프로인트(Freund)의 완전 보조제 또는 불완전 보조제를 더 포함하여 그 면역성을 증가시킬 수 있다. The pharmaceutical composition of the present invention may further include an adjuvant in addition to the active ingredient. The adjuvant may be used without limitation as long as it is known in the art, for example, Freund's complete adjuvant or incomplete adjuvant may be further included to increase the immunity thereof.
본 발명에 따른 약학 조성물은 유효성분을 약학적으로 허용된 담체에 혼입시킨 형태로 제조될 수 있다. 여기서, 약학적으로 허용된 담체는 제약 분야에서 통상 사용되는 담체, 부형제 및 희석제를 포함한다. 본 발명의 약학 조성물에 이용할 수 있는 약학적으로 허용된 담체는 이들로 제한되는 것은 아니지만, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로스, 메틸 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.The pharmaceutical composition according to the present invention may be prepared in a form in which the active ingredient is incorporated into a pharmaceutically acceptable carrier. Here, the pharmaceutically acceptable carrier includes carriers, excipients and diluents commonly used in the pharmaceutical field. Pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
본 발명의 약학 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀전, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다.The pharmaceutical composition of the present invention may be formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, or sterile injection solutions according to conventional methods, respectively. .
제제화할 경우에는 통상 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 그러한 고형 제제는 유효성분에 적어도 하나 이상의 부형제, 예를 들면 전분, 칼슘 카르보네이트, 수크로스, 락토오스, 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 일반적으로 사용되는 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수용성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수용성용제, 현탁제로는 프로필렌 글리콜, 폴리에틸렌 글리콜, 올리브유와 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 트윈(tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.In the case of formulation, it can be prepared using a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, surfactant, etc. commonly used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the active ingredient, for example, starch, calcium carbonate, sucrose, lactose, gelatin. It can be prepared by mixing and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid formulations for oral administration include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. can Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. As the base of the suppository, witepsol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
본 발명에 따른 약학 조성물은 개체에 다양한 경로로 투여될 수 있다. 투여의 모든 방식이 예상될 수 있는데, 예를 들면 경구, 정맥, 근육, 피하, 복강내 주사에 의해 투여될 수 있다.The pharmaceutical composition according to the present invention may be administered to an individual by various routes. Any mode of administration can be envisaged, for example, by oral, intravenous, intramuscular, subcutaneous, intraperitoneal injection.
본 발명에 따른 약학 조성물의 투여량은 개체의 연령, 체중, 성별, 신체 상태 등을 고려하여 선택된다. 상기 약학 조성물 중 포함되는 유효성분의 농도는 대상에 따라 다양하게 선택할 수 있음은 자명하며, 바람직하게는 약학 조성물에 0.01 ~ 5,000 ㎍/ml의 농도로 포함되는 것이다. 그 농도가 0.01 ㎍/ml 미만일 경우에는 약학 활성이 나타나지 않을 수 있고, 5,000 ㎍/ml를 초과할 경우에는 인체에 독성을 나타낼 수 있다.The dosage of the pharmaceutical composition according to the present invention is selected in consideration of the individual's age, weight, sex, physical condition, and the like. It is self-evident that the concentration of the active ingredient included in the pharmaceutical composition can be variously selected depending on the subject, and is preferably included in the pharmaceutical composition at a concentration of 0.01 to 5,000 μg/ml. If the concentration is less than 0.01 μg/ml, pharmaceutical activity may not appear, and if it exceeds 5,000 μg/ml, it may be toxic to the human body.
상기 약학 조성물은 다양한 경구 또는 비경구 투여 형태로 제형화될 수 있다.The pharmaceutical composition may be formulated in various oral or parenteral dosage forms.
경구 투여용 제형으로는 예를 들면 정제, 환제, 경질, 연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/ 또는 폴리에틸렌 글리콜)를 추가로 포함할 수 있다. 또한, 상기 정제는 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 트라가칸스, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제 및 감미제를 함유할 수 있다. 상기 제형은 통상적인 혼합, 과립화 또는 코팅 방법에 의해 제조될 수 있다.Formulations for oral administration include, for example, tablets, pills, hard, soft capsules, solutions, suspensions, emulsifiers, syrups, granules, and the like. crose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). In addition, the tablet may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and optionally starch, agar, alginic acid or a disintegrant such as its sodium salt or a boiling mixture and/or absorbent, coloring, flavoring and sweetening agent. The formulation may be prepared by conventional mixing, granulating or coating methods.
또한, 비경구 투여용 제형의 대표적인 것은 주사용 제제이며, 주사용 제제의 용매로서 물, 링거액, 등장성 생리식염수 또는 현탁액을 들 수 있다. 상기 주사용 제제의 멸균 고정 오일은 용매 또는 현탁 매질로서 사용할 수있으며 모노-, 디-글리세라이드를 포함하여 어떠한 무자극성 고정오일도 이러한 목적으로 사용될 수 있다.In addition, a representative formulation for parenteral administration is an injection formulation, and examples of the solvent for the injection formulation include water, Ringer's solution, isotonic saline, or suspension. The sterile, fixed oil of the injectable preparation may be used as a solvent or suspending medium, and any non-irritating fixed oil including mono- and di-glycerides may be used for this purpose.
또한, 상기 주사용 제제는 올레산과 같은 지방산을 사용할 수 있다.In addition, the injection preparation may use a fatty acid such as oleic acid.
또한, 본 발명은 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)를 유효성분으로 포함하는 면역 조절용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for immune regulation comprising myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) as active ingredients.
또한, 본 발명은 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)를 유효성분으로 포함하는 쇼그렌 증후군의 예방 및 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for preventing and improving Sjogren's syndrome, comprising myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) as active ingredients.
또한, 본 발명은 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)를 유효성분으로 포함하는 이식편대숙주병 예방 및 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for preventing and improving graft-versus-host disease, comprising myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as active ingredients. .
본 발명의 식품 조성물은 유효성분을 함유하는 것 외에 통상의 식품 조성물과 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다.In addition to containing the active ingredient, the food composition of the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients like a conventional food composition.
상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨,소르비톨, 에리트리톨 등의 당알콜이다. 상술한 향미제는 천연 향미제 (타우마틴), 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등) 및 합성 향미제 (사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 본 발명의 식품 조성물은 상기 약학적 조성물과 동일한 방식으로 제제화되어 기능성 식품으로 이용하거나, 각종 식품에 첨가할 수 있다. 본 발명의 조성물을 첨가할 수 있는 식품으로는 예를 들어, 음료류, 육류, 초코렛, 식품류, 과자류, 피자, 라면, 기타 면류, 껌류, 사탕류, 아이스크림류, 알코올 음료류, 비타민 복합제 및 건강보조식품류 등이 있다.Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. The above-mentioned flavoring agents can advantageously use natural flavoring agents (Taumatine), stevia extract (eg rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.). The food composition of the present invention may be formulated in the same manner as the pharmaceutical composition and used as a functional food or added to various foods. Foods to which the composition of the present invention can be added include, for example, beverages, meat, chocolate, foods, confectionery, pizza, ramen, other noodles, gums, candy, ice cream, alcoholic beverages, vitamin complexes and health supplements. There is this.
또한 상기 식품 조성물은 유효성분인 추출물 외에 여러 가지 영양제, 비타민, 광물 (전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제 (치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 식품 조성물은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.In addition, the food composition includes, in addition to the active ingredient extract, various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and thickeners (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. In addition, the food composition of the present invention may contain natural fruit juice and pulp for the production of fruit juice beverages and vegetable beverages.
본 발명의 기능성 식품 조성물은 정제,캅셀, 분말, 과립, 액상, 환 등의 형태로 제조 및 가공될 수 있다. 본 발명에서 '건강기능성 식품 조성물'이라 함은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 말하며, 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다. 본 발명의 건강기능식품은 통상의 식품 첨가물을 포함할 수 있으며, 식품 첨가물로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전청에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다. 상기 '식품 첨가물 공전'에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼슘, 니코틴산, 계피산 등의 화학적 합성물; 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물; L-글루타민산나트륨 제제, 면류첨가알칼리제, 보존료 제제, 타르색소제제 등의 혼합제제류 등을 들 수 있다. 예를 들어, 정제 형태의 건강기능식품은 본 발명의 유효성분을 부형제, 결합제, 붕해제 및 다른 첨가제와 혼합한 혼합물을 통상의 방법으로 과립화한 다음, 활택제 등을 넣어 압축성형하거나, 상기 혼합물을 직접 압축 성형할 수 있다. 또한 상기 정제 형태의 건강기능식품은 필요에 따라 교미제 등을 함유할 수도 있다. 캅셀 형태의 건강기능식품 중 경질 캅셀제는 통상의 경질 캅셀에 본 발명의 유효성분을 부형제 등의 첨가제와 혼합한 혼합물을 충진하여 제조할 수 있으며, 연질 캅셀제는 본 발명의 유효성분을 부형제 등의 첨가제와 혼합한 혼합물을 젤라틴과 같은 캅셀기제에 충진하여 제조할 수 있다. 상기 연질 캅셀제는 필요에 따라 글리세린 또는 소르비톨 등의 가소제, 착색제, 보존제 등을 함유할 수 있다. 환 형태의 건강기능식품은 본 발명의 유효성분과 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 성형하여 조제할 수 있으며, 필요에 따라 백당이나 다른 제피제로 제피할 수 있으며, 또는 전분, 탈크와 같은 물질로 표면을 코팅할 수도 있다. 과립 형태의 건강기능식품은 본 발명의 유효성분의 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 입상으로 제조할 수 있으며, 필요에 따라 착향제, 교미제 등을 함유할 수 있다.The functional food composition of the present invention may be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, and the like. In the present invention, the term 'health functional food composition' refers to food manufactured and processed using raw materials or ingredients useful for the human body according to Act No. 6727 of the Health Functional Food Act, and It refers to ingestion for the purpose of obtaining useful effects for health purposes, such as regulating nutrients or physiological effects. The health functional food of the present invention may contain normal food additives, and unless otherwise specified, whether it is suitable as a food additive is related to the item according to the general rules and general test method of food additives approved by the Food and Drug Administration. It is judged according to the standards and standards. The items listed in the 'Food Additives Code' include, for example, chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, high pigment, and guar gum; Mixed preparations, such as a sodium L-glutamate preparation, a noodle-added alkali agent, a preservative preparation, and a tar color preparation, etc. are mentioned. For example, a health functional food in tablet form is granulated by a conventional method by mixing a mixture of the active ingredient of the present invention with an excipient, binder, disintegrant and other additives, followed by compression molding by putting a lubricant, etc., or The mixture may be compression molded directly. In addition, the health functional food in the form of tablets may contain a corrosive agent and the like, if necessary. Among health functional foods in capsule form, hard capsules can be prepared by filling a mixture of the active ingredient of the present invention with additives such as excipients in a conventional hard capsule. It can be prepared by filling the mixture mixed with the capsule base such as gelatin. The soft capsules may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, if necessary. A health functional food in the form of a ring can be prepared by molding a mixture of the active ingredient of the present invention with an excipient, a binder, a disintegrant, etc. by a known method, Alternatively, the surface may be coated with a material such as starch or talc. The health functional food in the form of granules can be prepared in granular form by a conventionally known method by mixing a mixture of the active ingredient excipients, binders, disintegrants, etc. of the present invention, and may contain flavoring agents, flavoring agents, etc. as needed can
이하 본 발명을 실시예에 의하여 더욱 상세하게 설명한다. 이들 실시예는 단지 본 발명을 보다 구체적으로 설명한다.Hereinafter, the present invention will be described in more detail by way of Examples. These examples merely illustrate the invention in more detail.
실시예 1. 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)의 병용 처리에 따른 면역 조절능 향상Example 1. Improving immune regulation ability according to the combined treatment of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg)
1-1. MDSC 및 Treg 병용 처리에 따른 Foxp3+Treg 세포 조절 확인1-1. Confirmation of Foxp3+Treg cell regulation following MDSC and Treg combination treatment
Foxp3+Treg 세포의 조절을 확인하기 위하여, MDSC 또는 Treg 단독 처리 배양군과, MDSC 및 Treg의 병용 처리 배양군을 두어 배양하였다. 72시간 후 Foxp3+Treg 세포 확인 위한 flow cytometry analysis 진행하였다. In order to confirm the regulation of Foxp3+Treg cells, a culture group treated with MDSC or Treg alone and a culture group treated with MDSC and Treg were placed and cultured. After 72 hours, flow cytometry analysis was performed to confirm Foxp3+Treg cells.
도 1에 나타낸 바와 같이, MDSC 또는 Treg 단독 처리군보다, MDSC 및 Treg의 병용 처리군에서 Foxp3+Treg 세포가 유의적으로 증가하는 바, 면역 조절능이 유의적으로 뛰어남을 확인하였다.As shown in FIG. 1, Foxp3+Treg cells significantly increased in the combined treatment group of MDSC and Treg than in the MDSC or Treg alone treatment group, confirming that the immune modulatory ability was significantly superior.
1-2. MDSC 및 Treg 병용 처리에 따른 IL-10 유도한 CD1d+CD5+ Breg 세포 조절 확인1-2. Confirmation of IL-10-induced CD1d+CD5+ Breg cell regulation following MDSC and Treg combination treatment
IL-10 유도한 CD1d+CD5+ Breg 세포의 조절을 확인하기 위하여, MDSC 또는 Treg 단독 처리 배양군과, MDSC 및 Treg의 병용 처리 배양군을 두어 배양하였다. 72시간 후 IL-10 유도한 CD1d+CD5+ Breg 세포 확인 위한 flow cytometry analysis 진행하였다.In order to confirm the regulation of IL-10-induced CD1d+CD5+ Breg cells, a culture group treated with MDSC or Treg alone and a culture group treated with MDSC and Treg were cultured. After 72 hours, flow cytometry analysis was performed to confirm IL-10-induced CD1d+CD5+ Breg cells.
도 2에 나타낸 바와 같이, MDSC 또는 Treg 단독 처리군보다, MDSC 및 Treg의 병용 처리군에서 IL-10 유도한 CD1d+CD5+ Breg 세포가 유의적으로 증가함을 확인하여, 면역 조절능이 향상됨을 확인하였다. As shown in FIG. 2 , it was confirmed that IL-10-induced CD1d+CD5+ Breg cells were significantly increased in the combined treatment group of MDSC and Treg than in the MDSC or Treg alone treatment group, thereby confirming that the immunomodulatory ability was improved. .
1-3. MDSC 및 Treg 병용 처리에 따른 IL-17+CD4+T 세포 조절 확인1-3. Confirmation of IL-17+CD4+T cell regulation following MDSC and Treg combination treatment
IL-17+CD4+T 세포의 조절을 확인하기 위하여, MDSC 또는 Treg 단독 처리 배양군과, MDSC 및 Treg의 병용 처리 배양군을 두어 배양하였다. 72시간 후 IL-17+CD4+T 세포 확인 위한 flow cytometry analysis 진행하였다.In order to confirm the regulation of IL-17+CD4+T cells, a culture group treated with MDSC or Treg alone and a culture group treated with MDSC and Treg were placed and cultured. After 72 hours, flow cytometry analysis was performed to confirm IL-17+CD4+T cells.
도 3에 나타낸 바와 같이, MDSC 또는 Treg 단독 처리군보다, MDSC 및 Treg의 병용 처리군에서 IL-17+CD4+T 세포가 유의적으로 감소함을 확인하여, 면역 조절능이 우수함을 확인하였다. As shown in FIG. 3 , it was confirmed that IL-17+CD4+T cells were significantly reduced in the combined treatment group of MDSC and Treg than in the MDSC or Treg alone treatment group, confirming that the immune modulatory ability was excellent.
실시예 2 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)의 병용 처리에 따른 이식거부질환 치료 효과Example 2 Treatment effect of transplant rejection disease according to the combined treatment of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg)
이식거부질환 중 하나인 이식편대숙주병(graft-versus-host disease, GVHD) 동물모델을 제작하기 위하여, B6 donor의 BM (5x106)과 비장세포(1x107) 세포를 B/c 마우스(700cGy방사선조사) 마우스 주입하여 이식거부질환을 유도하였다. 유도 후 3주 동안 MDSC(5x105) 단독 처리군, Treg (1x106)세포 단독 처리군, MDSC 및 Treg의 병용 처리군(MT)을 두어 마우스에 정맥 주사하였다.To produce an animal model for graft-versus-host disease (GVHD), one of the transplant rejection diseases, B6 donor BM (5x10 6 ) and splenocytes (1x10 7 ) cells were transfected with B/c mice (700 cGy). Irradiation) was injected into mice to induce transplant rejection disease. For 3 weeks after induction, MDSC (5x10 5 ) alone treatment group, Treg (1x10 6 ) cell alone treatment group, MDSC and Treg combination treatment group (MT) were administered and intravenously injected into mice.
도 4에 나타낸 바와 같이, MDSC 또는 Treg 단독 처리군보다, MDSC 및 Treg의 병용 처리군(MT)에서 마우스의 GVHD 지수가 더 낮음을 확인하여, 본 발명의 MDSC 및 Treg 병용처리는 시너지 효과가 나타나 이식편대숙주병의 치료에 효과적임을 확인하였다.As shown in Figure 4, it was confirmed that the GVHD index of mice in the combined treatment group (MT) of MDSC and Treg was lower than that of MDSC or Treg alone treatment group. It was confirmed to be effective in the treatment of graft-versus-host disease.
실시예 3. 골수유래억제세포(MDSC, myeloid-derived suppressor cells) 및 조절 T 세포(regulatory T cell, Treg)의 병용 처리에 따른 쇼그렌 증후군 치료 효과Example 3. Sjogren's Syndrome Treatment Effect according to Combination Treatment of Myeloid-derived Suppressor Cells (MDSC) and Regulatory T Cells (Treg)
쇼그렌증후군 모델인 NOD마우스에 MDSC(5x105) 단독 처리군, Treg (1x106)세포 단독 처리군, MDSC 및 Treg의 병용 처리군(MT)을 두어 마우스에 정맥 주사하여, 쇼그렌증후군의 발병척도인 침량분비능을 조사하였다.MDSC (5x10 5 ) alone treatment group, Treg (1x10 6 ) cell alone treatment group, MDSC and Treg combination treatment group (MT) were placed in NOD mice, a model of Sjogren's syndrome, and intravenously injected into the mice. The salivary secretion was investigated.
도 5에 나타낸 바와 같이, MDSC 또는 Treg 단독 처리군보다, MDSC 및 Treg의 병용 처리군(MT)에서 침량분비능이 의미있게 증가됨을 확인하여, 시너지 효과가 나타나 쇼그렌 증후군의 치료효과가 나타남을 확인하였다. As shown in Figure 5, it was confirmed that the salivary secretion ability was significantly increased in the MDSC and Treg combination treatment group (MT) than in the MDSC or Treg alone treatment group, and it was confirmed that the synergistic effect appeared to show the therapeutic effect of Sjogren's syndrome. .
Claims (4)
상기 골수유래억제세포 및 조절 T 세포의 혼합비는 1:2의 세포수인 것이고,
Foxp3+Treg 세포 및 IL-10 유도한 CD1d+CD5+ Breg 세포를 증가시키고, IL-17+CD4+T 세포를 억제시키고,
침량분비능을 증가시키는 것인,
쇼그렌 증후군의 예방 및 치료용 약학 조성물.Contains myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) as active ingredients,
The mixing ratio of the bone marrow-derived suppressor cells and regulatory T cells is a cell number of 1:2,
Increase Foxp3 + Treg cells and IL-10 induced CD1d + CD5 + Breg cells, inhibit IL-17 + CD4 + T cells,
to increase salivary secretion,
A pharmaceutical composition for the prevention and treatment of Sjogren's syndrome.
상기 골수유래억제세포 및 조절 T 세포의 혼합비는 1:2의 세포수인 것이고,
Foxp3+Treg 세포 및 IL-10 유도한 CD1d+CD5+ Breg 세포를 증가시키고, IL-17+CD4+T 세포를 억제시키고,
침량분비능을 증가시키는 것인,
쇼그렌 증후군의 예방 및 개선용 건강기능식품 조성물.Contains myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) as active ingredients,
The mixing ratio of the bone marrow-derived suppressor cells and regulatory T cells is a cell number of 1:2,
Increase Foxp3 + Treg cells and IL-10 induced CD1d + CD5 + Breg cells, inhibit IL-17 + CD4 + T cells,
to increase salivary secretion,
A health functional food composition for preventing and improving Sjogren's syndrome.
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| KR1020210034472A KR102364723B1 (en) | 2018-03-12 | 2021-03-17 | Composition for modulating immunity comprising myeloid-derived suppressor cells and regulatory T cell |
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| KR20130106320A (en) * | 2012-03-19 | 2013-09-27 | 가톨릭대학교 산학협력단 | Composition for treatment or prevention of transplant rejection or autoimmune diseases comprising myeloid derived suppressor cell |
| KR101436728B1 (en) * | 2012-03-20 | 2014-09-02 | 가톨릭대학교 산학협력단 | Composition for preventing or treating immune disease comprising Myeloid derived suppressor cells and rebamipide |
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| Cell Reports, Vol. 17, pp. 3219-3232 (2016)* |
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