KR20240053223A - Composition for differentiating peripheral blood monocytes into regulatory t cells - Google Patents
Composition for differentiating peripheral blood monocytes into regulatory t cells Download PDFInfo
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- KR20240053223A KR20240053223A KR1020220133076A KR20220133076A KR20240053223A KR 20240053223 A KR20240053223 A KR 20240053223A KR 1020220133076 A KR1020220133076 A KR 1020220133076A KR 20220133076 A KR20220133076 A KR 20220133076A KR 20240053223 A KR20240053223 A KR 20240053223A
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- ethynyl
- tetrahydro
- benzoic acid
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Abstract
본 발명은 말초혈액단핵구를 조절 T 세포로 분화시키기 위한 조성물 및 상기 조성물을 사용하여 제조된 조절 T 세포의 의약 용도에 관한 것이다. 상기 조성물을 사용하면 말초혈액단핵구를 조절 T 세포로 효과적으로 분화시킬 수 있으며 조절 T 세포의 증식, 활성화 및 호밍 또한 촉진할 수 있다.The present invention relates to a composition for differentiating peripheral blood monocytes into regulatory T cells and the medicinal use of regulatory T cells produced using the composition. Using the composition, peripheral blood monocytes can be effectively differentiated into regulatory T cells, and proliferation, activation, and homing of regulatory T cells can also be promoted.
Description
본 발명은 말초혈액단핵구를 조절 T 세포로 분화시키기 위한 조성물 및 상기 조성물을 사용하여 제조된 조절 T 세포의 의약 용도, 조절 T 세포의 분화, 증식 또는 호밍 촉진용 조성물에 관한 것이다.The present invention relates to a composition for differentiating peripheral blood monocytes into regulatory T cells, the medicinal use of regulatory T cells prepared using the composition, and a composition for promoting differentiation, proliferation, or homing of regulatory T cells.
조절 T 세포(Regulatory T cells, Treg cells)는 T 세포의 소집단(Subpopulation)으로서 면역반응 조절과정에서 매우 중요한 역할을 한다. 또한 조절 T 세포는 사이토카인, 성장인자 등과 같은 다양한 물질을 분비하여 주변 세포에 영향을 줄 수 있다. 사이토카인은 면역 (Immunity), 염증 (Inflammation), 조혈 (Hematopoiesis) 등을 조절하는 신호전달분자의 카테고리로 면역세포 서로간의 상호작용 및 정보전달에 필수적인 물질이며 세포이동, 증식 및 염증성 반응에 관여한다.Regulatory T cells (Treg cells) are a subpopulation of T cells and play a very important role in regulating immune responses. Additionally, regulatory T cells can influence surrounding cells by secreting various substances such as cytokines and growth factors. Cytokines are a category of signaling molecules that regulate immunity, inflammation, and hematopoiesis. They are essential substances for interaction and information transfer between immune cells, and are involved in cell migration, proliferation, and inflammatory reactions. .
한편, 궤양성 대장염 (Ulceratice colitis, UC)과 크론병 (Crohn's disease, CD)으로 알려져 있는 염증성 장질환 (Inflammatory bowel disease, IBD)은 만성적 질환으로 재발과 악화를 반복함으로써 환자 삶의 질을 악화시킬 뿐만 아니라 대장암으로 진행될 위험성을 2~8배 이상 높인다 (비특허문헌 1 및 2). IBD의 전통적인 치료제로는 아르세날 (Arsenal), 아미노살리실산 (Aminosalicylate), 스테로이드, 면역억제제 (Cyclosporine, azathioprine, 6-mercaptopurine) 등이 있으나, 고용량으로 사용하면 심각한 부작용이 발생하기 때문에 장기적인 사용이 어려운 상황이다. 이에 부작용 없이 안전하게 사용할 수 있는 효과적인 IBD 치료제 개발이 절실하다. 이에 조절 T 세포를 염증성 장 질환 치료에 활용하고자 하는 연구가 진행되고 있다 (비특허문헌 3).Meanwhile, inflammatory bowel disease (IBD), also known as ulcerative colitis (UC) and Crohn's disease (CD), is a chronic disease that can worsen the patient's quality of life through repeated recurrence and worsening. In addition, it increases the risk of developing colon cancer by more than 2 to 8 times (Non-patent Documents 1 and 2). Traditional treatments for IBD include Arsenal, aminosalicylate, steroids, and immunosuppressants (Cyclosporine, azathioprine, 6-mercaptopurine), but serious side effects occur when used in high doses, making long-term use difficult. am. Therefore, there is an urgent need to develop an effective IBD treatment that can be used safely without side effects. Accordingly, research is underway to utilize regulatory T cells to treat inflammatory bowel disease (Non-patent Document 3).
상기와 같은 상황에서 본 발명자들은 조절 T 세포를 생산할 수 있는 방법을 연구하였고, 말초혈액단핵구에 특정 물질을 처리하여 배양하면 조절 T 세포로 분화시킬 수 있음을 확인하였다.In the above situation, the present inventors studied a method for producing regulatory T cells, and confirmed that peripheral blood monocytes could be differentiated into regulatory T cells by treating them with a specific substance and culturing them.
따라서, 본 발명의 목적은 말초혈액단핵구를 조절 T 세포로 분화시키기 위한 조성물 및 이로부터 얻어진 조절 T 세포의 의약 용도를 제공하는 것이다.Accordingly, the purpose of the present invention is to provide a composition for differentiating peripheral blood monocytes into regulatory T cells and the medicinal use of the regulatory T cells obtained therefrom.
또한, 해당 물질들은 조절 T 세포의 증식, 활성화 및 호밍 능력을 촉진시키는 효과도 나타내었다.Additionally, these substances also showed the effect of promoting the proliferation, activation, and homing ability of regulatory T cells.
따라서, 본 발명의 다른 목적은 조절 T 세포의 증식, 활성화 및 호밍 촉진용 조성물을 제공하는 것이다.Accordingly, another object of the present invention is to provide a composition for promoting proliferation, activation and homing of regulatory T cells.
상기 목적을 달성하기 위하여 본 발명의 일 양상은 3-[2-(5,6,7,8-테트라하이드로-5,5,8,8-테트라메틸-2-나프탈레닐)에티닐]벤조익산 (3-[2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoic acid, EC19), 4-[2-(5,6,7,8-테트라하이드로-5,5,8,8-테트라메틸-2-나프탈레닐)에티닐]벤조익산 (4-[2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl)]-benzoic acid, EC23), 4-[2-[1,2,3,4-테트라하이드로-4,4-디메틸-1-(1-메틸에틸)-6-퀴놀리닐]에티닐]벤조익산 (4-[2-[1,2,3,4-Tetrahydro-4,4-dimethyl-1-(1-methylethyl)-6-quinolinyl]ethynyl]benzoic acid, DC271), 전환성장인자-β (Transforming growth factor-β, TGF-β), 템시롤리무스 (Temsirolimus), 에버롤리무스 (Everolimus), 사모톨리십 (Samotolisib), N-{4-[3-(1-메틸-시클로헥실메틸)-2,4-디옥소-티아졸리딘-5-일리덴메틸]-페닐}-4-니트로-3-트리플루오로메틸-벤젠술폰아미드 (N-{4-[3-(1-Methyl-cyclohexylmethyl)-2,4-dioxo-thiazolidin-5-ylidenemethyl]-phenyl}-4-nitro-3-trifluoromethyl-benzenesulfonamide, OSU-53), 부티레이트 (Butyrate) 및 프로스타글란딘 E2 (Prostaglandin E2, PGE2)로 이루어진 군에서 선택되는 1종 이상의 물질을 포함하는 말초혈액단핵구를 조절 T 세포로 분화시키기 위한 조성물 및 키트를 제공한다.In order to achieve the above object, one aspect of the present invention is 3-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzo Iksan (3-[2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoic acid, EC19), 4-[2-(5,6, 7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoic acid (4-[2-(5,6,7,8-Tetrahydro-5,5, 8,8-tetramethyl-2-naphthalenyl)ethynyl)]-benzoic acid, EC23), 4-[2-[1,2,3,4-tetrahydro-4,4-dimethyl-1-(1-methylethyl) )-6-quinolinyl]ethynyl]benzoic acid (4-[2-[1,2,3,4-Tetrahydro-4,4-dimethyl-1-(1-methylethyl)-6-quinolinyl]ethynyl] benzoic acid, DC271), Transforming growth factor-β (TGF-β), Temsirolimus, Everolimus, Samotolisib, N-{4-[ 3-(1-methyl-cyclohexylmethyl)-2,4-dioxo-thiazolidin-5-ylidenemethyl]-phenyl}-4-nitro-3-trifluoromethyl-benzenesulfonamide (N- {4-[3-(1-Methyl-cyclohexylmethyl)-2,4-dioxo-thiazolidin-5-ylidenemethyl]-phenyl}-4-nitro-3-trifluoromethyl-benzenesulfonamide, OSU-53), Butyrate and Provided are compositions and kits for differentiating peripheral blood monocytes into regulatory T cells containing at least one substance selected from the group consisting of prostaglandin E2 (PGE2).
본 발명에서, 조절 T 세포 (Regulatory T cells, Tregs)는 CD4+CD25+CD127-를 표지자로 사용하고, T 세포 반응을 조절할 수 있는 세포를 말한다. 상기 조절 T 세포는 비정상적으로 활성화된 면역세포의 기능을 억제하여 염증 반응을 제어하는 특성이 있어서 염증 질환에 대한 치료 효과를 나타낼 수 있다.In the present invention, regulatory T cells (Tregs) use CD4 + CD25 + CD127 - as markers and refer to cells that can regulate T cell responses. The regulatory T cells have the property of controlling inflammatory responses by suppressing the function of abnormally activated immune cells, so they can exhibit a therapeutic effect on inflammatory diseases.
본 발명에서, 말초혈액단핵구 (Peripheral blood mononuclear cell, PBMC)는 둥근 핵을 가진 말초혈액세포로 본 발명에서 말초혈액단핵구는 통상적으로 사용되는 의미인 말초혈액에서 분리된 단핵구 (Mononuclear cell)를 의미한다.In the present invention, peripheral blood mononuclear cells (PBMC) are peripheral blood cells with round nuclei. In the present invention, peripheral blood mononuclear cells refer to mononuclear cells isolated from peripheral blood, which is the commonly used meaning. .
본 발명에서, 3-[2-(5,6,7,8-테트라하이드로-5,5,8,8-테트라메틸-2-나프탈레닐)에티닐]벤조익산은 상업적으로 EC19라는 이름으로 판매되고 있는 합성 레티노이드 (Retinoid)로 ATRA (Retinoid all-trans-retinoic acid)의 유사체 (Analog)이다. In the present invention, 3-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoic acid is commercially available under the name EC19. It is a commercially available synthetic retinoid and is an analog of ATRA (Retinoid all-trans-retinoic acid).
본 발명에서, 4-[2-(5,6,7,8-테트라하이드로-5,5,8,8-테트라메틸-2-나프탈레닐)에티닐]벤조익산은 EC23이라는 이름으로도 알려져 있는 합성 레티노이드로 ATRA의 유사체이다. 이는 인간 만능 배아 줄기세포를 신경으로 분화시킬 수 있는 것으로도 알려져 있다.In the present invention, 4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoic acid is also known as EC23. It is a synthetic retinoid and is an analogue of ATRA. It is also known that it can differentiate human pluripotent embryonic stem cells into neurons.
본 발명에서, 4-[2-[1,2,3,4-테트라하이드로-4,4-디메틸-1-(1-메틸에틸)-6-퀴놀리닐]에티닐]벤조익산은 DC271로 더 많이 알려져 있으며 형광 레티노익산 (Fluorescent retinoic acid analog)으로 역시 ATRA의 유사체이다.In the present invention, 4-[2-[1,2,3,4-tetrahydro-4,4-dimethyl-1-(1-methylethyl)-6-quinolinyl]ethynyl]benzoic acid is represented by DC271. It is better known as fluorescent retinoic acid analog, which is also an analog of ATRA.
본 발명에서, 템시롤리무스는 mTOR (Mammalian target of rapamycin) 억제제로 토리셀 (Torisel)이라는 이름으로 판매되고 있는 신장암 치료제이다.In the present invention, temsirolimus is an mTOR (Mammalian target of rapamycin) inhibitor and is a treatment for kidney cancer sold under the name Torisel.
본 발명의 실시예에서, DC271 또는 템시롤리무스를 포함하는 배지에서 말초혈액단핵구를 배양한 결과, 조절 T 세포의 마커 CD4 및 CD25의 발현이 증가하는 것을 확인하였다.In an example of the present invention, as a result of culturing peripheral blood mononuclear cells in a medium containing DC271 or temsirolimus, it was confirmed that the expression of regulatory T cell markers CD4 and CD25 increased.
따라서, 본 발명의 다른 양상은 분리된 말초혈액단핵구를 3-[2-(5,6,7,8-테트라하이드로-5,5,8,8-테트라메틸-2-나프탈레닐)에티닐]벤조익산 (EC19), 4-[2-(5,6,7,8-테트라하이드로-5,5,8,8-테트라메틸-2-나프탈레닐)에티닐]벤조익산 (EC23), 4-[2-[1,2,3,4-테트라하이드로-4,4-디메틸-1-(1-메틸에틸)-6-퀴놀리닐]에티닐]벤조익산 (DC271) 및 템시롤리무스로 이루어진 군에서 선택되는 1종 이상의 물질을 포함하는 조성물에서 배양하는 단계를 포함하는 말초혈액단핵구를 조절 T 세포로 분화시키는 방법을 제공한다.Accordingly, another aspect of the present invention is to treat isolated peripheral blood mononuclear cells with 3-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl ]benzoic acid (EC19), 4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoic acid (EC23), 4-[2-[1,2,3,4-tetrahydro-4,4-dimethyl-1-(1-methylethyl)-6-quinolinyl]ethynyl]benzoic acid (DC271) and temsirolimus It provides a method of differentiating peripheral blood monocytes into regulatory T cells, comprising culturing in a composition containing one or more substances selected from the group consisting of.
본 발명에서 "배양"은 생물체나 생물체의 일부 (기관·조직·세포 등)를 적당히 인공적으로 조절한 환경 조건에서 생육시키는 것을 의미한다. In the present invention, “culture” means growing an organism or part of an organism (organs, tissues, cells, etc.) under appropriately artificially controlled environmental conditions.
또한, 본 발명에서 "배지"는 미생물이나 세포, 혹은 이끼 같은 작은 식물 등을 증식시키기 위해 고안된 액체나 겔 (Gel) 상태의 영양원을 의미한다. 배지는 배양할 세포의 종류에 따라 각기 다른 종류의 배지를 사용한다. Additionally, in the present invention, “medium” refers to a nutrient source in a liquid or gel state designed to grow microorganisms, cells, or small plants such as moss. Different types of media are used depending on the type of cells to be cultured.
본 발명에 있어서, 상기 배지는 세포 배양에 이용될 수 있고, 상기 배지는 DMEM (Dulbecco's Modified Eagle's Medium), MEM (Minimal Essential Medium), BME (Basal Medium Eagle), RPMI, MEM-α (Minimal Essential Medium-α), G-MEM (Glasgow's Minimal Essential Medium), IMDM (Iscove's Modified Dulbecco's Medium), MacCoy's 5A 배지, AmnioMax complete 배지, AminoMax Ⅱ complete 배지, EBM (Endothelial Basal Medium) 배지, Chang's 배지, KBM, i-Medium 및 X-Vivo 배지로 이루어진 군으로부터 선택되는 하나 이상을 포함하는 배지 일 수 있으나, 이에 제한되지 않는다.In the present invention, the medium can be used for cell culture, and the medium is DMEM (Dulbecco's Modified Eagle's Medium), MEM (Minimal Essential Medium), BME (Basal Medium Eagle), RPMI, MEM-α (Minimal Essential Medium) -α), G-MEM (Glasgow's Minimal Essential Medium), IMDM (Iscove's Modified Dulbecco's Medium), MacCoy's 5A medium, AmnioMax complete medium, AminoMax Ⅱ complete medium, EBM (Endothelial Basal Medium) medium, Chang's medium, KBM, i- It may be a medium containing one or more selected from the group consisting of Medium and X-Vivo medium, but is not limited thereto.
본 발명의 구체예에 따르면, 상기 배양은 1일 내지 30일, 바람직하게는 1일 내지 15일 동안 이루어질 수 있다. 배양 과정에서, 조절 T 세포의 분화를 유도하는 물질은 배지에 주기적으로 첨가될 수 있다.According to an embodiment of the present invention, the culture may be performed for 1 to 30 days, preferably 1 to 15 days. During the culture process, substances that induce differentiation of regulatory T cells may be periodically added to the medium.
본 발명은 또한, 본 발명에 따라 얻어진 조절 T 세포를 유효성분으로 포함하는 염증성 장 질환 예방 또는 치료용 약학 조성물을 제공한다.The present invention also provides a pharmaceutical composition for preventing or treating inflammatory bowel disease containing regulatory T cells obtained according to the present invention as an active ingredient.
본 명세서에서 사용된 용어, "유효성분"이란 의약품 또는 의약외품의 효과를 발휘시키는 성분을 의미하는 것으로, 본 발명에서는 자가면역 질환 개선 및 치료 활성 효과를 발휘시키는 성분을 의미한다.As used herein, the term “active ingredient” refers to an ingredient that exerts the effect of a drug or quasi-drug, and in the present invention, it refers to an ingredient that exerts an autoimmune disease improvement and therapeutic effect.
본 명세서에서 사용된 용어, "치료"란 본 발명의 조절 T 세포를 함유하는 조성물의 투여로 자가면역 질환의 증세가 호전되거나 완치되는 모든 행위를 의미한다.As used herein, the term “treatment” refers to any action in which symptoms of an autoimmune disease are improved or completely cured by administration of a composition containing regulatory T cells of the present invention.
본 발명에서 사용된 용어 "약학 조성물"은 질병 치료 등을 목적으로 인체에 투여하는 의약품을 의미한다.The term “pharmaceutical composition” used in the present invention refers to a medicine administered to the human body for the purpose of treating diseases, etc.
본 명세서에서, "염증성 장 질환"이란 장에 발생하는 원인 불명의 만성적인 염증을 뜻하며 복통, 설사, 혈변, 체중 감소 등의 증상이 보통 수개월 간 나타난다. 통상적으로는 특발성 염증성 장질환인 궤양성 대장염과 크론병을 지칭한다. 염증성 장질환의 발병 원인에 대해서는 아직까지 알려진 것이 많지 않아 뚜렷한 예방법도 없는 실정으로 단지 유전, 환경, 면역 등 여러 요인이 복합적으로 작용할 것이라고 추측되고 있다.As used herein, “inflammatory bowel disease” refers to chronic inflammation of unknown cause that occurs in the intestines, and symptoms such as abdominal pain, diarrhea, bloody stool, and weight loss usually appear for several months. It usually refers to ulcerative colitis and Crohn's disease, which are idiopathic inflammatory bowel diseases. As not much is known about the cause of inflammatory bowel disease and there is no clear prevention method, it is assumed that several factors such as genetics, environment, and immunity play a combined role.
궤양성 대장염은 염증이 대장에만 국한되어 생기고 주로 장 점막의 얕은 부분에 연속적으로 분포하며 대표적인 증상은 혈변이다. 크론병은 입부터 항문까지 소화관 전체에 걸쳐 염증이 발생할 수 있고 염증이 산발적으로 여러 곳에 퍼져 있으며, 깊은 궤양을 동반한다. 복통과 체중 감소가 주된 증상이다.Ulcerative colitis occurs when inflammation is limited to the large intestine and is mainly distributed continuously in the shallow part of the intestinal mucosa. The representative symptom is bloody stool. Crohn's disease can cause inflammation throughout the digestive tract, from the mouth to the anus, and the inflammation spreads sporadically to several places and is accompanied by deep ulcers. Abdominal pain and weight loss are the main symptoms.
본 발명에서, 상기 염증성 장 질환은 크론병 또는 궤양성 대장염 (Ulceratice colitis)일 수 있다.In the present invention, the inflammatory bowel disease may be Crohn's disease or ulcerative colitis.
조절 T 세포는 항염증 물질인 IL-10 및 TGF-β를 분비하므로 과도한 염증에 의한 염증성 장 질환을 치료 및/또는 개선할 수 있다.Regulatory T cells secrete anti-inflammatory substances IL-10 and TGF-β, so they can treat and/or improve inflammatory bowel disease caused by excessive inflammation.
상기 약학 조성물은 목적 조직에 도달할 수 있는 한 경구 또는 비경구의 다양한 경로를 통하여 투여될 수 있다. 비경구 투여, 예를 들어 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 국소 투여, 비내 투여, 폐내 투여, 직장내 투여될 수 있으나, 이에 제한되지 않는다.The pharmaceutical composition can be administered through various oral or parenteral routes as long as it can reach the target tissue. Parenteral administration, for example, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, topical administration, intranasal administration, intrapulmonary administration, or intrarectal administration, is not limited thereto.
또한, 상기 약학 조성물은 일반적으로 사용되는 약제학적 담체와 함께 적합한 형태로 제형화될 수 있다. 또한 상기 약학 조성물은 생리학적으로 허용되고 인간에게 투여될 때 통상적으로 위장 장애, 현기증 등과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 조성물을 의미한다. 약학 조성물에 허용되는 담체로는 예를 들면, 물, 적합한 오일, 식염수, 수성 글루코스 및 글리콜 등과 같은 비경구 투여용 담체 등이 있으며 안정화제 및 보존제를 추가로 포함할 수 있다. 적합한 안정화제로는 아황산수소나트륨, 아황산나트륨 또는 아스코르브산과 같은 항산화제가 있고, 적합한 보존제로는 벤즈알코늄 클로라이드, 메틸- 또는 프로필-파라벤 및 클로로부탄올이 있으나, 이에 제한되지 않는다. 그 밖의 약학적으로 허용되는 담체로는 다음의 문헌에 기재되어 있는 것을 참고로 할 수 있다 (Remington's Pharmaceutical Sciences, 19thed., Mack Publishing Company, Easton, PA, 1995).Additionally, the pharmaceutical composition may be formulated in a suitable form with a commonly used pharmaceutical carrier. In addition, the pharmaceutical composition refers to a composition that is physiologically acceptable and does not usually cause allergic reactions such as gastrointestinal disorders, dizziness, etc., or similar reactions when administered to humans. Acceptable carriers for pharmaceutical compositions include, for example, water, suitable oils, saline solutions, carriers for parenteral administration such as aqueous glucose and glycols, and may further include stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid, and suitable preservatives include, but are not limited to, benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. As for other pharmaceutically acceptable carriers, those described in the following literature may be referred to (Remington's Pharmaceutical Sciences, 19thed., Mack Publishing Company, Easton, PA, 1995).
본 발명의 일 구체예에서, DC271과 템시롤리무스는 분화된 조절 T 세포의 증식, 활성화 및 호밍을 촉진시켰다 (도 3 내지 5).In one embodiment of the present invention, DC271 and temsirolimus promoted proliferation, activation, and homing of differentiated regulatory T cells (FIGS. 3 to 5).
구체적으로 말초혈액단핵구를 DC271 및/또는 템시롤리무스를 포함하는 배지에서 배양하여 유도한 조절 T 세포는 대조군과 비교하여 현저히 높은 수준의 (Interleukin-10, IL-10)을 분비하였다 (도 3). 활성화된 조절 T 세포는 항염증 사이토카인인 IL-10을 분비하므로 IL-10의 분비 수준이 높다는 것은 조절 T 세포가 활성화되었음을 의미한다.Specifically, regulatory T cells induced by culturing peripheral blood mononuclear cells in a medium containing DC271 and/or temsirolimus secreted significantly higher levels of (Interleukin-10, IL-10) compared to the control group (Figure 3) . Activated regulatory T cells secrete IL-10, an anti-inflammatory cytokine, so a high secretion level of IL-10 means that regulatory T cells are activated.
말초혈액단핵구를 DC271 및 템시롤리무스를 포함하는 배지에서 배양하여 유도한 조절 T 세포는 세포 증식율 및 생존율 또한 우수하였고 (도 4), 호밍 수용체인 α4β7의 발현도 증가하였다 (도 5).Regulatory T cells induced by culturing peripheral blood mononuclear cells in a medium containing DC271 and temsirolimus also had excellent cell proliferation and survival rates (Figure 4), and expression of the homing receptor α4β7 was also increased (Figure 5).
조절 T 세포는 혈액 내에서 이동하다가 염증 발생 부위에서 발현되는 MadCAM-1, CCL25 (Chemokine (C-C motif) ligand 25)를 찾으면 세포 표면에 발현되어 있는 α4β7 또는 CCR9 (C-C chemokine receptor 9)를 통해 MadCAM-1 (Mucosal addressin cell adhesion molecule-1) 또는 CCL25와 결합하여 해당 부위로 호밍한다. 조절 T 세포에서 α4β7의 발현이 증가했다는 것은 조절 T 세포의 호밍 능력이 증가했음을 의미한다.Regulatory T cells move in the blood and when they find MadCAM-1 or CCL25 (Chemokine (C-C motif) ligand 25) expressed at the site of inflammation, they activate MadCAM-1 through α4β7 or CCR9 (C-C chemokine receptor 9) expressed on the cell surface. 1 (Mucosal addressin cell adhesion molecule-1) or CCL25 and homing to the relevant site. Increased expression of α4β7 in regulatory T cells indicates increased homing ability of regulatory T cells.
즉, 본 명세서에서, "조절 T 세포의 호밍"이란 조절 T 세포가 특정 부위, 염증 발생 부위로 이동할 수 있는 능력을 의미한다.That is, as used herein, “homing of regulatory T cells” refers to the ability of regulatory T cells to move to a specific site or site of inflammation.
이에 본 발명의 또 다른 양상은 3-[2-(5,6,7,8-테트라하이드로-5,5,8,8-테트라메틸-2-나프탈레닐)에티닐]벤조익산 (EC19), 4-[2-(5,6,7,8-테트라하이드로-5,5,8,8-테트라메틸-2-나프탈레닐)에티닐]벤조익산 (EC23), 4-[2-[1,2,3,4-테트라하이드로-4,4-디메틸-1-(1-메틸에틸)-6-퀴놀리닐]에티닐]벤조익산 (DC271) 및 템시롤리무스로 이루어진 군에서 선택되는 1종 이상의 물질을 포함하는 조절 T 세포의 증식, 활성화 또는 호밍 (Homing) 촉진용 조성물, 촉진용 키트를 제공한다.Accordingly, another aspect of the present invention is 3-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoic acid (EC19) , 4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoic acid (EC23), 4-[2-[ 1,2,3,4-tetrahydro-4,4-dimethyl-1-(1-methylethyl)-6-quinolinyl]ethynyl]benzoic acid (DC271) and temsirolimus. Provided are compositions and kits for promoting proliferation, activation, or homing of regulatory T cells containing one or more substances.
또한, 상기 물질들이 1종 이상 포함된 배지에서 조절 T 세포를 배양하는 단계를 포함하는 조절 T 세포의 증식, 활성화 또는 호밍을 촉진시키는 방법을 제공한다.Additionally, a method for promoting proliferation, activation, or homing of regulatory T cells is provided, comprising culturing the regulatory T cells in a medium containing one or more of the above substances.
본 명세서에서 달리 정의되지 않은 용어들은 본 발명이 속하는 기술분야에서 통상적으로 사용되는 의미를 갖는다.Terms not otherwise defined in this specification have meanings commonly used in the technical field to which the present invention pertains.
본 발명의 조성물을 사용하면 말초혈액단핵구를 조절 T 세포로 효과적으로 분화시킬 수 있고, 조절 T 세포의 증식, 활성화 및 호밍 또한 촉진할 수 있다.Using the composition of the present invention, peripheral blood monocytes can be effectively differentiated into regulatory T cells, and proliferation, activation, and homing of regulatory T cells can also be promoted.
도 1은 말초혈액단핵구에 조절 T 세포 분화 유도 물질인 DC271 또는 템시롤리무스를 처리하여 배양한 후 CD4 및 CD25의 발현 수준을 확인한 결과이다.
도 2는 말초혈액단핵구에 조절 T 세포 분화 유도 물질인 DC271 또는 템시롤리무스를 처리하여 배양한 후 CD127의 발현 수준을 확인한 결과이다.
도 3은 말초혈액단핵구에 조절 T 세포 분화 유도 물질인 DC271 또는 템시롤리무스를 처리하여 배양한 후 IL-10의 분비 수준을 확인한 결과이다.
도 4는 말초혈액단핵구에 조절 T 세포 분화 유도 물질인 DC271 또는 템시롤리무스를 처리하여 배양한 후 세포 증식 수준 (A) 및 세포 생존율 (B)을 확인한 결과이다.
도 5는 말초혈액단핵구에 조절 T 세포 분화 유도 물질인 DC271 또는 템시롤리무스를 처리하여 배양한 세포에서 호밍 수용체인 α4β7의 발현 수준을 확인한 결과이다.Figure 1 shows the results of confirming the expression levels of CD4 and CD25 after culturing peripheral blood monocytes with DC271 or temsirolimus, a regulatory T cell differentiation inducer.
Figure 2 shows the results of confirming the expression level of CD127 after culturing peripheral blood monocytes with DC271 or temsirolimus, a regulatory T cell differentiation inducer.
Figure 3 shows the results of confirming the secretion level of IL-10 after culturing peripheral blood monocytes with DC271 or temsirolimus, a regulatory T cell differentiation inducer.
Figure 4 shows the results of confirming the level of cell proliferation (A) and cell survival rate (B) after culturing peripheral blood monocytes with DC271 or temsirolimus, a regulatory T cell differentiation inducer.
Figure 5 shows the results of confirming the expression level of α4β7, a homing receptor, in cells cultured by treating peripheral blood monocytes with DC271 or temsirolimus, a regulatory T cell differentiation inducer.
이하 하나 이상의 구체예를 실시예를 통하여 보다 상세하게 설명한다. 그러나 이들 실시예는 하나 이상의 구체예를 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, one or more specific examples will be described in more detail through examples. However, these examples are for illustrative purposes of one or more specific examples and the scope of the present invention is not limited to these examples.
실시예 1: 조절 T 세포 분화 유도 물질의 효과 확인Example 1: Confirmation of the effect of regulatory T cell differentiation inducing substances
혈액에서 말초혈액단핵구 (Peripheral blood mononuclear cell; 이하, PBMC로 기재함)를 분리하여 CD8+ 세포를 제거 (Pepletion)하였다. 이후 CD8+ 세포가 제거된 PBMC를 조절 T 세포 분화 유도 물질인 DC271 또는 템시롤리무스 (Pemsirolimus)를 각각 1 uM 또는 10 ng/㎖ 농도로 포함하는 배지에서 24시간 동안 배양하였다.Peripheral blood mononuclear cells (hereinafter referred to as PBMC) were isolated from the blood, and CD8+ cells were removed (pepletion). Afterwards, the PBMCs from which CD8+ cells were removed were cultured for 24 hours in a medium containing DC271 or Pemsirolimus, a regulatory T cell differentiation inducer, at a concentration of 1 uM or 10 ng/ml, respectively.
배지를 교체하지 않고, 배양 2, 4일차에 상기 농도의 조절 T 세포 분화 유도 물질을 배지에 추가로 첨가하였다. 9일 동안 배양한 후 세포를 회수하여 조절 T 세포의 마커인 CD4 및 CD25의 발현 여부를 확인하였다. 그 결과, 조절 T 세포 분화 유도 물질을 처리하지 않은 대조군과 비교하여 조절 T 세포 분화 유도 물질을 처리했을 때 CD4 및 CD25의 발현 수준이 더 높은 것을 확인할 수 있었다 (도 1). 특히, DC271보다 템시롤리무스를 처리했을 때 CD4 및 CD25의 발현 수준이 더 높았는데 이는 템시롤리무스가 PBMC에서 mTOR (Pammalian target of rapamycin) 신호 경로를 억제하여 조절 T 세포로 분화를 유도했다고 판단할 수 있다.Without replacing the medium, the above concentration of regulatory T cell differentiation-inducing substance was additionally added to the medium on days 2 and 4 of culture. After culturing for 9 days, the cells were recovered and the expression of CD4 and CD25, markers of regulatory T cells, was checked. As a result, it was confirmed that the expression levels of CD4 and CD25 were higher when treated with regulatory T cell differentiation-inducing substances compared to the control group that was not treated with regulatory T cell differentiation-inducing substances (Figure 1). In particular, the expression levels of CD4 and CD25 were higher when treated with temsirolimus than with DC271, which suggests that temsirolimus induced differentiation into regulatory T cells by inhibiting the mTOR (Pammalian target of rapamycin) signaling pathway in PBMC. You can.
또한, 대조군과 비교하여 조절 T 세포 분화 유도 물질을 처리했을 때 CD127의 발현 수준이 약간 감소하는 것을 확인할 수 있었으며, 두 물질을 같이 처리했을 때 CD127의 발현 감소가 더 우수하였다 (도 2).In addition, compared to the control group, a slight decrease in the expression level of CD127 was confirmed when treated with a regulatory T cell differentiation-inducing substance, and when the two substances were treated together, the reduction in CD127 expression was superior (Figure 2).
도 1 및 도 2의 결과는 조절 T 세포 분화 유도 물질이 PBMC의 조절 T 세포로의 분화를 효과적으로 유도할 수 있음을 의미한다.The results in Figures 1 and 2 mean that the regulatory T cell differentiation-inducing agent can effectively induce differentiation of PBMC into regulatory T cells.
조절 T 세포가 많이 분비하는 항염증성 사이토카인인 IL-10 (Interleukin-10)의 분비를 ELISA로 확인한 결과, 대조군과 비교하여 조절 T 세포 분화 유도 물질을 처리했을 때 IL-10의 분비 수준이 높은 것을 알 수 있었다 (도 3). 또한, 조절 T 세포 분화 유도 물질에 의한 세포 증식 및 세포 생존율의 변화를 확인한 결과, 세포 증식 및 생존율 또한 증가하는 것을 알 수 있었다 (도 4). 조절 T 세포에서 발현되는 호밍 수용체 (Homing receptor)인 α4β7의 발현 또한 증가하였다 (도 5).As a result of confirming the secretion of IL-10 (Interleukin-10), an anti-inflammatory cytokine secreted in large quantities by regulatory T cells, by ELISA, the secretion level of IL-10 was higher when treated with regulatory T cell differentiation-inducing substances compared to the control group. It was found that (Figure 3). In addition, as a result of confirming changes in cell proliferation and cell survival rate caused by regulatory T cell differentiation-inducing substances, it was found that cell proliferation and survival rate also increased (Figure 4). The expression of α4β7, a homing receptor expressed in regulatory T cells, also increased (Figure 5).
Claims (8)
3-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoic acid (3-[2-(5,6, 7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoic acid, EC19), 4-[2-(5,6,7,8-tetrahydro-5,5,8 ,8-Tetramethyl-2-naphthalenyl)ethynyl]benzoic acid (4-[2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl) -benzoic acid, EC23], 4-[2-[1,2,3,4-tetrahydro-4,4-dimethyl-1-(1-methylethyl)-6-quinolinyl]ethynyl]benzoic acid (4-[2-[1,2,3,4-Tetrahydro-4,4-dimethyl-1-(1-methylethyl)-6-quinolinyl]ethynyl]benzoic acid, DC271) and Temsirolimus A composition for differentiating peripheral blood monocytes into regulatory T cells, comprising at least one substance selected from the group consisting of.
Isolated peripheral blood mononuclear cells were treated with 3-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoic acid (EC19), 4 -[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoic acid (EC23), 4-[2-[1, 2,3,4-tetrahydro-4,4-dimethyl-1-(1-methylethyl)-6-quinolinyl]ethynyl]benzoic acid (DC271) and one selected from the group consisting of temsirolimus A method of differentiating peripheral blood monocytes into regulatory T cells, comprising culturing in a composition containing the above substances.
3-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoic acid (EC19), 4-[2-(5 ,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoic acid (EC23), 4-[2-[1,2,3,4- Peripherals containing one or more substances selected from the group consisting of tetrahydro-4,4-dimethyl-1-(1-methylethyl)-6-quinolinyl]ethynyl]benzoic acid (DC271) and temsirolimus. Kit for differentiating blood monocytes into regulatory T cells.
A pharmaceutical composition for preventing or treating inflammatory bowel disease, comprising regulatory T cells obtained according to claim 2 as an active ingredient.
The pharmaceutical composition for preventing or treating inflammatory bowel disease according to claim 4, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
3-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoic acid (EC19), 4-[2-(5 ,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoic acid (EC23), 4-[2-[1,2,3,4- Control comprising one or more substances selected from the group consisting of tetrahydro-4,4-dimethyl-1-(1-methylethyl)-6-quinolinyl]ethynyl]benzoic acid (DC271) and temsirolimus. A composition for promoting proliferation, activation, or homing of T cells.
3-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoic acid (EC19), 4-[2-(5 ,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoic acid (EC23), 4-[2-[1,2,3,4- Control comprising one or more substances selected from the group consisting of tetrahydro-4,4-dimethyl-1-(1-methylethyl)-6-quinolinyl]ethynyl]benzoic acid (DC271) and temsirolimus. Kit for promoting proliferation, activation or homing of T cells.
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Non-Patent Citations (3)
| Title |
|---|
| 1. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med 2009;361(21):2066-2078. |
| 2. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 2001;48(4):526-535. |
| 3. Megan E Himmel et al. Regulatory T-cell therapy for inflammatory bowel disease: more questions than answers. Immunology. 2012 Jun; 136(2): 115-122. |
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