KR20170141914A - Composition for preventing or treating immune disease comprising berbamine - Google Patents
Composition for preventing or treating immune disease comprising berbamine Download PDFInfo
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- KR20170141914A KR20170141914A KR1020160074921A KR20160074921A KR20170141914A KR 20170141914 A KR20170141914 A KR 20170141914A KR 1020160074921 A KR1020160074921 A KR 1020160074921A KR 20160074921 A KR20160074921 A KR 20160074921A KR 20170141914 A KR20170141914 A KR 20170141914A
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- transplantation
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Abstract
Description
본 발명은 면역반응의 이상으로 유발되는 면역질환을 예방 또는 치료하는데 사용될 수 있는 베르바민 화합물의 약학적 용도에 관한 것으로서, 보다 구체적으로는 베르바민 화합물을 유효성분으로 포함하는 자가면역질환; 염증성질환; 또는 세포, 조직 또는 기관의 이식거부반응의 예방 또는 치료용 조성물에 관한 것이다. The present invention relates to a pharmaceutical use of a verbamine compound which can be used for the prevention or treatment of immune diseases caused by abnormality of an immune response. More specifically, the present invention relates to an autoimmune disease comprising a verbamine compound as an active ingredient; Inflammatory disease; Or a composition for preventing or treating transplant rejection of cells, tissues or organs.
면역질환은 포유류 면역계의 구성성분들이 포유류의 병리상태를 야기하거나, 매개하거나 또는 기타 공헌하는 질환으로서, 특히 염증성 장애는 전 세계에서 가장 중요한 건강 문제 중 하나이다. 염증은 일반적으로 외부 물질 또는 해로운 자극에 의한 숙주 침입에 대해 신체 조직의 국소화된 보호 반응이다. 염증의 원인은 박테리아, 바이러스 및 기생충과 같은 감염성 원인; 화상 또는 방사선 조사와 같은 물리적 원인; 독소, 약물 또는 산업적 제제와 같은 화학약품; 알레르기 및 자가면역 반응과 같은 면역적 반응, 또는 산화성 스트레스와 연관된 상태일 수 있다.Immune disorders are diseases in which constituents of the mammalian immune system cause, mediate, or contribute to the pathology of mammals, particularly inflammatory disorders being one of the most important health problems in the world. Inflammation is generally a localized protective response of the body tissue to host infiltration by foreign substances or by harmful stimuli. Causes of inflammation include infectious causes such as bacteria, viruses and parasites; Physical causes such as burns or irradiation; Chemicals such as toxins, drugs or industrial formulations; An immune response such as an allergic and autoimmune response, or a condition associated with oxidative stress.
염증은 통증, 적화현상, 부기, 열 및 감염된 영역의 궁극적인 기능 손실을 그 특징으로 한다. 이들 증상은 면역계의 세포사이에서 일어나는 일련의 복잡한 상호작용의 결과이다. 세포의 반응으로 인해 결과적으로 여러 그룹의 염증 매개자의 상호작용 네트워크가 생성된다: 단백질(예를 들면, 사이토카인, 효소(예를 들면 프로테아제, 퍼옥시다제), 주요 염기성 단백질, 점착 분자(ICAM, VCAM), 지질 매개자(예를 들면, 에이코사노이드, 프로스타글란딘, 류코트라이엔, 혈소판 활성화 인자(PAF)), 반응성 산소 종(예를 들면, 하이드로퍼옥사이드, 슈퍼옥사이드 음이온 O2-, 산화질소(NO) 등). 그러나 염증의 이들 매개자중 대부분은 또한 정상적인 세포 활성의 조절자이다. 따라서 염증 반응의 결핍으로 인해 숙주가 제어되지 않으면서 손상(즉, 감염)되고, 따라서 만성 염증으로 인해 부분적으로는 상기 언급된 매개자중 여럿이 과다 생성됨으로써 매개되는 염증성 질환이 야기된다.Inflammation is characterized by pain, numbness, swelling, heat and ultimate loss of function in the affected area. These symptoms are the result of a series of complex interactions that take place between cells of the immune system. The reaction of cells results in a network of interaction groups of inflammatory mediators as a result: proteins (eg, cytokines, enzymes (eg proteases, peroxidases), major basic proteins, (E.g., VCAM), lipid mediators (e.g., eicosanoids, prostaglandins, leukotrienes, platelet activating factors (PAF)), reactive oxygen species such as hydroperoxides, superoxide anions O2-, ), Etc. However, many of these mediators of inflammation are also regulators of normal cellular activity, so that the deficiency of the inflammatory response leads to damage (i.e., infection) without control of the host, and thus partly due to chronic inflammation Inflammatory diseases mediated by the overproduction of several of the above-mentioned mediators.
또한, 면역질환 중 하나인 자가면역질환은 면역 체계가 그 자신의 기관을 공격하여 자발적인 반응을 일으키는 것을 특징으로 한다. 이러한 반응들은 T 림프구에 의한 자가항원(auto-antigen)의 인식에 기인하며, 이로 인하여 체액상(자가항원 생성) 및 세포상 (림프구 및 대식세포 세포독성 활성 증가) 면역 반응이 유발된다. 자가면역질환으로서는 다음과 같은 것들을 들 수 있다: 류마티스성 질환, 건선, 전신성 피부근염, 다발성 경화증, 홍반성 낭창, 또는 항원에 의한 면역반응 악화, 즉, 천식, 약물 또는 음식에 대한 알레르기 등 이러한 질환들은 모두 제한성이고 만성인 질환들이며, 경우에 따라서는 치명적이고 현재까지 상기 질환들을 치료할 수 있는 효과적인 치료 방법이 존재하지 않는 실정이다. 그러므로 이들 질환의 진행 중에 질환을 경감시키거나 완화시킬 수 있는 약물, 의약 또는 매체라면 환자의 건강을 위해서 중요한 해결 수단이 된다고 할 것이다.Also, an autoimmune disease, one of the immune diseases, is characterized by the immune system attacking its own organ and causing a spontaneous reaction. These responses are due to the recognition of auto-antigen by T lymphocytes, which leads to immune responses in the body fluid (autoantigen production) and in the cellular phase (increased lymphocyte and macrophage cytotoxic activity). Examples of autoimmune diseases include: rheumatic diseases, psoriasis, systemic dermatomyositis, multiple sclerosis, lupus erythematosus, or immune reactions caused by antigens, such as allergies to asthma, drugs or food Are all limited and chronic diseases, and in some cases they are lethal and there are no effective treatments available to date to treat these diseases. Therefore, drugs, medicines or media that can alleviate or alleviate the disease during the course of these diseases will be an important solution for the health of the patient.
많은 연구자들은 자가면역질환의 치료방법을 탐색하여 적당한 약물과 방법을 찾고자 집중적인 노력을 해왔으며, 오늘날, 자가면역질환의 치료는 주로 면역억제 약물, 예컨대 글루코코르티코이드(glucocorticoids), 칼시뉴린 억제제(calcineurin inhibitors) 및 증식억제제-대사물 작용 억제제(antiproliferatives-antimetabolites)의 사용에 근거한 것이다. 그러나 이와 같은 약리 요법은 다양한 표적들에 대하여 작용하므로, 전체적으로는 면역기능을 저하시킬 수 있다. 그렇지 않으면, 이러한 약리 요법을 장기간 사용하였을 경우 여러 가지 세포 독성 작용이 문제가 되어, 면역 체계를 비특이적인 방식으로 억제함으로써, 환자를 감염증 및 암에 걸릴 위험에 노출시킬 수 있다. 칼시뉴린과 글루코코르티코이드는, 그들의 신독성과 당뇨병 유발 특성에 기인하여 또 다른 문제점을 나타내기 때문에, 몇 가지 임상학적 증상의 경우(예: 신기능 부전, 당뇨병 등)에는 그 사용이 제한된다.Many researchers have focused their efforts on finding suitable medicines and methods to find ways to treat autoimmune diseases. Today, treatment of autoimmune diseases is mainly based on immunosuppressive drugs such as glucocorticoids, calcineurin inhibitors) and antiproliferatives-antimetabolites. However, such pharmacological therapies act on a variety of targets, and as a whole may impair immune function. Otherwise, long-term use of this pharmacotherapy can lead to a number of cytotoxic effects, which can lead to exposure of the patient to infection and cancer by inhibiting the immune system in a nonspecific manner. The use of calcineurin and glucocorticoids is limited in the case of some clinical symptoms (eg, renal insufficiency, diabetes, etc.), as they present another problem due to their nephrotoxicity and diabetes-inducing properties.
따라서 자가면역질환, 염증성 질환, 이식거부반응 등과 같은 면역질환을 치료할 수 있는 물질로서, 부작용이 없으면서도 치료 효과가 우수한 새로운 치료제의 개발이 필요한 실정이다.Therefore, there is a need to develop a new therapeutic agent that can treat immune diseases such as autoimmune diseases, inflammatory diseases, rejection of transplantation, etc., and has excellent therapeutic effects without side effects.
이에 본 발명자들은 베르바민 화합물이 염증성 사이토카인의 생성을 효과적으로 억제할 수 있으며, STAT3의 활성억제와 함께 동종반응을 억제할 수 있어, 면역질환 특히 자가면역질환; 염증성 질환; 또는 세포, 조직 또는 기관의 이식거부반응을 예방 또는 치료할 수 있는 새로운 치료제로서의 사용 가능성을 확인함으로써 본 발명을 완성하였다.Thus, the present inventors have found that verbamine compounds can effectively inhibit the production of inflammatory cytokines and can inhibit homologous reactions together with the inhibition of the activity of STAT3, so that the immune diseases, particularly autoimmune diseases; Inflammatory disease; Or as a novel therapeutic agent capable of preventing or treating rejection of transplantation of cells, tissues or organs.
따라서 본 발명의 목적은 베르바민(Berbamine) 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 면역질환의 예방 또는 치료용 조성물을 제공하는 것이다.It is therefore an object of the present invention to provide a composition for the prevention or treatment of an immune disease comprising a berbamine compound or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명의 다른 목적은 베르바민(Berbamine) 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 면역질환의 예방 또는 개선용 건강기능성 식품을 제공하는 것이다.Another object of the present invention is to provide a health functional food for preventing or ameliorating an immunological disease comprising a berbamine compound or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 베르바민(Berbamine) 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 면역질환의 예방 또는 치료용 조성물을 제공한다. In order to accomplish the above object, the present invention provides a composition for preventing or treating immune diseases comprising a berbamine compound or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 일실시예에 있어서, 상기 베르바민(Berbamine) 화합물 또는 이의 약학적으로 허용 가능한 염은 1~30uM의 농도로 상기 조성물에 함유되어 있을 수 있다.In one embodiment of the present invention, the Berbamine compound or a pharmaceutically acceptable salt thereof may be contained in the composition at a concentration of 1 to 30 uM.
본 발명의 일실시예에 있어서, 상기 베르바민(Berbamine) 화합물 또는 이의 약학적으로 허용 가능한 염은 염증성 사이토카인의 생성을 감소 또는 억제시키고, STAT3의 활성을 감소 도는 억제시키는 기작을 통해 치료 효과를 나타내는 것일 수 있다.In one embodiment of the present invention, the Berbamine compound or a pharmaceutically acceptable salt thereof reduces or inhibits the production of inflammatory cytokines, reduces the activity of STAT3, .
본 발명의 일실시예에 있어서, 상기 염증성 사이토카인은 IL-17, IFN-r, IL-10, IL-6 또는 TNF-a일 수 있다.In one embodiment of the invention, the inflammatory cytokine may be IL-17, IFN-r, IL-10, IL-6 or TNF-a.
본 발명의 일실시예에 있어서, 상기 염증성 사이토카인은 anti-CD3 또는 LPS 에 의해 유도되는 것일 수 있다.In one embodiment of the present invention, the inflammatory cytokine may be one induced by anti-CD3 or LPS.
본 발명의 일실시예에 있어서, 상기 면역질환은 자가면역질환; 염증성질환; 또는 세포, 조직 또는 기관의 이식거부반응으로 이루어진 군 중에서 선택되는 것일 수 있다.In one embodiment of the invention, the immune disease is autoimmune disease; Inflammatory disease; Or transplant rejection of cells, tissues or organs.
본 발명의 일실시예에 있어서, 상기 자가면역질환은 류마티스 관절염 (Rheumatoid Arthritis), 천식 (Asthma), 피부염 (Dermititis), 건선 (Psoriasis), 낭섬유증 (Cystic Fibrosis), 다발성 경화증 (Multiple Sclerosis), 전신성 홍반성 루푸스(systemic lupus erythematosus), 쇼그렌 증후군(Sjogren syndrome), 하시모토 갑상선(Hashimoto thyroiditis), 다발성근염(polymyositis), 경피증(scleroderma), 아디슨병(Addison disease), 백반증(vitiligo), 악성빈혈(pernicious anemia), 사구체신염(glomerulonephritis) 및 폐섬유증(pulmonary fibrosis), 염증성장질환 (Inflammatory Bowel Dieseses), 자가면역성 당뇨 (Autoimmune Diabetes), 당뇨 망막증 (Diabetic retinopathy), 비염 (Rhinitis), 혀혈-재관류 손상 (Ischemia-reperfusion injury), 혈관성형술후 재협착 (Post-angioplasty restenosis), 만성 폐색성 심장 질환 (Chronic obstructive pulmonary diseases; COPD), 그레이브병 (Graves disease), 위장관 알러지 (Gastrointestinal allergies), 결막염 (Conjunctivitis), 죽상경화증 (Atherosclerosis), 관상동맥질환 (Coronary artery disease), 협심증 (Angina), 암 전이 및 소동맥 질환으로 이루어진 군으로부터 선택되는 것일 수 있다.In one embodiment of the present invention, the autoimmune disease is selected from the group consisting of rheumatoid arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, multiple sclerosis, Systemic lupus erythematosus, Sjogren's syndrome, Hashimoto thyroiditis, polymyositis, scleroderma, Addison disease, vitiligo, malignant anemia pernicious anemia, glomerulonephritis and pulmonary fibrosis, inflammatory bowel dieses, autoimmune diabetes, diabetic retinopathy, rhinitis, gingival reperfusion injury Ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary diseases (COPD), Graves disease, Minister of allergy (Gastrointestinal allergies), conjunctivitis (Conjunctivitis), atherosclerosis (Atherosclerosis), coronary artery disease (Coronary artery disease), angina pectoris (Angina), may be selected from the group consisting of cancer metastasis and arterioles disease.
본 발명의 일실시예에 있어서, 상기 세포, 조직 또는 기관의 이식거부반응은 골수 이식, 심장 이식, 각막 이식, 장 이식, 간 이식, 폐 이식, 췌장 이식, 신장 이식 및 피부이식의 거부반응 으로 이루어진 군 중에서 선택되는 것일 수 있다.In one embodiment of the present invention, the graft rejection reaction of the cells, tissues or organs is a rejection reaction of bone marrow transplantation, heart transplantation, corneal transplantation, intestinal transplantation, liver transplantation, lung transplantation, pancreas transplantation, kidney transplantation and skin transplantation May be selected from the group consisting of
또한, 본 발명은 베르바민(Berbamine) 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 면역질환의 예방 또는 개선용 건강기능성 식품을 제공한다.The present invention also provides a health functional food for preventing or ameliorating an immunological disease comprising a berbamine compound or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명에 따른 베르바민 화합물은 염증성 사이토카인의 생성 및 분비를 억제하는 활성을 가지며, STAT3 활성 억제와 함께 동종반응을 억제 또는 감소시킬 수 있어, 각종 면역반응의 조절 이상으로 유발되는 자가면역질환, 염증성질환 및 이식거부질환과 같은 면역질환을 예방 또는 치료할 수 있는 약학적 조성물 또는 건강기능성 식품의 유효성분으로 유용하게 사용할 수 있다.The verbamine compound according to the present invention has an activity of inhibiting the production and secretion of inflammatory cytokines, and can inhibit or reduce the homologous reaction together with the suppression of STAT3 activity, and thus can prevent the autoimmune diseases, Inflammatory diseases and graft-rejection diseases, as well as health functional foods.
도 1은 본 발명의 일실시예에서 마우스로부터 분리된 비장세포를 anti-CD3로 자극한 후, 농도별 베르바민 화합물 처리에 따른 염증성 사이토카인의 억제 정도를 ELISA 실험을 통해 분석한 결과이다.
도 2는 본 발명의 일실시예에서 마우스로부터 분리된 비장세포를 LPS3로 자극한 후, 농도별 베르바민 화합물 처리에 따른 염증성 사이토카인의 억제 정도를 ELISA 실험을 통해 분석한 결과이다.
도 3은 정상인의 분리된 말초단핵구 세포에 농도별 베르바민 화합물을 처리하고 anti-CD3로 자극한 후, 염증성 사이토카인의 수준을 ELISA 실험을 통해 분석한 결과이다.
도 4는 정상인의 말초단핵구로부터 분리된 CD4+T 세포에 농도별 베르바민 화합물을 처리하고 anti-CD3로 자극한 후, 염증성 사이토카인의 수준을 ELISA 실험을 통해 분석한 결과이다.
도 5는 간질환 말기의 환자로부터 분리된 말초단핵구 세포에 농도별 베르바민 화합물을 처리하고 anti-CD3로 자극한 후, 염증성 사이토카인의 수준을 ELISA 실험을 통해 분석한 결과이다.
도 6은 베르바민 화합물의 STAT3 억제활성 여부를 루시퍼라제 어세이를 통해 분석한 결과이다.
도 7은 베르바민 화합물에 의한 동종반응 억제효과를 3H Thymidine양의 분석을 통해 확인한 결과이다.FIG. 1 shows the result of ELISA analysis of inhibition of inflammatory cytokines by treatment with verbamine compounds by stimulating splenocytes isolated from mice with anti-CD3 in an embodiment of the present invention.
FIG. 2 is a graph showing the results of ELISA analysis of inhibitory levels of inflammatory cytokines following treatment with verbamine compounds by stimulating splenocytes isolated from mice with LPS3.
FIG. 3 shows the results of ELISA analysis of levels of inflammatory cytokines after treatment of normal peripheral mononuclear cells with verbamine compounds at different concentrations and stimulation with anti-CD3.
FIG. 4 shows the results of ELISA analysis of levels of inflammatory cytokines after treating with CD4 + T cells isolated from normal peripheral mononuclear cells and stimulated with anti-CD3 by a concentration of verbamine compound.
FIG. 5 shows the results of ELISA analysis of levels of inflammatory cytokines after treating peripheral mononuclear cells isolated from patients at the end of the liver disease with a concentration-specific verbamine compound and stimulating with anti-CD3.
FIG. 6 shows the results of analysis of the inhibitory activity of verbamine compound for STAT3 through Luciferase assay.
FIG. 7 shows the result of confirming the inhibitory effect of alluvium compound on allogens by analyzing the amount of 3H thymidine.
본 발명은 면역질환을 효과적으로 예방 또는 치료할 수 있는 새로운 치료제로서 베르바민(berbamine) 화합물을 사용할 수 있음을 최초로 규명한 점에 특징이 있다. The present invention is characterized in that berbamine compound can be used as a novel therapeutic agent for effectively preventing or treating immune diseases.
베르바민 화합물은 C37H40N2O6의 분자식을 가지며, 하기 화학식을 갖는 화합물이다. 베르바민 화합물은 간암세포의 활성을 억제하는 항암활성이 있다는 연구내용이 보고된 바 있고, 혈관재협착 방지 효과가 있음이 보고된 바 있을 뿐, 약리학적 기능 및 기타 생리활성에 대한 연구가 거의 이루어지지 않은 물질이다.The verbamine compound is a compound having the molecular formula of C 37 H 40 N 2 O 6 and having the following formula: It has been reported that the verbamine compound has anticancer activity that inhibits the activity of hepatic cancer cells. It has been reported that the verbamine compound has anti-vascular restenosis effect, and studies on pharmacological function and other physiological activities are almost completed It is a non-existent material.
<베르바민 화합물의 화학식>≪ Formula of verbamine compound >
이에 본 발명자들은 베르바민(berbamine) 화합물이 면역질환의 치료 효과가 있음을 최초로 규명하였다.Therefore, the inventors of the present invention firstly confirmed that berbamine compounds have therapeutic effects on immune diseases.
구체적으로 본 발명의 일실시예에 따르면, 본 발명의 베르바민(berbamine) 화합물은 마우스의 비장세포, 인간의 말초단핵구세포, CD4+T 세포 모두에서 염증성인자를 유발시키는 anti-CD3 및 LPS에 의한 염증성사이토카인의 생성 정도를 효과적으로 억제할 수 있음을 확인하였다.Specifically, according to one embodiment of the present invention, the berbamine compound of the present invention is administered to a subject by anti-CD3 and LPS inducing inflammatory factors in both spleen cells, human peripheral mononuclear cells, and CD4 + T cells of mice It was confirmed that the degree of inflammatory cytokine production can be effectively inhibited.
또한, 본 발명의 다른 일실시예에 따르면, 간질환 환자로부터 분리한 말초단핵구 세포를 대상으로 염증유발 인자에 의한 염증반응 유도 조건 하에서 베르바민 화합물을 처리할 경우, 처리하지 않은 대조군에 비해 염증성 사이토카인의 생성이 현저하게 감소되는 것도 확인할 수 있었다.In addition, according to another embodiment of the present invention, when peripheral blood mononuclear cells isolated from patients with liver disease were treated with the verbamine compound under the inflammatory reaction inducing conditions by the inflammatory inducer, the inflammatory cytokine It was confirmed that the production of cain was remarkably reduced.
나아가 본 발명의 다른 일실시예에서는 세포 또는 조직 이식에 따른 이식거부 반응에 대해, 본 발명의 베르바민 화합물을 처리할 경우, 동종반응을 억제하는 활성이 있음을 확인하였다.Further, in another embodiment of the present invention, it was confirmed that when the verbamine compound of the present invention was treated with transplant rejection reaction by cell or tissue transplantation, the activity of inhibiting homologous reaction was confirmed.
따라서 이러한 결과를 통해 본 발명자들은 베르바민 화합물이 면역질환을 효과적으로 치료할 수 있는 새로운 치료제로서의 가능성을 확인할 수 있었다.Therefore, the inventors of the present invention have confirmed the possibility of the verbamine compound as a novel therapeutic agent for effectively treating immune diseases.
그러므로 본 발명은 베르바민(Berbamine) 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 면역질환의 예방 또는 치료용 조성물을 제공할 수 있다.Therefore, the present invention can provide a composition for the prevention or treatment of an immune disease comprising a berbamine compound or a pharmaceutically acceptable salt thereof as an active ingredient.
한편, 각종 병원체에 대한 생체 방어 시스템으로 면역계에서 중심적 역할을 담당하는 세포군의 하나로 T 세포가 있다. T 세포는 인체의 흉선에서 생성되며 일련의 분화 과정을 거치면서 고유의 특성을 지닌 T 세포로 분화하게 되는데, 분화를 완료한 T 세포는 그 기능에 따라 크게 1형 보조 세포(Th1)와 2형 보조 세포(Th2)로 구분된다. 이 중에서 Th1 세포의 주된 기능은 세포 매개성 면역에 관여하고, Th2 세포는 체액성 면역에 관여하며, 면역계에서 이러한 두 세포 집단은 서로 과 활성화되지 않도록 서로 견제를 통해 면역계의 균형을 유지하고 있다. On the other hand, there are T cells as one of the cell groups which plays a central role in the immune system as a bio-defense system for various pathogens. T cells are produced in the thymus of the human body, and undergo a series of differentiation processes, resulting in differentiation into T cells with inherent characteristics. The differentiated T cells are largely classified into type 1 (Th1) Auxiliary cells (Th2). Among these, Th1 cells are mainly involved in cell mediated immunity, Th2 cells are involved in humoral immunity, and in the immune system, these two cell populations maintain the balance of the immune system through mutual checks to prevent mutual activation with each other.
따라서 면역 질환의 대부분은 이러한 두 면역 세포간의 불균형에 기인하는 것으로 볼 수 있는데, 예를 들어 Th1 세포의 활성이 비정상적으로 증가하는 경우 자가면역질환이 발생할 수 있고, Th2 세포의 활성이 비정상적으로 증가하는 경우 과민반응에 의한 면역질환이 발생하는 것으로 알려져 있다. Therefore, most of the immune diseases are caused by the imbalance between these two immune cells. For example, when the activity of Th1 cells abnormally increases, an autoimmune disease may occur and the activity of Th2 cells abnormally increases It is known that immune diseases are caused by hypersensitivity reactions.
한편, Th1 세포의 분화에 대한 최근 연구 결과에 따르면, Th1 세포의 활성을 조절할 수 있는 새로운 그룹인 면역조절 T 세포(Treg)의 존재가 알려지면서 이를 이용한 면역질환의 치료에 대한 연구가 대두되고 있는데, Treg 세포는 비정상적으로 활성화된 면역세포의 기능을 억제하여 염증 반응을 제어하는 특성이 있어, Treg 세포의 활성을 증가시키는 작용을 통해 면역질환을 치료하는 실험들이 많이 보고되고 있다. On the other hand, recent studies on the differentiation of Th1 cells have revealed the existence of a new group of immunoregulatory T cells (Tregs) capable of regulating the activity of Th1 cells, , Treg cells have the property of suppressing the function of abnormally activated immune cells and controlling the inflammatory reaction, and there have been reported many experiments for treating immune diseases through the action of increasing the activity of Treg cells.
또한, Treg 세포 이 외에 분화 과정에서 만들어지는 또 다른 그룹으로 Th17 세포가 있는데, Th17 세포는 미분화 T세포의 분화 과정에서 Treg 세포의 분화와 유사한 과정을 거치며 형성되는 것으로 알려져 있다. 즉, Treg 세포와 Th17 세포의 분화는 공통적으로 TGF-β의 존재 하에서 이루어지지만 Treg 세포의 경우 IL-6을 필요로 하지 않는 반면, Th17 세포의 경우에는 TGF-β와 함께 IL-6가 존재하는 상황에서 분화를 한다. 또한, 분화된 Th17 세포는 IL-17을 분비하는 것을 특징으로 한다. In addition, Th17 cells are known to be formed through a process similar to the differentiation of Treg cells in the differentiation process of undifferentiated T cells. That is, the differentiation of Treg cells and Th17 cells is commonly performed in the presence of TGF-β, whereas IL-6 is not required for Treg cells, while IL-6 is present along with TGF-β for Th17 cells Differentiate in situations. In addition, differentiated Th17 cells are characterized by secretion of IL-17.
Th17 세포는 Treg 세포와는 달리 면역질환에서 보이는 염증반응의 최전방에서 관여하여 염증 반응의 신호를 최대화시켜 질병의 진행을 가속화시키는 것이 밝혀지고 있다. 그러므로 자가면역질환 중 Treg 세포에 의해 제어되지 않는 자가면역질환의 경우, Th17 세포 활성의 억제를 표적으로 하는 자가면역질환의 치료제 개발이 크게 부각되고 있다. Th17 cells, unlike Treg cells, are involved in the forefront of the inflammatory response seen in immune diseases, thereby maximizing the signal of the inflammatory response and accelerating the progression of the disease. Therefore, in the case of autoimmune diseases which are not controlled by Treg cells among autoimmune diseases, the development of therapeutic agents for autoimmune diseases targeting the inhibition of Th17 cell activation has been greatly emphasized.
그러나 현재 사용되고 있는 면역질환치료제로는 T 세포에서의 신호변환 경로를 차단하는 면역 억제제가 가장 많이 사용되고 있는데, 이러한 면역억제제들은 독성, 감염, 임파종, 당뇨병, 진전(tremor), 두통, 설사, 고혈압, 오심, 신기능 장애 등의 부작용이 발생하는 문제점이 있다.However, immunosuppressants that block signal transduction pathways in T cells are the most commonly used therapeutic agents for immune diseases. These immunosuppressants are toxic, infectious, lymphoid, diabetes, tremor, headache, diarrhea, hypertension, Nausea, and renal dysfunction.
또한, T 세포의 활성화를 억제하는 방법을 통해 면역질환을 치료하는 방법 이외에도 면역 세포로부터 분비되는 사이토카인의 양을 조절하는 치료법 및 면역 세포로부터 분비되는 사이토카인을 표적으로 하는 항체를 이용한 치료법이 개발 중에 있다. In addition to the method of treating immune diseases through the method of inhibiting the activation of T cells, a method of regulating the amount of cytokine secreted from the immune cells and a method of using the antibody targeting the cytokine secreted from the immune cells have been developed .
이러한 점에서 본 발명에 따른 베르바민 화합물은 염증성사이토카인 생성 억제 효과가 우수하고 동시에 STAT3 억제 활성 및 동종반응을 억제하는 활성을 모두 가지고 있어 종래 치료제보다 효과적으로 면역질환을 치료할 수 있을 것으로 보인다. In this respect, the verbamine compound according to the present invention has excellent inhibitory effect on the inflammatory cytokine production, and simultaneously has STAT3 inhibiting activity and inhibiting allogeneic action, so that the immune diseases can be treated more effectively than the conventional therapeutic agents.
본 발명의 베르바민 화합물이 억제할 수 있는 염증성사이토카인으로는 염증 반응 또는 면역질환을 유발할 수 있는 사이토카인이라면 모두 포함할 수 있으며, 이에 제한되지는 않으나, IL-17, IFN-r, IL-10, IL-6 또는 TNF-a일 수 있다.The inflammatory cytokines that can be inhibited by the verbamine compound of the present invention include all cytokines capable of inducing an inflammatory reaction or an immunological disease, and include, but are not limited to, IL-17, IFN-r, IL- 10, IL-6 or TNF-a.
앞서 기술한 바와 같이, 본 발명의 일실시예의 결과를 보면, 베르바민 화합물이 STAT3의 활성을 억제하는 작용이 있음을 확인할 수 있었는데, 최근에는 다양한 암 종에서 STAT1, STAT3 및 STAT5의 활성화된 형태가 발견되고 있으며, STAT3는 백혈병과 같은 혈액암 뿐만 아니라, 유방암, 두부경부암, 흑색종, 난소암, 폐암, 췌장암, 전립선암과 같은 다양한 고형암에서 활성화되어 있어 중요한 항암 타겟이 되고 있다(Hua Yu and Richard Jove, Nature Review Cancer.,2004, 8, 945). As described above, according to the results of one embodiment of the present invention, it was confirmed that the verbamine compound inhibits the activity of STAT3. Recently, activated forms of STAT1, STAT3 and STAT5 in various cancer species STAT3 is an important cancer target because it is activated not only in blood cancer such as leukemia but also in a variety of solid tumors such as breast cancer, head and neck cancer, melanoma, ovarian cancer, lung cancer, pancreatic cancer and prostate cancer (Hua Yu and Richard Jove, Nature Review Cancer ., 2004, 8, 945).
또한, STAT3의 활성은 세포사멸을 억제하고, 신생혈관(angiogenesis)을 유도하며, 면역회피를 유도하는 것으로 알려진 바 있다((Wang T. et al., Nature Medicine., 2004, 10, 48). 따라서 STAT3 활성 억제는 복합적인 항암 기작으로 종양을 제어할 수 있는 효과가 있고, STAT3 단백질은 종양뿐만 아니라 다양한 세포내 기능에도 관여하므로 이의 저해제 발굴은 면역질환, 특히 자가면역질환 및 이식거부반응의 치료를 위한 면역억제제로의 개발도 가능하다. In addition, the activity of STAT3 has been known to inhibit apoptosis, induce angiogenesis, and induce immune evasion (Wang T. et al., Nature Medicine ., 2004, 10, 48). Therefore, inhibition of STAT3 activity has an effect of controlling tumor by a complex anticancer mechanism. Since STAT3 protein is involved not only in tumor but also in various cellular functions, its inhibitor can be used for treatment of immune diseases, especially autoimmune diseases and graft rejection It is also possible to develop an immunosuppressive agent for.
면역계는 정상상태에서는 자가 항원에 대한 특이적 면역반응을 제어하고 있으며, 외부항원에 대한 면역반응도 억제하고 있는 경우가 있는데, 예컨대 임산부의 태아에 대한 반응 및 만성감염상태에 있는 미생물에 대한 면역반응을 들 수 있다. 이러한 현상들은 항원 특이적 면역관용이 유도될 수 있는 기전으로 클론 제거(clonal deletion), 클론 무반응(anergy) 및 면역조절 T 세포(Treg)에 의한 능동적 통제에 의해 유도되는 것으로 알려져 있다. 이식항원에 대한 면역관용이 우연히 획득된 일부 환자나 실험적으로 면역관용을 유도한 동물모델을 조사해 보면 위의 세 가지 기전 모두 이식면역관용에 관여한다는 사실이 확인되고 있고, 특히 최근에는 면역조절 T 림프구가 이식면역반응 뿐만 아니라 자가면역, 종양면역, 감염면역반응 등 생체의 거의 모든 면역반응을 통제하는데 관여하는 중요한 세포로 주목받고 있다.In the normal state, the immune system controls the specific immune response to the autoantigen and also suppresses the immune response to the external antigen. For example, the immune response to the fetus of the pregnant woman and the immune response to the microorganism in the chronic infection state . These phenomena are known to be induced by clonal deletion, clonal anergy, and active control by immunoregulatory T cells (Treg) as a mechanism by which antigen-specific immune tolerance can be induced. Some of the patients who have been successfully obtained immunostimulants for the transplantation antigen or those who have experimentally induced immune tolerance have been confirmed to be involved in the transplantation immunity tolerance in all three mechanisms. In particular, recently, immunocontrol T lymphocytes Has been attracting attention as an important cell involved in controlling virtually all immune responses in living bodies such as autoimmune, tumor immunity, and infectious immune response as well as transplantation immune response.
그러므로 본 발명에서 제공하는 상기 면역질환의 예방 또는 치료용 약학적 조성물은, 베르바민 화합물 또는 상기 화합물의 염을 유효성분으로 포함하며, 베르바민(Berbamine) 화합물 또는 이의 약학적으로 허용 가능한 염은 1~30uM의 농도로 상기 조성물에 함유되어 있을 수 있다.Therefore, the pharmaceutical composition for prevention or treatment of the immune diseases provided by the present invention comprises a verbamine compound or a salt thereof as an active ingredient, wherein the Berbamine compound or a pharmaceutically acceptable salt thereof is 1 Lt; RTI ID = 0.0 > uM. ≪ / RTI >
상기 염은 바람직하게는 약학적으로 허용 가능한 염의 형태로 사용될 수 있는데, 상기 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의하여 형성된 산 부가염이 바람직하며, 상기 유리산으로는 유기산과 무기산을 사용할 수 있다. 상기 유기산은 이에 제한되는 것은 아니나, 구연산, 초산, 젖산, 주석산, 말레인산, 푸마르산, 포름산, 프로피온산, 옥살산, 트리플로오로아세트산, 벤조산, 글루콘산, 메타술폰산, 글리콜산, 숙신산, 4-톨루엔술폰산, 글루탐산 및 아스파르트산을 포함한다. 또한 상기 무기산은 이에 제한되는 것은 아니나, 염산, 브롬산, 황산 및 인산을 포함한다. The salt may preferably be used in the form of a pharmaceutically acceptable salt, wherein the salt is preferably an acid addition salt formed by a pharmaceutically acceptable free acid, Inorganic acids may be used. The organic acids include, but are not limited to, citric, acetic, lactic, tartaric, maleic, fumaric, formic, propionic, oxalic, trifluroacetic, benzoic, gluconic, methosulfonic, glycolic, succinic, Glutamic acid and aspartic acid. The inorganic acid includes, but is not limited to, hydrochloric acid, bromic acid, sulfuric acid, and phosphoric acid.
본 발명에 따른 화합물은 천연으로부터 분리되거나 당업계에 공지된 화학적 합성법으로 제조된 것을 사용할 수 있다. The compound according to the present invention can be isolated from nature or can be prepared by chemical synthesis methods known in the art.
본 발명에서 상기 "면역질환"은 포유류 면역계의 구성성분들이 포유류의 병리상태를 야기하거나, 매개하거나 또는 기타 공헌하는 질환을 의미한다. 또한, 면역 반응의 자극 또는 중단이 그 질병의 진행에 보상적인 효과를 갖는 질환을 모두 포함할 수 있는데, 본 발명에서는 과민성 면역반응으로 인해 야기되는 질환들을 포함할 수 있다. 이러한 면역질환의 예로는 이에 제한되지는 않으나, 자가면역질환; 염증성질환; 및 세포, 조직 또는 기관의 이식거부(transplantation rejection)질환 등을 모두 포함할 수 있다.In the present invention, the term "immune disease" means diseases in which constituents of the mammalian immune system cause, mediate, or contribute to a pathological condition of a mammal. In addition, the stimulation or discontinuation of the immune response may include all diseases that have a compensatory effect on the progress of the disease, and the present invention may include diseases caused by an irritable immune response. Examples of such immune disorders include, but are not limited to, autoimmune diseases; Inflammatory disease; And transplantation rejection diseases of cells, tissues or organs, and the like.
또한, 모든 정상 개체에 있어서 가장 중요한 특성 중의 하나는 자기(self)를 구성하고 있는 항원물질에 대해서는 해롭게 반응하지 않는 반면, 비자기(non-self) 항원들에 대해서는 이를 인식하고 반응하여 제거할 수 있는 능력을 가지고 있다. 이처럼 자기항원에 대한 생체의 무반응을 면역학적 무반응성(immunologic unresponsiveness) 또는 관용(tolerance)이라고 한다.In addition, one of the most important properties of all normal individuals is that they do not react negatively to the antigenic material that constitutes the self, while non-self antigens are recognized and reacted to remove I have the ability. Such a non-response of a living body to a self-antigen is called immunologic unresponsiveness or tolerance.
그러나 이러한 자기관용을 유도하거나 계속 유지하는데 있어서 문제가 생기게 되면 자기항원에 대하여 면역반응이 일어나게 되고, 이로 인하여 자신의 조직을 공격하는 현상이 발생하는데 이러한 과정에 의해 발생되는 질환을 "자가면역질환"이라고 한다.However, when problems arise in inducing or maintaining such self-tolerance, an immune response to the self-antigen occurs, thereby attacking the tissue of the self. The disease caused by this process is called "autoimmune disease" .
또한, "염증성 질환"이란 염증유발인자 또는 방사선조사 등 유해한 자극으로 인해 인체 면역체계를 과도하게 항진시켜 대식세포와 같은 면역세포에서 분비되는 TNF-(tumor necrosis factor-), LPS, IL-17, IL-10, IFN-r, IL-1(interleukin-1), IL-6, 프로스타글란딘(prostagladin), 루코트리엔(luecotriene) 또는 산화질소(nitric oxide, NO)와 같은 염증유발물질(염증성 사이토카인)에 의해 유발되는 질환을 말한다."Inflammatory diseases" refer to TNF- (tumor necrosis factor-), LPS, IL-17, and IL-17 secreted from immune cells such as macrophages by overexpressing the human immune system due to harmful stimuli such as inflammation inducers or radiation. Inflammatory agents such as IL-10, IFN-r, IL-1 (interleukin-1), IL-6, prostagladin, luecotriene or nitric oxide Cain). ≪ / RTI >
또한 성공적인 장기 이식을 위해서는 이식할 세포 및 장기에 대한 수혜자의 면역 거부반응을 극복해야 한다. 이식면역거부반응의 주요 매개체는 T 세포로서, 이식편(graft)에 발현되어져 있는 주조직적합성분자(major histocompatibility complex, MHC)를 T 세포 수용체(T cell receptor)가 인지함으로써 면역반응이 유도되어 이식거부반응이 발생되게 된다. 주조직적합성분자는 당단백 항원의 종류에 따라 결정되는데, 조직적합항원이 일치하지 않아서 일어나는 면역반응은 성공적인 이식을 가로막는 장애가 되고 있어, 조직적합항원 검사의 정확성과 일치 여부의 조사는 매우 중요한 요소이다. Successful organ transplants also need to overcome the recipient's immune rejection response to cells and organs to be transplanted. The main mediator of transplantation immune rejection is T cell, which is expressed in the graft. Major histocompatibility complex (MHC) is recognized by T cell receptor (T cell receptor) A reaction occurs. The main histocompatibility molecule is determined by the type of glycoprotein. The immune response caused by the inconsistency of the histocompatibility antigens is an obstacle to successful transplantation. Therefore, it is very important to investigate the accuracy of the histocompatibility antigen test.
사람에게는 여러 종류의 조직적합항원이 있는데, 그 중 HLA-A, -B, -C를 포함하는 Class I 항원이 있고, HLA-DR,-DP, -DQ를 포함하는 Class II 항원이 있다. 이들 항원의 생물학적 기능은 T 림프구에게 항원을 전달하며, Class I 항원은 대부분의 유핵세포에서 발현되며 이를 통해 전달되는 항원들은 CD8+ 세포독성 T 림프구에 의해 인식된다. Class II 항원은 항원제시세포로 알려진 수지상세포, B 림프구, 활성화된 T 림프구, 큰포식세포 등에서 발현되며, CD4+ T 림프구에게 항원을 전달하는 기능을 한다. T 림프구에 전달된 항원들은 T 림프구 수용체에 결합함으로써 T 림프구가 항원을 인식하게 되는데 이식하는 과정에서 자신의 것이 아닌 다른 사람으로부터 유래한 조직적합항원을 높은 빈도로 인식하게 된다. 공여자 또는 환자의 전체 T 림프구 중 1~10% 정도가 환자 또는 공여자로부터 유래한 조직적합항원을 인식하여 이에 대한 반응으로 증식하게 되고, 일련의 면역반응을 일으키게 되는데 이를 "동종반응(Alloresponse)"라고 한다. 또한 공여자의 T 림프구가 환자의 조직적합항원에 대하여 면역반응을 일으키는 것을 이식편대숙주질환(GVDH)"라고 하며, 반대로 환자의 T 림프구가 공여자의 조직적합항원에 대하여 일으키는 반응을 이식거부반응(graft rejection)"이라고 한다.There are several types of histocompatibility antigens in humans, including Class I antigens that include HLA-A, -B, and -C, and Class II antigens that include HLA-DR, -DP, and -DQ. The biological function of these antigens is to transmit antigens to T lymphocytes. Class I antigens are expressed in most nucleated cells, and the antigens transferred through them are recognized by CD8 + cytotoxic T lymphocytes. Class II antigens are expressed in dendritic cells known as antigen presenting cells, B lymphocytes, activated T lymphocytes, and large predominant cells, and function to transfer antigen to CD4 + T lymphocytes. The T lymphocytes recognize the antigen by binding to the T lymphocyte receptor, and the transplantation recognizes the tissue-compatible antigen from other people as a high frequency. About 1% to 10% of the total T lymphocytes of the donor or patient recognize a tissue-compatible antigen derived from the patient or donor and multiply in response to this, resulting in a series of immune responses called "alloresponse" do. In addition, the donor T lymphocyte responds to the tissue-specific antigen (GVDH) of the patient, and the response of the patient's T lymphocytes to donor tissue-positive antigen is called graft rejection rejection ".
따라서 이식 과정에서 발생하는 면역반응에 의한 비정상적인 반응을 감소시키기 위해 면역억제제들이 사용되고 있는데 이러한 면역억제제들의 공통된 목적은 이식편에 대한 T 세포-매개 면역반응을 억제하는 것이다. 이러한 점에서 본 발명의 베르바민 화합물은 동종반응 억제 효과가 있어 이식거부 반응의 치료제로 사용할 수 있다. Immunosuppressive agents have been used to reduce abnormal reactions caused by immune reactions during transplantation. A common goal of these immunosuppressants is to inhibit T cell-mediated immune responses to grafts. In this respect, the verbamine compound of the present invention has an allogeneic inhibitory effect and can be used as a therapeutic agent for graft rejection.
본 발명에서 예방 및 치료할 수 있는 상기 면역질환에서, 상기 자가면역질환은 이에 제한되지는 않으나, 류마티스 관절염 (Rheumatoid Arthritis), 천식 (Asthma), 피부염 (Dermititis), 건선 (Psoriasis), 낭섬유증 (Cystic Fibrosis), 다발성 경화증 (Multiple Sclerosis), 전신성 홍반성 루푸스(systemic lupus erythematosus), 쇼그렌 증후군(Sjogren syndrome), 하시모토 갑상선(Hashimoto thyroiditis), 다발성근염(polymyositis), 경피증(scleroderma), 아디슨병(Addison disease), 백반증(vitiligo), 악성빈혈(pernicious anemia), 사구체신염(glomerulonephritis) 및 폐섬유증(pulmonary fibrosis), 염증성장질환 (Inflammatory Bowel Dieseses), 자가면역성 당뇨 (Autoimmune Diabetes), 당뇨 망막증 (Diabetic retinopathy), 비염 (Rhinitis), 혀혈-재관류 손상 (Ischemia-reperfusion injury), 혈관성형술후 재협착 (Post-angioplasty restenosis), 만성 폐색성 심장 질환 (Chronic obstructive pulmonary diseases; COPD), 그레이브병 (Graves disease), 위장관 알러지 (Gastrointestinal allergies), 결막염 (Conjunctivitis), 죽상경화증 (Atherosclerosis), 관상동맥질환 (Coronary artery disease), 협심증 (Angina), 암 전이 및 소동맥 질환 등을 포함할 수 있다.In the above immunological diseases which can be prevented and treated in the present invention, the autoimmune diseases include, but are not limited to, rheumatoid arthritis, asthma, dermatitis, psoriasis, cystic fibrosis Fibrosis, Multiple Sclerosis, Systemic lupus erythematosus, Sjogren's syndrome, Hashimoto thyroiditis, polymyositis, scleroderma, Addison disease Glomerulonephritis and pulmonary fibrosis, Inflammatory Bowel Dieses, Autoimmune Diabetes, Diabetic retinopathy, and the like. The term " diabetic retinopathy " , Rhinitis, Ischemia-reperfusion injury, Post-angioplasty restenosis, Chronic obstruciton (Chronic obstruc- tive) cystic fibrosis, ctive pulmonary diseases (COPD), Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina, cancer metastasis, Diseases, and the like.
또한, 상기 세포, 조직 또는 기관의 이식거부반응은 이에 제한되지는 않으나, 골수 이식, 심장 이식, 각막 이식, 장 이식, 간 이식, 폐 이식, 췌장 이식, 신장 이식 및 피부이식의 거부반응을 포함할 수 있다. The transplant rejection of the cells, tissues or organs includes, but is not limited to, bone marrow transplantation, heart transplantation, corneal transplantation, intestinal transplantation, liver transplantation, lung transplantation, pancreas transplantation, kidney transplantation, can do.
그러므로 본 발명에 따른 상기 조성물은 면역질환을 예방 또는 치료할 수 있는 약학적 조성물로 사용될 수 있고, 상기 "치료"란, 달리 언급되지 않는 한, 상기 용어가 적용되는 질환 또는 질병, 또는 상기 질환 또는 질병의 하나 이상의 증상을 역전시키거나, 완화시키거나, 그 진행을 억제하거나, 또는 예방하는 것을 의미하며, 본원에서 사용된 상기 치료란 용어는 "치료하는"이 상기와 같이 정의될 때 치료하는 행위를 말한다. 따라서 포유동물에 있어서 면역질환의 "치료" 또는 "치료요법"은 하기의 하나 이상을 포함할 수 있다:Therefore, the composition according to the present invention can be used as a pharmaceutical composition capable of preventing or treating an immunological disease, and the above-mentioned "treatment" means a disease or a disease to which the term is applied, Refers to reversing, alleviating, inhibiting, or preventing the progression of one or more symptoms of one or more symptoms of a disease or disorder, wherein the term treatment as used herein refers to the act of treating when "treating & It says. Thus, "treatment" or "treatment regimen" of an immune disorder in a mammal may include one or more of the following:
(1) 면역질환의 성장을 저해함, 즉, 그 발달을 저지시킴,(1) inhibiting the growth of the immune system, i.e., inhibiting its development,
(2) 면역질환의 확산을 예방함, 즉, 전이를 예방함,(2) preventing the spread of immune diseases, i.e., preventing metastasis,
(3) 면역질환을 경감시킴.(3) Reducing immune diseases.
(4) 면역질환의 재발을 예방함, 및(4) preventing the recurrence of immune disorders, and
(5) 면역질환의 증상을 완화함(palliating)(5) palliating symptoms of immune disorders
본 발명에 따른 면역질환의 예방 또는 치료용 조성물은 약학적으로 유효한 양의 베르바민 화합물 또는 그의 염을 단독으로 포함하거나 하나 이상의 약학적으로 허용되는 담체, 부형제 또는 희석제를 포함할 수 있다. 상기에서 약학적으로 유효한 양이란 면역질환의 증상을 예방, 개선 및 치료하기에 충분한 양을 말한다.The composition for the prophylaxis or treatment of immune diseases according to the present invention may comprise a pharmaceutically effective amount of a verbamine compound or a salt thereof alone or may comprise one or more pharmaceutically acceptable carriers, excipients or diluents. A pharmaceutically effective amount as used herein refers to an amount sufficient to prevent, ameliorate, and treat symptoms of an immune disease.
본 발명에 따른 상기 베르바민 화합물 또는 그의 염의 약학적으로 유효한 양은 면역질환 증상의 정도, 환자의 연령, 체중, 건강상태, 성별, 투여 경로 및 치료기간 등에 따라 적절히 변화될 수 있다.The pharmaceutically effective amount of the verbamine compound or its salt according to the present invention may be appropriately changed depending on the degree of the symptoms of the immune disease, the age, body weight, health condition, sex, administration route and treatment period of the patient.
또한, 상기에서 약학적으로 허용되는이란 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 조성물을 말한다. 상기 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다. Also, the pharmaceutically acceptable hereinabove is physiologically acceptable and refers to a composition which, when administered to a human, does not normally cause an allergic reaction such as a gastrointestinal disorder, dizziness, or the like. Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Further, it may further include a filler, an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and an antiseptic agent.
또한, 본 발명의 조성물은 포유동물에 투여된 후 활성 성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 당업계에 공지된 방법을 사용하여 제형화될 수 있다. 제형은 분말, 과립, 정제, 에멀젼, 시럽, 에어로졸, 연질 또는 경질 젤라틴 캅셀, 멸균 주사용액, 멸균 분말의 형태일 수 있다. In addition, the compositions of the present invention may be formulated using methods known in the art so as to provide rapid, sustained or delayed release of the active ingredient after administration to the mammal. The formulations may be in the form of powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatine capsules, sterile injectable solutions, sterile powders.
또한, 본 발명에 따른 면역질환의 예방 또는 치료용 조성물은 경구, 경피, 피하, 정맥 또는 근육을 포함한 여러 경로를 통해 투여될 수 있으며, 활성 성분의 투여량은 투여 경로, 환자의 연령, 성별, 체중 및 환자의 중증도 등의 여러 인자에 따라 적절히 선택될 수 있고, 본 발명에 따른 면역질환의 예방 또는 치료용 조성물은 면역질환의 증상을 예방, 개선 또는 치료하는 효과를 가지는 공지의 화합물과 병행하여 투여할 수 있다.In addition, the composition for preventing or treating immunological diseases according to the present invention may be administered through various routes including oral, transdermal, subcutaneous, intravenous, or muscular, and the dose of the active ingredient may be appropriately determined depending on the route of administration, The composition of the present invention can be appropriately selected according to various factors such as body weight and the severity of the patient and the composition for preventing or treating immune diseases according to the present invention can be used in combination with known compounds having the effect of preventing, Lt; / RTI >
본 발명은 또한, 포유동물에게 치료상 유효량의 본 발명의 약제학적 조성물을 투여하는 것을 포함하는 면역질환의 예방 또는 치료방법을 제공한다.The present invention also provides methods of preventing or treating immune disorders comprising administering to a mammal a therapeutically effective amount of a pharmaceutical composition of the invention.
여기에서 사용된 용어 "포유동물"은 치료, 관찰 또는 실험의 대상인 포유동물을 말하며, 바람직하게는 인간을 말한다.The term "mammal " as used herein refers to a mammal that is the subject of treatment, observation or experimentation, preferably a human.
여기에서 사용된 용어 "치료상 유효량"은 연구자, 수의사, 의사 또는 기타 임상에 의해 생각되는 조직계, 동물 또는 인간에서 생물학적 또는 의학적 반응을 유도하는 유효 성분 또는 약학적 조성물의 양을 의미하는 것으로, 이는 치료되는 질환 또는 장애의 증상의 완화를 유도하는 양을 포함한다. 본 발명의 유효 성분에 대한 치료상 유효 투여량 및 투여횟수는 원하는 효과에 따라 변화될 것임은 당업자에게 자명하다. 그러므로, 투여될 최적의 투여량은 당업자에 의해 쉽게 결정될 수 있으며, 질환의 종류, 질환의 중증도, 조성물에 함유된 유효성분 및 다른 성분의 함량, 제형의 종류, 및 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 분비율, 치료기간, 동시 사용되는 약물을 비롯한 다양한 인자에 따라 조절될 수 있다.The term "therapeutically effective amount " as used herein refers to the amount of active ingredient or pharmaceutical composition that induces a biological or medical response in a tissue system, animal or human, as contemplated by a researcher, veterinarian, physician or other clinician, The amount that induces the relief of the symptoms of the disease or disorder being treated. It will be apparent to those skilled in the art that the therapeutically effective dose and the number of administrations of the active ingredient of the present invention will vary depending on the desired effect. Thus, the optimal dosage to be administered can be readily determined by those skilled in the art and will vary with the nature of the disease, the severity of the disease, the amount of active and other ingredients contained in the composition, the type of formulation, and the age, The age, body weight, sex, diet, time of administration, route of administration and fraction of the composition, duration of treatment, concurrent medication, and the like.
또한, 본 발명은 베르바민을 유효성분으로 포함하는 면역질환의 예방 또는 개선용 건강기능식품을 제공한다.The present invention also provides a health functional food for preventing or ameliorating an immune disease comprising verbamine as an active ingredient.
본 발명의 건강기능식품은 면역질환의 예방 또는 개선을 목적으로, 정제, 캅셀, 분말, 과립, 액상, 환 등의 형태로 제조 및 가공할 수 있다.The health functional food of the present invention can be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, and rings for the purpose of preventing or improving immunological diseases.
본 발명에서 건강기능식품이라 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 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.In the present invention, the term "health functional food" refers to a food prepared and processed by using raw materials or ingredients having useful functions in accordance with Law No. 6727 on Health Functional Foods, and the nutritional control on the structure and function of the human body Or for the purpose of obtaining a beneficial effect for health use such as physiological action.
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.The health functional foods of the present invention may contain conventional food additives and, unless otherwise specified, whether or not they are suitable as food additives are classified according to the General Rules for Food Additives approved by the Food and Drug Administration, Standards and standards.
상기 식품 첨가물 공전에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼슘, 니코틴산, 계피산 등의 화학적 합성물; 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물; L-글루타민산나트륨제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류 등을 들 수 있다.Examples of the food items included in the above food additives include chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; Natural additives such as persimmon extract, licorice extract, crystalline cellulose, high color pigment and guar gum; L-glutamic acid sodium preparations, noodle-added alkalis, preservative preparations, tar coloring preparations and the like.
예를 들어, 정제 형태의 건강기능식품은 본 발명의 유효성분인 베르바민을 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.For example, the health functional food in the form of tablets may be prepared by granulating a mixture of verbamine, an active ingredient of the present invention, with an excipient, a binder, a disintegrant and other additives in a usual manner, and then adding a lubricant, Alternatively, the mixture can be directly compression molded. In addition, the health functional food of the tablet form may contain a mating agent or the like if necessary.
캅셀 형태의 건강기능식품 중 경질 캅셀제는 통상의 경질 캅셀에 본 발명의 유효성분인 베르바민을 부형제 등의 첨가제와 혼합한 혼합물을 충진하여 제조할 수 있으며, 연질 캅셀제는 베르바민을 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.The hard capsule of the capsule type health functional food can be prepared by filling a normal hard capsule with a mixture of verbamine, an active ingredient of the present invention, with an excipient such as an excipient. The soft capsule is prepared by adding verbamine as an excipient And filling the mixture with a capsule base such as gelatin. The soft capsule may contain a plasticizer such as glycerin or sorbitol, a coloring agent, a preservative and the like, if necessary.
환 형태의 건강기능식품은 본 발명의 유효성분인 베르바민을 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.The ring-shaped health functional food can be prepared by molding a mixture of verbamine, which is an active ingredient of the present invention, with an excipient, a binder, a disintegrant, etc., by a conventionally known method, and if necessary, Or the surface may be coated with a material such as starch, talc.
과립 형태의 건강기능식품은 본 발명의 유효성분인 베르바민과 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 입상으로 제조할 수 있으며, 필요에 따라 착향제, 교미제 등을 함유할 수 있다.The granular form of the health functional food may be prepared by granulating a mixture of verbamine, an active ingredient of the present invention, excipient, binder, disintegrant, etc., into granules by a known method, and if necessary, adding a flavoring agent, ≪ / RTI >
상기 건강기능식품은 음료류, 육류, 초코렛, 식품류, 과자류, 피자, 라면, 기타 면류, 껌류, 사탕류, 아이스크림류, 알코올 음료류, 비타민 복합제 및 건강보조식품류 등일 수 있다. The health functional food may be a beverage, a meat, a chocolate, a food, a confectionery, a pizza, a ramen, a noodle, a gum, a candy, an ice cream, an alcoholic beverage, a vitamin complex and a health supplement food.
이하 본 발명을 실시예에 의하여 더욱 상세하게 설명한다. 이들 실시예는 단지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. It will be apparent to those skilled in the art that these embodiments are merely illustrative of the present invention and that the scope of the present invention is not limited to these embodiments.
<실시예 1>≪ Example 1 >
베르바민(berbamine)에 의한 염증성 사이토카인 억제 활성분석Analysis of inflammatory cytokine inhibitory activity by berbamine
본 발명자들은 베르바민(berbamine)이 염증성 사이토카인을 억제하는 활성이 있는지 확인하기 위해 하기와 같이 마우스 및 인간 말초단핵구 세포를 대상을 실험을 수행하였다.The present inventors conducted experiments on mouse and human peripheral mononuclear cells as described below to confirm that berbamine has an inflammatory cytokine inhibitory activity.
<1-1> 마우스 <1-1> Mouse 비장세포에서In splenocytes 베르바민에Verbamin 의한 염증성 사이토카인 억제 효과 분석 Of inflammatory cytokine inhibition
DBA1/J 정상 마우스군의 CD4 T 세포를 분리하였으며 분리된 세포에 anti-CD3 (0.5ug/ml)를 처리하여 세포 자극을 유도하였다. 이때 anti-CD3 처리와 동시에 베르바민 화합물을 각각 농도별(2uM, 10uM)로 처리하고 3일간 세포를 배양한 후, 배양액을 수득하였고, 수득한 배양액을 대상으로 ELISA 방법을 이용하여 IL-17, IFN-r, IL-10의 농도를 분석하였다.CD4 T cells from DBA1 / J normal mouse group were isolated and treated with anti-CD3 (0.5 ug / ml) to induce cell stimulation. At this time, the verbamine compound was treated with the anti-CD3 treatment (2 uM, 10 uM) at the same time, and the cells were cultured for 3 days. Then, the culture solution was obtained, and the obtained culture was subjected to ELISA, IFN-r, and IL-10 were analyzed.
또한, 본 발명자들은 상기 방법으로 수득한 DBA1/J 정상 마우스군의 CD4 T 세포를 대상으로 LPS(100ng/ml)처리와 동시에 베르바민 화합물을 각각 농도별(2uM, 10uM)로 처리하고 3일간 세포를 배양한 후, 배양액을 수득하였고, 수득한 배양액을 대상으로 ELISA 방법을 이용하여 IL-6, TNF-a, IL-10의 농도를 분석하였다. In addition, the present inventors treated the CD4 T cells of the DBA1 / J normal mouse group obtained by the above method with LPS (100 ng / ml) and verbamine compounds at the concentration (2 uM, 10 uM) , And the culture solution was obtained. The concentrations of IL-6, TNF-a and IL-10 were analyzed using the ELISA method.
상기 실험에서 대조군으로는 각각 anti-CD3 단독 및 LPS 단독 처리군을 사용하였다.In this experiment, anti-CD3 alone and LPS alone treatment groups were used as control groups, respectively.
분석 결과, 도 1에 나타낸 바와 같이, anti-CD3만을 처리한 세포들에서는 염증성 사이토카인인 IL-17, IFN-r, IL-10의 생성이 현저히 증가되어 있었으나, 베르바민 화합물을 함께 처리한 군에 대해서는 대조군에 비해 IL-17, IFN-r, IL-10의 생성이 현저하게 억제되어 있는 것으로 나타났고, 특히 베르바민 화합물을 2uM의 농도로 처리한 경우가 10uM로 처리한 경우에 비해 염증성 사이토카인의 생성 억제효능이 더 우수한 것을 알 수 있었다.As shown in FIG. 1, IL-17, IFN-r and IL-10, which are inflammatory cytokines, were significantly increased in cells treated with anti-CD3 alone, The production of IL-17, IFN-r and IL-10 was markedly suppressed in comparison with the control group. In particular, when the verbamine compound was treated at a concentration of 2 uM, the inflammatory cytokine It was found that the effect of inhibiting the formation of cain was better.
또한, LPS로 세포 자극을 유도한 경우에는 도 2에 나타낸 바와 같이 LPS만 처리한 대조군에 비해 베르바민 화합물을 처리한 군에서 농도 의존적으로 염증성 사이토카인인 IL-6, TNF-a, IL-10의 생성이 억제되는 것을 알 수 있었다.2, IL-6, TNF-a, and IL-10, which are concentration-dependent in a concentration-dependent manner in the group treated with verbamine compared to the control group treated with LPS alone, Was suppressed.
<1-2> 인간의 말초단핵구 세포(PBMC)에서 베르바민에 의한 염증성 사이토카인 억제 효과 분석<1-2> Inhibitory effect of verbamine on inflammatory cytokine in human peripheral mononuclear cell (PBMC)
정상인으로부터 말초단핵구세포(peripheral blood mononuclear cells, PBMC)를 Ficoll Paque TM으로 원심분리기로 비중차를 이용하여 분리하였다. 분리한 말초단핵구세포를 대상으로 anti-CD3(0.5ug/ml)을 2시간동안 plate bound form으로 coating 한 후 이 well에 베르바민 화합물을 10uM 및 20uM의 농도로 각각 처리 후 3일간 배양한 세포배양액을 수득하여 ELISA 방법을 통해 IL-17, IFN-r의 농도를 측정하였다. 이때 대조군으로는 anti-CD3(0.5ug/ml)만 단독 처리한 군을 사용하였다. Peripheral blood mononuclear cells (PBMCs) from normal subjects were separated by centrifugation using a Ficoll Paque TM using a specific gravity difference. Separated peripheral mononuclear cells were coated with anti-CD3 (0.5 ug / ml) for 2 hours in a plate bound form, and the cells were treated with verbamine compound at a concentration of 10 uM and 20 uM for 3 days, And the concentrations of IL-17 and IFN-r were measured by an ELISA method. At this time, anti-CD3 (0.5 ug / ml) alone group was used as the control group.
분석결과, 도 3에 나타낸 바와 같이, 베르바민 화합물 처리에 의해 anti-CD3 자극에 따른 염증성 사이토카인인 IL-17, IFN-r의 생성이 모두 억제되는 것으로 나타났고, 베르바민 화합물 농도 의존적으로 억제되는 것으로 나타났다. As shown in FIG. 3, the production of IL-17 and IFN-r, which are inflammatory cytokines induced by anti-CD3 stimulation, was all suppressed by the treatment with verbamine compound, .
<1-3> 인간 <1-3> Human CD4TCD4T 세포에서 In a cell 베르바민에Verbamin 의한 염증성 사이토카인 억제 효과 분석 Of inflammatory cytokine inhibition
상기 실시에 <1-2>에서 분리한 인간 말초단핵구 세포로부터 인간 CD4+T세포를 분리하였는데, CD4+ T 세포는 분리된 PBMC를 CD4 Microbeads를 4℃에서 15분간 반응시킨 후, MACs 버퍼로 세척한 뒤 MS column을 사용하여 양성분획으로 CD4 + T세포를 분리하였다. 분리된 CD4+ T세포는 PBS로 세척하였고 55℃에서 30분 동안 불활성화된 10% 우태아 혈청, 페니실린(100U/mL) 및 스트렙토마이신(100 g/mL)이 포함된 세포 배양액 (RPMI1640 배지, Gibco BRL, USA)에서 배양하여 실험에 사용하였다. Human CD4 + T cells were isolated from the human peripheral mononuclear cells isolated in the above <1-2>. CD4 + T cells were isolated from the PBMCs by reacting with CD4 Microbeads at 4 ° C for 15 minutes and then washed with MACs buffer CD4 + T cells were isolated with positive fractions using the back MS column. Separated CD4 + T cells were washed with PBS and cultured in a cell culture medium (RPMI1640 medium, Gibco (R)) containing 10% fetal bovine serum, penicillin (100 U / mL) and streptomycin BRL, USA).
상기 방법으로 분리된 CD4+ T세포에 anti-CD3(0.5ug/ml)을 2시간동안 plate bound form으로 coating 한 후 이 well에 베르바민 화합물을 10uM 및 20uM의 농도로 각각 처리 후 3일간 배양한 세포배양액을 수득하였고, 배양액을 대상으로 ELISA 방법을 통해 IL-17, IFN-r의 농도를 측정하였다. 이때 대조군으로는 anti-CD3(0.5ug/ml)만 단독 처리한 군을 사용하였다.The CD4 + T cells isolated by the above method were coated with anti-CD3 (0.5 ug / ml) for 2 hours in a plate bound form, followed by treatment with verbamine compound at a concentration of 10 uM and 20 uM for 3 days And the concentrations of IL-17 and IFN-r were measured by ELISA. At this time, anti-CD3 (0.5 ug / ml) alone group was used as the control group.
분석결과, 도 4에 나타낸 바와 같이, 인간 CD4+ T세포에서도 베르바민 화합물 처리에 의해 anti-CD3 자극에 의한 IL-17, IFN-r의 생성이 모두 억제되는 것으로 나타났고, 베르바민 화합물 농도 의존적으로 억제되었다.As a result of the analysis, as shown in Fig. 4, the production of IL-17 and IFN-r by the anti-CD3 stimulation was also inhibited by the treatment with verbamine compound in human CD4 + T cells, .
따라서 본 발명자들은 상기와 같은 결과를 통해, 본 발명의 베르바민 화합물이 염증성 사이토카인의 생성을 효과적으로 억제할 수 있다는 사실을 확인함으로써 베르바민 화합물이 염증성 사이토카인에 의한 면역질환을 효과적으로 예방 또는 치료할 수 있음을 알 수 있었다.Therefore, the present inventors confirmed that the verbamine compound of the present invention can effectively inhibit the production of inflammatory cytokines through the above-mentioned results, so that the verbamine compound can effectively prevent or treat immune diseases caused by inflammatory cytokines .
<실시예 2>≪ Example 2 >
간질환 환자의 말초단핵구 세포에서 베르바민(berbamine)에 의한 염증성 사이토카인 억제 활성분석Analysis of inflammatory cytokine inhibitory activity by berbamine in peripheral mononuclear cells of patients with liver disease
베르바민 화합물이 자가면역질환, 특히 이식거부질환에 대한 치료제로서의 사용 가능성이 있는지 확인하기 위해, 간질환 환자의 말초단핵구 세포에서 베르바민 화합물에 의한 염증성 사이토카인 억제 여부를 분석하였다.To determine whether the verbamine compound could be used as a therapeutic agent for autoimmune diseases, particularly transplant rejection diseases, the inhibition of inflammatory cytokines by verbamine compounds in peripheral mononuclear cells of liver disease patients was analyzed.
이를 위해, 간질환 말기 환자로부터 말초단핵구 세포를 수득하였는데, 수득 방법은 상기 실시예 <1-2>의 방법과 동일하게 수행하여 세포를 분리하였다. 분리된 간질환 환자의 PBMC 세포에 anti-CD3(0.5ug/ml)을 2시간동안 plate bound form으로 coating 한 후 이 well에 베르바민 화합물을 10uM 및 20uM의 농도로 각각 처리 후 3일간 배양한 세포배양액을 수득하였고, 배양액을 대상으로 ELISA 방법을 통해 IL-17, IFN-r의 농도를 측정하였다. 이때 대조군으로는 anti-CD3(0.5ug/ml)만 단독 처리한 군을 사용하였다. To this end, peripheral mononuclear cells were obtained from patients at the end of liver disease, and the cells were isolated by performing the same method as in Example <1-2>. PBMCs from patients with isolated liver disease were coated with anti-CD3 (0.5 ug / ml) in a plate-bound form for 2 hours, then treated with verbamine compound at concentrations of 10 uM and 20 uM for 3 days And the concentrations of IL-17 and IFN-r were measured by ELISA. At this time, anti-CD3 (0.5 ug / ml) alone group was used as the control group.
그 결과, 도 5에 나타낸 바와 같이, 환자의 말초단핵구 세포에서도 베르바민 화합물 처리 시, 염증성 사이토카인(IL-17, IFN-r)의 생성이 억제되는 것으로 나타났다. As a result, as shown in Fig. 5, the peripheral mononuclear cells of the patients were also found to inhibit the production of inflammatory cytokines (IL-17, IFN-r) upon treatment with verbamine compounds.
따라서 이러한 결과를 통해 본 발명자들은 세포 이식을 수행할 때, 염증성사이토카인에 의해 유발되는 이식거부 반응을 베르바민이 효과적으로 억제하여 이식 거부 반응을 억제할 수 있다는 것을 알 수 있었다.Therefore, the inventors of the present invention have found that verbamine effectively inhibits the graft rejection reaction induced by inflammatory cytokines when the cell transplantation is carried out, thereby inhibiting the graft rejection reaction.
<실시예 3>≪ Example 3 >
베르바민에 의한 STAT3 활성 억제 분석STAT3 activity inhibition assay by verbamine
베르바민 화합물이 STAT3의 활성을 억제하는 작용이 있는지 분석하였다. 이를 위해 STAT3 luciferase 벡터로 형질 전환된 세포주인 HeLa 세포주를 사용하였다. STAT3가 과발현 되어 있는 세포주에 약물을 농도별로 처리 한 후에 48시간 배양 후에 luciferase assay를 통해서 값을 측정 하였다. 대조군으로는 아무것도 도입하지 않은 HeLa 세포주를 사용하였다.We examined whether the verbamine compound inhibits the activity of STAT3. For this, HeLa cell line transformed with STAT3 luciferase vector was used. STAT3 overexpression was measured by luciferase assay after culturing for 48 hours. As a control group, a HeLa cell line was used, in which nothing was introduced.
분석결과, 도 6에 나타낸 바와 같이, 베르바민 화합물이 STAT3의 활성을 억제하는 작용이 있음을 알 수 있었고, 다양한 농도에서 활성 정도를 분석한 결과, 5uM로 베르바민을 처리한 군이 다른 군에 비해 우수한 STAT3 활성 억제를 보였다.As a result of the analysis, it was found that the verbamine compound inhibits the activity of STAT3 as shown in FIG. 6. As a result of analyzing the degree of activity at various concentrations, the group treated with verbamine at 5 uM was divided into the other group Showed a superior inhibition of STAT3 activity.
<실시예 4><Example 4>
베르바민에 의한 동종반응(Alloresponse) 억제효과 분석Analysis of inhibition of alloresponse by verbamine
이식 후, 베르바민 화합물이 거부반응을 억제할 수 있는지 확인하기 위해, In vitro에서 96well의 각 웰 당 1×105개의 정상 수여자(Balb/c, responder)의 CD4+T cell와 1×105개의 방사선으로 조사시킨 수여자(동종동형) 또는 공여자(C57BL/6, stimulator,동종이형) 유래 T 세포 제거 비장세포를 넣고 혼합 배양시켜 동종반응을 유도하였다. 또한, 이때 베르바민 화합물을 2uM 및 10uM을 함께 처리한 후 72시간 배양시켰다. 배양완료 16시간 전에 배양된 세포에서 T 세포 증식 반응 정도를 3H Thymidine을 처리하고 세포증식 정도를 b 카운터로 3H Thymidine의 양을 측정하여 확인하였다.In order to ensure that after transplantation, suberic bamin compound can suppress rejection, CD4 + T cell with 1 × 10 in each well of the 96well 1 × 10 5 of the top grantor (Balb / c, responder) in In vitro T cell removal from 5 irradiated recipients (homozygous isotype) or donor (C57BL / 6, stimulator, allogeneic type) splenocytes were added and cultured to induce allogeneic responses. At this time, the verbamine compound was treated with 2 uM and 10 uM, followed by incubation for 72 hours. The degree of T cell proliferation was examined by measuring the amount of 3H thymidine in the b-counter by treating 3H thymidine in the cultured cells 16 hours before culturing.
그 결과 도 7에서 나타낸 바와 같이, 본 발명의 베르바민 화합물을 처리한 실험군에서 동종반응(Alloresponse)이 두드러지게 억제되는 것을 확인할 수 있었다.As a result, as shown in Fig. 7, it was confirmed that the alloresponse was remarkably inhibited in the experimental group treated with the verbamine compound of the present invention.
따라서 이러한 결과를 통해 본 발명자들은 베르바민 화합물이 이식 과정에서 발생할 수 있는 T 세포의 이식후 거부반응 및 동종반응을 효과적으로 억제할 수 있어 이식에 의한 질환 치료를 성공적으로 유도할 수 있다는 사실을 알 수 있었다. Accordingly, the present inventors have found that the verbamine compound can effectively inhibit post-graft rejection reaction and homologous reaction that can occur in the transplantation process, and can successfully induce the treatment of the disease by graft there was.
이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.
Claims (12)
상기 베르바민(Berbamine) 화합물 또는 이의 약학적으로 허용 가능한 염은 1~30uM의 농도로 상기 조성물에 함유되어 있는 것을 특징으로 하는 면역질환의 예방 또는 치료용 조성물. The method according to claim 1,
Wherein the Berbamine compound or a pharmaceutically acceptable salt thereof is contained in the composition at a concentration of 1 to 30 uM.
상기 베르바민(Berbamine) 화합물 또는 이의 약학적으로 허용 가능한 염은 염증성 사이토카인의 생성을 감소 또는 억제시키고, STAT3의 활성을 감소 또는 억제시키는 기작을 통해 치료 효과를 나타내는 것을 특징으로 하는 면역질환의 예방 또는 치료용 조성물. The method according to claim 1,
Wherein the Berbamine compound or a pharmaceutically acceptable salt thereof reduces or inhibits the production of inflammatory cytokines and exhibits a therapeutic effect through a mechanism of decreasing or inhibiting the activity of STAT3. Or < / RTI >
상기 염증성 사이토카인은 IL-17, IFN-r, IL-10, IL-6 또는 TNF-a인 것을 특징으로 하는 면역질환의 예방 또는 치료용 조성물. The method of claim 3,
Wherein said inflammatory cytokine is IL-17, IFN-r, IL-10, IL-6 or TNF-a.
상기 염증성 사이토카인은 anti-CD3 또는 LPS 에 의해 유도되는 것을 특징으로 하는 면역질환의 예방 또는 치료용 조성물. The method of claim 3,
Wherein the inflammatory cytokine is induced by anti-CD3 or LPS.
상기 면역질환은 자가면역질환; 염증성질환; 또는 세포, 조직 또는 기관의 이식거부반응으로 이루어진 군 중에서 선택되는 것을 특징으로 하는 면역질환의 예방 또는 치료용 조성물. The method according to claim 1,
The immunological disease is autoimmune disease; Inflammatory disease; Or transplant rejection of cells, tissues or organs. ≪ RTI ID = 0.0 > 18. < / RTI >
상기 자가면역질환은 류마티스 관절염 (Rheumatoid Arthritis), 천식 (Asthma), 피부염 (Dermititis), 건선 (Psoriasis), 낭섬유증 (Cystic Fibrosis), 다발성 경화증 (Multiple Sclerosis), 전신성 홍반성 루푸스(systemic lupus erythematosus), 쇼그렌 증후군(Sjogren syndrome), 하시모토 갑상선(Hashimoto thyroiditis), 다발성근염(polymyositis), 경피증(scleroderma), 아디슨병(Addison disease), 백반증(vitiligo), 악성빈혈(pernicious anemia), 사구체신염(glomerulonephritis) 및 폐섬유증(pulmonary fibrosis), 염증성장질환 (Inflammatory Bowel Dieseses), 자가면역성 당뇨 (Autoimmune Diabetes), 당뇨 망막증 (Diabetic retinopathy), 비염 (Rhinitis), 혀혈-재관류 손상 (Ischemia-reperfusion injury), 혈관성형술후 재협착 (Post-angioplasty restenosis), 만성 폐색성 심장 질환 (Chronic obstructive pulmonary diseases; COPD), 그레이브병 (Graves disease), 위장관 알러지 (Gastrointestinal allergies), 결막염 (Conjunctivitis), 죽상경화증 (Atherosclerosis), 관상동맥질환 (Coronary artery disease), 협심증 (Angina), 암 전이 및 소동맥 질환으로 이루어진 군으로부터 선택되는 것을 특징으로 하는 면역질환의 예방 또는 치료용 조성물. The method according to claim 6,
The autoimmune diseases include rheumatoid arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, multiple sclerosis, systemic lupus erythematosus, Sjogren's syndrome, Hashimoto's thyroiditis, polymyositis, scleroderma, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, And inflammatory diseases such as pulmonary fibrosis, inflammatory bowel dieses, autoimmune diabetes, diabetic retinopathy, rhinitis, ischemia-reperfusion injury, angioplasty, Post-angioplasty restenosis, chronic obstructive pulmonary diseases (COPD), Graves disease, gastrointestinal allergies wherein the disease is selected from the group consisting of atherosclerosis, atherosclerosis, coronary artery disease, angina, cancer metastasis and arteriovenous disease. Composition.
상기 면역질환은 자가면역질환; 염증성질환; 또는 세포, 조직 또는 기관의 이식거부반응인 것을 특징으로 하는 면역질환의 예방 또는 개선용 건강기능성 식품.10. The method of claim 9,
The immunological disease is autoimmune disease; Inflammatory disease; Or a graft rejection reaction of cells, tissues or organs.
상기 자가면역질환은 류마티스 관절염 (Rheumatoid Arthritis), 천식 (Asthma), 피부염 (Dermititis), 건선 (Psoriasis), 낭섬유증 (Cystic Fibrosis), 다발성 경화증 (Multiple Sclerosis), 전신성 홍반성 루푸스(systemic lupus erythematosus), 쇼그렌 증후군(Sjogren syndrome), 하시모토 갑상선(Hashimoto thyroiditis), 다발성근염(polymyositis), 경피증(scleroderma), 아디슨병(Addison disease), 백반증(vitiligo), 악성빈혈(pernicious anemia), 사구체신염(glomerulonephritis) 및 폐섬유증(pulmonary fibrosis), 염증성장질환 (Inflammatory Bowel Dieseses), 자가면역성 당뇨 (Autoimmune Diabetes), 당뇨 망막증 (Diabetic retinopathy), 비염 (Rhinitis), 혀혈-재관류 손상 (Ischemia-reperfusion injury), 혈관성형술후 재협착 (Post-angioplasty restenosis), 만성 폐색성 심장 질환 (Chronic obstructive pulmonary diseases; COPD), 그레이브병 (Graves disease), 위장관 알러지 (Gastrointestinal allergies), 결막염 (Conjunctivitis), 죽상경화증 (Atherosclerosis), 관상동맥질환 (Coronary artery disease), 협심증 (Angina), 암 전이 및 소동맥 질환으로 이루어진 군으로부터 선택되는 것을 특징으로 하는 면역질환의 예방 또는 개선용 건강기능성 식품.11. The method of claim 10,
The autoimmune diseases include rheumatoid arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, multiple sclerosis, systemic lupus erythematosus, Sjogren's syndrome, Hashimoto's thyroiditis, polymyositis, scleroderma, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, And inflammatory diseases such as pulmonary fibrosis, inflammatory bowel dieses, autoimmune diabetes, diabetic retinopathy, rhinitis, ischemia-reperfusion injury, angioplasty, Post-angioplasty restenosis, chronic obstructive pulmonary diseases (COPD), Graves disease, gastrointestinal allergies wherein the disease is selected from the group consisting of atherosclerosis, atherosclerosis, coronary artery disease, angina, cancer metastasis and small artery disease. Health functional foods.
상기 세포, 조직 또는 기관의 이식거부반응은 골수 이식, 심장 이식, 각막 이식, 장 이식, 간 이식, 폐 이식, 췌장 이식, 신장 이식 및 피부이식의 거부반응 으로 이루어진 군 중에서 선택되는 것을 특징으로 하는 면역질환의 예방 또는 개선용 건강기능성 식품.
11. The method of claim 10,
The transplant rejection reaction of the cell, tissue or organ is selected from the group consisting of bone marrow transplantation, heart transplantation, corneal transplantation, intestinal transplantation, liver transplantation, lung transplantation, pancreas transplantation, kidney transplantation and rejection of skin transplantation Health functional food for prevention or improvement of immune diseases.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20210111057A (en) * | 2020-03-02 | 2021-09-10 | 영남대학교 산학협력단 | Pharmaceutical composition for the prevention or treatment of inflammatory diseases or immune disease |
| WO2024091485A1 (en) * | 2022-10-25 | 2024-05-02 | The Regents Of The University Of California | Compositions and methods for treating or preventing pulmonary fibrosis |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20210111057A (en) * | 2020-03-02 | 2021-09-10 | 영남대학교 산학협력단 | Pharmaceutical composition for the prevention or treatment of inflammatory diseases or immune disease |
| WO2024091485A1 (en) * | 2022-10-25 | 2024-05-02 | The Regents Of The University Of California | Compositions and methods for treating or preventing pulmonary fibrosis |
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