• BMB Reports
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• 제49권6호
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• pp.331-336
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• 2016

In murine collagen-induced arthritis (CIA), self-reactive T cells can recognize peptide antigens derived from type-II collagen (CII). Activation of T cells is an important mediator of autoimmune diseases. Thus, T cells have become a focal point of study to treat autoimmune diseases. In this study, we evaluated the efficacy of recombinant MHC class II molecules in the regulation of antigen-specific T cells by using a self peptide derived from CII (CII260-274; IAGFKGEQGPKGEPG) linked to mouseI-A^q in a murine CIA model. We found that recombinant I-A^q/CII260-274 molecules could be recognized by CII-specific T cells and inhibit the same T cells in vitro. Furthermore, the development of CIA in mice was successfully prevented by in vivo injection of recombinant I-A^q/CII260-274 molecules. Thus, treatment with recombinant soluble MHC class II molecules in complex with an immunodominant self-peptide might offer a potential therapeutic for chronic inflammation in autoimmune disease such as rheumatoid arthritis.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1994년도 춘계학술대회 and 제3회 신약개발 연구발표회
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• pp.230-230
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• 1994

Human leukocyte elastase(HLE)는 폐와 피부, 혈관등의 Connective tissue의 주요 구성물인 elastin을 분해하는 효소로써, 백혈구의 식균작용에도 관여한다. 그러나 이효소가 과다하게 분비되면 pulmonary emphysema와 adult respiratory distress syndrome, rheumatoid arthritis를 유발한다고 알려지고 있다. 지금까지 HLE억제제로 시판되는 의약품은 없으나, 최근에 Cephalosporin유도체가 이 효소의 억제제로 우수한 효과가 있다는 보고가 있은 후, HLE억제제로써 이들의 유도체가 개발되고 있다. 연구자들은 다음일반식에서 2번과 3번위치에 치환기를 도입시킨 수종의 Cephalosporin Sulfone의 유도체들을 합성하고. 이들의 HLE억제 효과를 Spectrophotometerqkdtlr을 이용하여 측정하였다. 합성화합물증 몇가지는 우수한 HLE억제효과를 보여주었고, 2번위치에 diphenylcyclopropyl ring과 같은 부피가 큰 치환체를 도입하면 효소억제력이 증가되었다.

• Journal of Acupuncture Research
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• 제24권4호
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• pp.81-97
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• 2007

Objective: The purpose of this study was to observe the effects of Cnidii Rhizoma herbal-acupuncture solution(CR-HAS) at Joksamni($ST_{36}$) on arthritis induced by Collagen II in mice. Methods : The author performed several experimental items. The severity of arthritis, changes of mouse weight, size of the spleen and the degree of stenosis, changes of cytokine level, IgG, IgM and anti-collagen II, changes of immunocyte count, histological changes of the CIA mouse joint were analyzed. Results: 1. In the CR-HA, the arthritis index, the incidence of arthritis, the degree of joint edema was significantly decreased. 2. In the CR-HA, weight, spleen size and stenosis rate was low and maintained as the normal group was. 3. In the CR-HA, cytokine level, IgG, IgM and anti-collagen II were significantly decreased. 4. In the CR-HA, on changes of immunocyte count were maintained to the levels of normal group. 5. In histological changes of the CIA mouse joint, the cartilage destruction and synovial cell proliferation were decreased. Conclusions : These results suggest that CR-HA at the $ST_{36}$ has an important role to control the immune reactions and suppress inflammatory response on the collagen induced rheumatoid arthritis. This study can be a significant supporting evidence that CR-HA will be chosen to be the principal therapy for clinical practice of the rheumatoid arthritis in the future.

• Korean Journal of Acupuncture
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• 제24권3호
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• pp.117-137
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• 2007

Objectives & Methods : The purpose of this study is to observe the effects of Gentianae macrophyllase Radix herbal-acupuncture solution(GR-HAS) at Joksamni(ST36) on Collagen-induced arthritis(CIA) in DBA/1J mice. The author performed several experimental items to analyze arthritis evaluation, change of weight, spleen size and adhesion rate, change of cytokine level, IgG, IgM and anti-collagen II , change of immunocyte count, histological change of CIA mouse joint related with RA. Results : 1. In the GR-HA group, the arthritis index, the incidence of arthritis and joint edema were significantly decreased. 2. In GR-HA group, there were no weight loss and similarly maintained as normal group. Spleen size, adhesion rate and the edema and transformation of knee joint were low and similarly maintained as normal group. 3. In the GR-HA, cytokine level, IgG, IgM and anti-collagen II were significantly decreased. 4. In the GR-HA, the change of immunocyte count were similarly maintained as normal group. 5. In the histological changes of the CIA mouse joint, the cartilage destruction and synovial cell proliferation were decreased in the GR-HA(Hematoxylin and eosin stain). The collagen fiber expressions in the GR-HA were similar with that of the normal group(Masson's Trichrome stain) Conclusions : These results suggest that GR-HA at ST36 has an effect to control immune reaction and suppress inflammation, synovial cell proliferation and cartilage destruction in rheumatoid arthritis.

• 대한약리학회지
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• 제26권1호
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• pp.51-54
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• 1990

사람 중성구내의 azurophil granule 내에 존재하는 serine protease인 cathepsin G는 정상 반응에서는 항 박테리아 작용을 나타내는데 관여하지만, 이들의 효소활성이 비정상적으로 증가되었을 때는 오히려 인체 정상 조직을 파괴함으로써 rheumatoid arthritis를 비롯한 여러가지 염증성 질환을 야기시킨다고 알려져 있다. 항염증제로 작용하는데 있어서 prostaglandin 합성을 억제하는 작용 이외에 다른 작용 기전이 있는가 하는것은 대단히 흥미있는 연구 과제이었으므로 neutral protease 중의 하나인 cathepsin G와 이 염증반응에 직접적으로 관여하는지 알아보기 위하여 본 연구에서는 두 단계의 크로마토그라피를 거쳐 순수한 cathepsin G를 분리하고, 여러가지 비스테로이드성 항염증제를 이용하여 cathepsin G에 대한 억제 정도를 관찰하였다. 이중 sulindac, salicylate, phenylbutazone, oxyphenbutazone 그리고 salicyluric acid가 각각 4.3mM, 14.3mM, 6.5mM, 11mM, 15mM의 $IC_{50}$로써 cathepsin G의 활성도를 억제하였다. 따라서 NSAIDs의 항염증 작용 기전은 기존에 알려지고 있는 cyclooxygenase 억제에 따른 prostaglanndin 합성, 분비 억제 기전이외에 rheumatoid arthritis 부위에 직접적 원인으로 작용할 가능성이 있는 cathepsin G를 억제 함으로써 조직 파괴를 막는 역할을 하고 있을 가능성이 있는 것으로 사료된다.

• Journal of Acupuncture Research
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• 제23권3호
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• pp.129-142
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• 2006

Objectives : The purpose of this study is to observe the effects of Eucomiae Cortex herbal-acupuncture solution(EC-HAS) at Joksamni(ST36) on arthritis of mice induced by Collagen II. Methods : The author performed several experimental items. First, it is the cell survival rate of mice lung fibroblasts. Second, it is the incidence rate of arthritis and arthritis index of CIA. Third, it is the levels of IL-6, $TNF-{\alpha}$, $IFN-{\gamma}$, $IL-{\beta}$, IgG, IgM and anti-collagen II in serum and the level of IFN-y,$IFN-{\gamma}$/IL -4 ratio in CIA mouse spleen cell culture. Fourth, it is histological analysis of the mice joint. Fifth, it is expression ratio of $CD3e^+$ to $CD19^+$+ cell, $CD4^+$ to $CD8^+$ cell, $CD69^+/CD3e^+$/cells, $CD11a^+/CD19^+$/cells, $CD11b^+/Gr-1^+$ cells and $CD4^+/CD25^+$ cells. Results & Conclusion : 1. In the EC-HA, the incidence of arthritis and arthritis index were significantly decreased. 2. In EC-HA, the levels of IL-6, $IFN-{\gamma}$, $TNF-{\alpha}$, $IL-1{\beta}$, IgG, IgM and anti-collagen II in serum of CIA mice and the level of $IFN-{\gamma}$, IL-4, $IFN-{\gamma}$/lL-4 ratio in CIA mouse spleen cell culture were significantly decreased. 3. In the histological study, the cartilage destruction and synovial cell proliferation were decreased in the EC-HA, and the collagen fiber expressions in the EC-HA were similar with that of the Normal group. 4. In the EC-HA, the expression ratio of $CD3e^+$ to $CD19^+$ cell and $CD4^+$ to $CD8^+$ cell were similarly maintained as Normal group in lymph nodes, and $CD69^+/CD3e^+$ cells and $CD11a^+/CD19^+$ cells were decreased in lymph nodes, and $CD11b^+/Gr-1^+$ cells and $CD4^+/CD25^+$ cells were decreased in synovium. These results suggest that EC-HA at ST36 has an effect to control synovial cell proliferation and cartilage destruction in rheumatoid arthritis, and to be put to practical use in the future rheumatoid arthritis clinic.

• 대한약리학회지
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• 제23권1호
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• pp.25-31
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• 1987

$Cu^{++}$ 촉매작용에 의한 과산화현상이 관절조직손상의 한 형태인 Collagen 손상에 관여할 수 있음을 알아보고, sodium salicylate의 항 염증기전의 일부를 설명해 보고자 sodium salicylate가 이 과산화반응에 미치는 효과를 검토하였다. 쥐피부로 부터 얻은 Collagen을 이용하여 Collagen gelation에 대한 $Cu^{++}$와$H_2O_2$의 효과를 관찰한 결과 $Cu^{++}$ 또는 $H_2O_2$ 단독으로는 gelation에 영향을 미치지 못하였으나, $Cu^{++}$와 $H_2O_2$가 동시에 첨가된 경우 gelation이 억제되어 maximal turbidity가 감소되고, lag phase가 연장됨을 보였다. 그리고 같은 반응 조건에서 sodium salicylate 첨가에 의해 $Cu^{++}$와 $H_2O_2$에 의해 억제된 gelation이 회복됨을 볼 수 있었으며 회복정도는 salicylate 농도 증가에 의존적이었다. 한편 $Cu^{++}$에 의한 $H_2O_2$의 decomposition rate가 sodium salicylate에 의해 증가됨을 보였고, salicylate 농도 증가에 의해 점차 saturation되는 양상을 보였다. 이상의 결과로 부터 $Cu^{++}$ 촉매작용에 의한 과산화 현상은 collagen에 작용하여 구조적 또는 기능적인 변화를 초래함을 알 수 있었고, salicylate에 의해 이러한 과산화 현상이 억제되는 것은 $Cu^{++}$에 의한 $H_2O_2$의 decomposition rate를 증가시킨 결과임을 알 수 있었다. 그러므로 $Cu^{++}$ 촉매작용에 의한 과산화현상은 만성염증 반응 특히 rheumatoid arthritis에서 나타나는 관절조직 손상에 관여할 수 있으며, sodium salicylate는 이 과산화반응에 작용하여 항 염증효과를 나타낼 수 있으리라 믿어졌다.

• Journal of Acupuncture Research
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• 제23권6호
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• pp.29-44
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• 2006

Objectives : The purpose of this study is to observe the effects of Mori Ramulus herbal-acupuncture solution(MR-HAS) on arthritis of mice induced by Collagen II at Joksamni(ST36). Methods : The author performed several experimental items. First, it is the cell survival rate of mice lung fibroblasts. Second, it is the incidence rate of arthritis and arthritis index of CIA. Third, it is the levels of IL-6, $TNF-{\alpha}$, $IFN-{\gamma}$, $IL-1{\beta}$, IgG, IgM and anti-collagen II in serum and the level of $IFN-{\gamma}$, $IFN-{\gamma}/IL-4$ ratio in CIA mouse spleen cell culture. Fourth, it is histological analysis of the mice joint. Fifth, it is expression ratio of CD3e+ to CD19+ cell, CD4+ to CD8+ cell, CD69+/CD3e+ cells, CD11a+/CD19+ cells and CD11b+/Gr-l+ cells and CD4+/CD25+ cells. Results : 1. In the MR-HA, the incidence of arthritis and the arthritis index were significantly decreased. 2. In MR-HA, the levels of IL-6, $IFN-{\gamma}$, $TNF-{\alpha}$, $IL-1{\beta}$, IgG, IgM and anti-collagen II in serum of CIA mice and the level of $IFN-{\gamma}$, IL-4, $IFN-{\gamma}$, IL-4 ratio in CIA mouse spleen cell culture were significantly decreased. 3. In histology, the cartilage destruction and synovial cell proliferation were decreased in the MR-HA, and the collagen fiber expressions in the MR-HA were similar with that of the Normal group. 4. In the MR-HA, the expression ratio of CD3e+ to CD19+ cell and CD4+ to CD8+ cell were similarly maintained as Normal group in lymph nodes, and CD69+/CD3e+ cells and CD11a+/CD19+ cells were decreased in lymph nodes, and CD11b+/Gr-1+ cells and CD4+/CD25+ cells were decreased in synovium. Conclusion : These results suggest that MR-HA at ST36 has an effect to control synovial cell proliferation and cartilage destruction in rheumatoid arthritis, as well as prophylaxis is important to treat rheumatoid arthritis in clinic.

• Korean Journal of Acupuncture
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• 제22권2호
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• pp.89-105
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• 2005

Objective & Methods : This study is performed to observe the effect of Herbal-acupuncture with Notopterygii Radix Herbal-Acupuncture Solution(NR-HAS) at Joksamni(ST36) on Collagen II-induced arthritis (CIA) in DBA/1J mice. Result : 1. The highest survival rate of mice lung fibroblasts were measured in the 1% NR-HAS, and the expression of $TNF-{\alpha}$ in synovial cells were significantly decreased in the 1% and 10% NR-HAS. 2. The incidence of arthritis and the spleen weight were significantly decreased by Notopterygii Radix Herbal-acupuncture(NR-HA) at ST36. 3. The levels of IL-6, $INF-{\gamma},\;TNF-{\alpha}$, IgG, IgM, anti-collagen II in serum of CIA mice were significantly decreased by NR-HA at ST36. 4. In histology, the cartilage destruction and synovial cell proliferation were decreased by NR-HA at ST36, and the collagen fiber expressions in the NR-HA I II groups were similar with that of the normal group. 5. In lymph node, the expression ratios of $CD3e^+\;to\;CD19^+$ cell and $CD4^+\;to\;CD8^+$ cell in the NR-HA I II groups were similarly maintained as those in the normal group. 6. In lymph node, $CD69^+/CD3e^+$ cells and $CD11a^+/CD19^+$ cells were decreased by NR-HA at ST36. 7. In the articular joint, $CD11b^+/Gr-1^+$ cells were decreased by NR-HA at ST36. 8. NR-HA at ST36 did not make a considerable difference in DBA/1J mice without CIA 9. Throughout the overall experimental result, NR-HA I group showed more predominant effect than the NR-HA II group. Conclusion : These results suggest that NR-HA at ST36 has an effect to control synovial cell proliferation and cartilage destruction in rheumatoid arthritis, as well as prophylaxis is important to treat rheumatoid arthritis in clinic.

• Journal of Acupuncture Research
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• 제22권3호
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• pp.227-241
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• 2005

세신약쇄(細辛藥鎖)이 Collagen-induced arthritis에 미치는 영향(影響)을 DBA/1J mouse를 이용한 실험(實驗)을 통하여 관찰(觀察)한 결과(結果), 다음과 같은 결론(結論)을 얻었다. 1. 세포독성(細胞毒性) 측정(測定) 및 TNF-${\alpha}$ 발현(發現) 억제효과(抑制效果) 1) 세신약침액(細辛藥鍼液) 1%의 농도(濃度)에서 가장 높은 세포생존률(細胞生存率)이 관찰(觀察)되었다. 2) 세행약침액(細幸藥鍼液) 1%의 농도(濃度)에서 TNF-${\alpha}$가 유의성(有意性)있게 감소(減少)하였다. 2. 관식염(關飾炎) 발병률(發病率)과 비장(脾臟)의 무게 관찰(觀察) 1) 세행약침(細幸藥鍼) I군과(群) 세행약침(細幸藥鍼) II군에(群)서 관절염(關節炎) 발병률(發病率)이 현저하게 감소(減少)하였다. 2) 세신약침(細辛藥鍼) I군과(群) 세졸약침(細卒藥鍼) II군의(群) 비장(脾臟) 무게가 대조체(對照諦)에 비하여 감소(減少)하였다. 3. 세신약침(細辛藥鍼)이 각종 싸이토카인, 면역 글로불린 및 Anti-collagen II에 미치는 영향(影響) 1) 혈청(血淸)내 IL-6, LNF-${\gamma}$, TNF-${\alpha}$는 세행약침(細幸藥鍼) I군과(群) 세행약침(細幸藥鍼)II군에(群)서 대조군(對照群)에 비하여 유의성(有意性)있게 감소(減少)하였다. 2) IgG, IgM은 세행약침(細幸藥鍼) I군과(群) 세행약침(細幸藥鍼)II군에(群)서 대조군(對照群)에 비하여 유의성(有意性)있게 감소(減少)하였다. 3) Anti-collagen II는 세행약침(細幸藥鍼) I군과(群) 세행약침(細幸藥鍼) II군에(群)서 대조군(對照群)에 비하여 유의성(有意性)있게 감소(減少)하였다 4. 세신약침(細辛藥鍼)이 관절(關節)의 조직학적(組織學的) 변화(變化)에 미치는 영향(影響) 1) Hematoxylin and eosin stain에서 세행약침(細幸藥鍼) I군과(群) 세행약침(細幸藥鍼)II군이(群) 연골(軟骨)의 파괴(破壞)와 활막(滑膜)의 증식(增殖)이 감소(減少)되고 정상군(正常群)에 류사(類似)한 구조(構造)로 회부(回復)되었다. 2) Masson's Tricho me stain에서 세행약침(細幸藥鍼) I군과(群) 세행약침(細幸藥鍼)II군의(群) 교원질섬유가 정상군(正常群)과 같이 유지(維持)되었다. 5. 세신약침(細辛藥鍼)이 면역세포(免疫細胞)의 발현(發現)에 미치는 영향(影響) 1) 림파절내(淋巴節內) 4CD3e^+$ 세포(細胞)와 $CDl9^+$ 세포(細胞)의 비율(比率), $CD4^+$ 세포(細胞)와 $CD8^+$ 세포(細胞)의 비율(比率)은 細幸藥鍼I군과(細幸藥鍼I群) 세행약침(細幸藥鍼)II군에(群)서 Control군에(群) 비하여 정상군(正常群)과 유사(類似)한 비율(比率)이 유지(維持)되었다. 2) 임파절내(淋巴節內) $CD69^+/CD3e^+$ 세포(細胞)와 $CDlla^+/CDl9^+$ 세포(細胞)는 세행약침(細幸藥鍼)I군과(群) 세행약침(細幸藥鍼)II군에(群)서 대조군(對照群)에 비하여 감소(減少)하였다. 3) 관절내(關節內) $CD11b^+/Gr-1^+$ 세포(細胞)는 세행약침(細幸藥鍼)I군과(群) 세행약침(細幸藥鍼)II군에(群)서 대조군(對照群)에 비하여 감소(減少)하였다. 이상(以上)의 모든 결과(結果)에 있어서, 세행약침(細幸藥鍼)II군보(群)다 예방(豫防)과 치료(治療)를 겸(兼)한 세행약침(細幸藥鍼)I군이(群) 싸이토카인 및 항체(沆體)의 감소(減少)와 면역세포(免疫細胞)의 발현(發現) 억제(抑制)에 있어서 탁월한 효과(效果)를 나타내었다.