• Journal of Yeungnam Medical Science
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• v.40 no.1
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• pp.23-29
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• 2023

The pathological hallmark of rheumatoid arthritis (RA) is a synovial pannus that comprises proliferating and invasive fibroblast-like synoviocytes, infiltrating inflammatory cells, and an associated neoangiogenic response. Animal models have been established to study these pathological features of human RA. Spontaneous and induced animal models of RA primarily reflect inflammatory aspects of the disease. Among various induced animal models, collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) models are widely used to study the pathogenesis of RA. Improved transplantation techniques for severe combined immunodeficiency (SCID) mouse models of RA can be used to evaluate the effectiveness of potential therapeutics in human tissues and cells. This review provides basic information on various animal models of RA, including CIA and CAIA. In addition, we describe a SCID mouse coimplantation model that can measure the long-distance migration of human RA synoviocytes and cartilage destruction induced by these cells.

• Journal of Physiology & Pathology in Korean Medicine
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• v.21 no.1
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• pp.62-69
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• 2007

To evaluate effect of CYTG on inhibiting the occurrence of arthritis, we performed the experiments including production of inflammatory cytokine and immunoglobulin in collagen arthritis model. The results were obtained as fellows. CYTG group showed inhibitory effect on arthritis incidence than control group for four weeks. Arthritis index of CYTG group reduced compared with control group. In CYTG group, production of cytokines which show suppressive effect on inflammation(IL-2, COX-2) was increased and which promotes inflammation(IL-10) was decreases in spleen. In CYTG group, production of immunoglobulin (IgG-RF) was reduced compared with control, and rate of CD3+CD69+T cell is lower in lymph node and CD4+CD25+ T cell is higher in lymph node and spleen. And synovial infiltration in the knee were observed in the controls (PBS-treated mice), whereas CYTG-treated mice exhibited significantly reduced histologic evidence of destruction and inflammation. So, the histopathological scoring average of CYTG group was 2.5 compared with control group(CIA mice) 4.5. It was thought that our data express high effect via immune system specially through the controling the inflammatory cytokines and immunoglobulins. CYTG could be usefully applied for the prevention and treatment of RA, and also is expected to be clinically helpful on the treatment of RA through modification.

• Journal of Physiology & Pathology in Korean Medicine
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• v.21 no.5
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• pp.1278-1284
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• 2007

Solanum Iyratum Thunb (Solanaceae) has multiple applications in korean traditional medicine because of its cytotoxic, immunological and anti-inflammatory activities. However, no study on the anti-arthritic activity of Solanum Iyratum Thunb has been reported in vivo. Rheumatoid arthritis (RA) is a systemic autoimmune disease with chronic inflammation characterized by hyperplasia of synovial cells in affected joints, which ultimately leads to the destruction of cartilage and bone. Cytokine production were assessed during CIA(collagen-induced arthritis) model mice in lymph node (LN), in knee joint and spleen, using ELISA. DBA/1j mice were immunized with bovine type II collagen. After a second collagen immunization, mice were treated with Solanum Iyratum Thunb (SLT) orally at 400, 200 mg/kg once a day for 4 weeks. The severity of arthritis within the knee joints was evaluated by histological assessment of cartilage destruction and pannus formation. SLT significantly suppressed the progression of CIA and inhibited the production of TNF-alpha and IFN-gamma in serum and spleen cell culture supernatant. The erosion of cartilage was dramatically reduced in mouse knees after treatment with SLT. In conclusion, our results demonstrates that SLT significantly suppressed the progression of CIA. This action was characterized by suppression of arthritis index, cartilage erosion and synovial cell infiltration and the decreased production of $TNF-{\alpha}$, $IFN-{\gamma}$, CD4+, CD19+, CD3+/CD69+ cells (in lymph node), CD11b+/Gr-1 + (in knee joint).

• Journal of Acupuncture Research
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• v.23 no.2
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• pp.125-137
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• 2006

Objectives : The effect of water extract of the pilose antler of Cervus korean TEMMINCK var. mantchuricus Swinhoe (Nokyong), a traditional immuno-suppressive and immuno-activating Korean oriental medicine, on collagen-induced arthritis (CIA) mice model was studied. Identification of common Nokyong capable of affording protection or modulating the onset and severity of arthritis may have important human health implications. Methods : Nokyong has shown to possess anti-inflammatory and anticarcinogenic properties in experimental animals. In this study we determined the effect of DAE on collagen-induced arthritis in mice. Results : In three independent experiments mice given DAE in water exhibited significantly reduced incidence of arthritis (33% to 50%) as compared with mice given no DAE in water (84% to 100%). The arthritis index also was significantly lower in DAE-fed animals. Western blot analysis showed a marked reduction in the expression of inflammatory mediators such as cyclooxygenase 2 (Cox-2), $Interferon-{\gamma}\;(INF-{\gamma})$, and tumor necrosis factor ${\alpha}\;(TNF-{\alpha})$ in arthritic joints of DAE-fed mice. The neutral endopeptidase (NEP) activity was approximately 6-fold higher in arthritic joints of non-DAE-fed mice in comparison to nonarthritic joints of nonimmunized mice whereas it was only 2-fold higher in the arthritic joints of DAE-fed mice. Additionally, total IgG and type II collagen-specific IgG levels were lower in the arthritic joints of DAE-fed mice. Conclusion : Taken together our studies suggest that DAE may be useful in the prevention of onset and severity of arthritis.

• Journal of Acupuncture Research
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• v.23 no.2
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• pp.73-90
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• 2006

Objectives : The effects of water extract of deer antler herbal-acupunture solution(DHS), prepared from the pilose antler of Cervus korea TEMMINCK var. mantchuricus Swinhoe (Nokyong), a traditional immunosuppressive and immune-activating Korean herbal- acupuncture, on collagen-induced arthritis(CIA:RA model) in mice was studied. Destruction of cartilage and bone are hallmarks of human rheumatoid arthritis, and controlling these erosive processes is the most challenging objective in the treatment of RA. Methods : We investigated the tissue protective effects of deer antler treatment using established murine collagen-induced arthritis(CIA) as a model. Potential synergy of low dosages of anti-inflammatory glucocorticosteroids and deer antler was also evaluated. Results : Treatment of established murine CIA with deer antler herbal-acupunture solution(DHS) $(10-50{\mu}g/day)$ suppressed disease activity and protected against cartilage and bone destruction. Although $10-50{\mu}g/day$ DHS had only a moderate effect on the inflammatory component of the disease activity, it strongly reduced cartilage pathology, as determined by histological examination. Serum cartilage oligomeric matrix protein(COMP) levels were significantly reduced, confirming decreased cartilage involvement. Histological analysis showed that bone destruction was prevented. DHS administration increased serum IL-1Ra levels and reduced anticollagen type II antibody levels. Treatment with low-dose $DHS(1{\mu}g/day)$ was ineffective in suppressing disease score, serum COMP or joint destruction. Synergistic suppression of both arthritis oseverity and COMP levels was noted when low-dose DHS was combined with prednisolone(0.05mg/kg/day), however, which in itself was not effective. Conclusion : DHS was shown to have the inhibiting effects against $IL-1{\alpha}-$ and $IL-1{\beta}-stimulated$ bone resorption. These results indicated that the DAS is not only highly stable and applicable to clinical uses in bone resorption, but also it will be served as a potent anti-inflammatory and anti-arthritic agents for treatment of human RA.

• Journal of the Korean Applied Science and Technology
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• v.39 no.1
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• pp.18-26
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• 2022

The present study aimed to evaluate the effect of Eucommia ulmoides extracts on rheumatoid arthritis biomarker in a CIA-induced DBA/1 mice. For evaluation, Eucommia ulmoides extracts was administered orally at dose of 100 mg/kg/day for 4 weeks after production of an animal model of rheumatoid arthritis and we confirmed the treatments' effects based on serum biomarker, radiological, structural parameter analysis. Compared to the negative control group, the Eucommia ulmoides extracts treatments significantly reduced the serum level of inflammation and immunoglobulin markers (i.e., TNF-α, IgG, and hs-CRP), and significantly decreased the monocyte count of white blood cells. Furthermore, the Eucommia ulmoides extracts treatments effectively preserved the joint destruction, and little the joint deformation. Moreover, compared to the negative control group, the Eucommia ulmoides extracts treatments increased the bone volume, and significantly decreased bone inflammation. The results indicate that the Eucommia ulmoides extracts improved rhrumatoid arthritis symptoms. Thus, the Eucommia ulmoides extracts may be a novel therapeutic option for the management of rheumatoid arthritis.

• Journal of Physiology & Pathology in Korean Medicine
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• v.20 no.5
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• pp.1311-1314
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• 2006

This study was peformed to investigate possible mechanisms underlying possible effect of Coicis Semen composition (CSC) on inflammatory diseases using in vivo model of RA in the mice. Results are summarized as follows. In production of inflammatory cytokines, INF-${\gamma}$ in the spleen and IL-6 in the serum were decreased by CSC treatment. TNF-${\alpha}$ in serum was significantly decreased, IL-4 in the spleen was significantly increased by CSC treatment. In production of rheumatoid factors, IgM and IgG were significantly decreased by CSC treatment. The present data suggest that CSC treatment can improve pathological damage by CIA. So we expect that CSC should be used as a effective drugs for not only rheumatoid arthritis but also another autoimmune disease. Therefore we have to survey continuously in looking for the effective substance and mechanism in the future.

• IMMUNE NETWORK
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• v.3 no.2
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• pp.136-144
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• 2003

Oral administration of antigen has long been considered as a promising alternative for the treatment of chronic autoimmune diseases including rheumatoid arthritis (RA), and oral application of type II collagen (CII) has been proven to improve pathogenic symptoms in RA patients without problematic side effects. To further current understandings about the immune suppression mechanisms mediated by orally administered antigens, we examined the changes in IgG subtypes, T-cell proliferative response, and proportion of interleukin (IL)-10 producing Th subsets in a time course study of collagen induced arthritis (CIA) animal models. We found that joint inflammation in CIA mouse peaked at 5 weeks after first immunization with CII, which was significantly subdued in mice pre-treated by repeated oral administration of CII. Orally tolerized mice also showed increase in their serum level of IgG1, while the level of IgG2a was decreased. T-cell proliferation upon CII stimulation was also suppressed in lymph nodes of mice given oral administration of CII compared to non-tolerized controls. When cultured in vitro in the presence of CII, T-cells isolated from orally tolerized mice presented higher proportion of $CD4^+IL-10^+$ subsets compared to non-tolerized controls. Interestingly, such increase in IL-10 producing cells were obvious first in Peyer's patch, then by 5 weeks after immunization, in mesenteric lymph node and spleen instead. This result indicates that a particular subset of T-cells with immune suppressive functions might have migrated from the original contact site with CII to inflamed joints via peripheral blood after 5 weeks post immunization.

• Journal of Physiology & Pathology in Korean Medicine
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• v.23 no.5
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• pp.1095-1105
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• 2009

This study was carried out to know the immunological effect of GDGT on CIA(collagen induced arthritis) mice, a model of rheumatoid arthritis. For this purpose, GDGT was orally administerd to mice with arthritis induced by collagen II and then value of cytotoxicity on hFLSs and liver, the arthritis index, immunocyte in paw joint and DNL, rheumatoid factor (IgG and IgM), collagen II specific antibody in the serum were measured. The cytotoxicity were not shown on hFLSs and liver. The arthritis index decreased significantly after 3 week. In total cell counts of DLN and paw joint, there was a significant increase in DLN and significant decrease in paw joint. In DNL, $CD19^+$, $CD3^+$, $CD4^+$, $CD3^+/CD69^+$, $CD8^+$, $CD4^+/CD25^+$, $ CD3^+/CD49b^+$ cells increased significantly. In Paw joints, $CD3^+$, $ CD4^+$, $CD4^+/CD25^+$ cells decreased significantly. The level of serum IgG and IgM decreased significantly. The level of collagen II in the serum was decreased significantly. Marginal erosion, necrotic chodrocytes, cartilage and bone degradation were improved in histological section of paw joints. The results present significant immunological effect of GDGT on rats with arthritis induced by collgen II. So we expect that GDGT should be used as a effective drugs for not only rheumatoid arthritis but also another auto-immune disease.

• Journal of Physiology & Pathology in Korean Medicine
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• v.22 no.4
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• pp.871-877
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• 2008

Heme oxygenase-1 (HO-1), an inducible heme-degrading enzyme, is expressed by macrophages and endothelial cells in response to various stresses and mediators of inflammation. HO-1 has been recently implicated in regulation of angiogenesis via expression of VEGF. The purpose of this study was to determine the effects of HO-1 modulation on the collagen-induced arthritis (CIA) model and on angiogenesis via up- regulation of VEGF expression in human synovial fibroblast. DBA/1J mice were treated with an inhibitor of HO-1, tin protoporphyrin IX (SnPP), or with an inducer of HO-1, cobalt protoporphyrin IX (CoPP), from day 1 to day 35 after CIA induction. The clinical evolution of disease was monitored visually. At the end of the experiment, histopathologic changes were examined on the joints. VEGF expression in paws were measured by immunohistochemical stain. mRNA expression of HO-1 and VEGF stimulated with various concentration of $TNF-{\alpha}$, CoPP accessed on human synovial fibroblast by RT-PCR. Effects of pretreatment with SnPP on mRNA expression of HO-1 and VEGF in the presence of CoPP and $TNF-{\alpha}$ in synovial fibroblast was accessed by Real-time RT-PCR. Administration of cobalt protoporphyrin IX significantly induced the inflammatory response, with increased arthritis index and expression of VEGF in the paws of the arthritis models. Treatment with SnPP significantly reduced the severity of CIA through inhibition of joint inflammation and cartilage destruction. The expression of VEGF were also significantly reduced by SnPP treatment in the paw. CoPPIX as inducer of HO-1, increased HO-1 and VEGF expression dose dependently in synovial fibroblast. In contrast, inhibition of HO-1 activity by SnPPIX abrogated CoPPIX-induced HO-1 and VEGF production in synovial fibroblast. Stimulation with $TNF-{\alpha}$ increased HO-1 and VEGF expression itself and showed additive effect on HO-1 and VEGF expression when it treated with CoPP. When SnPP was treated with CoPP and $TNF-{\alpha}$, it abrogated the CoPP induced HO-1 and VEGF expression and also abrogated $TNF-{\alpha}$ induced HO-1 and VEGF expression in synovial fibroblast. The effects of HO-1 induction in rheumatoid arthritis results in aggravation of arthritis via up-regulation of VEGF. I concluded that inhibition of the expression or activity of HO-1 could be a therapeutic target of rheumatoid arthritis.