• IMMUNE NETWORK
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• 제22권1호
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• pp.8.1-8.20
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• 2022

Rheumatoid arthritis (RA) is a representative autoimmune disease that is primarily characterized by persistent inflammation and progressive destruction of synovial joints. RA has a complex and heterogeneous pathophysiology, involving interactions among various immune and joint stromal cells and a diverse network of cytokines and intracellular signaling pathways. With improved understanding of RA, over the past decades, therapeutic strategies have become considerably advanced and now included targeted molecular therapies, such as tumor necrosis factor inhibitors, IL-6 blockers, B-cell depletion agents, as well as inhibitors of T-cell co-stimulation and Janus kinases. However, a considerable proportion of RA patients experience refractory disease and interrupted treatment owing to the associated risk of developing serious infections and cancers. In contrast, although IL-1β, IL-17A, and p38α play significant roles in RA pathogenesis, several drugs targeting these factors have not been approved because of their low efficacy and severe adverse effects. In this review, we provide an overview of the working mechanism, advantages, and limitations of the currently available targeted drugs for RA. Additionally, we suggest potential mechanistic causes for clinically approved and failed drugs. Thus, this review provides perspectives on approaches for basic and translational studies that hold promise for identifying future next-generation therapeutics for RA.

• IMMUNE NETWORK
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• 제3권4호
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• pp.302-309
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• 2003

Background: CTLA4 (CD152), which is expressed on the surface of T cells following activation, has a much higher affinity for B7 molecules comparing to CD28, and is a negative regulator of T cell activation. In contrast to stimulating and agonistic capabilities of monoclonal antibodies specific to CTLA-4, CTLA4Ig fusion protein appears to act as CD28 antagonist and inhibits in vitro and in vivo T cell priming in variety of immunological conditions. We've set out to confirm whether inhibition of the CD28-B7 costimulatory response using a soluble form of human CTLA4Ig fusion protein would lead to persistent inhibition of alloreactive T cell activation. Methods: We have used CHO-$dhfr^-$ cell-line to produce CTLA4Ig fusion protein. After serum free culture of transfected cell line we purified this recombinant molecule by using protein A column. To confirm characterization of fusion protein, we carried out a series of Western blot, SDS-PAGE and silver staining analyses. We have also investigated the efficacy of CTLA4Ig in vitro such as mixed lymphocyte reaction (MLR) & cytotoxic T lymphocyte (CTL) response and in vivo such as experimental autoimmune encephalomyelitis (EAE), graft versus host disease (GVHD) and skin-graft whether this fusion protein could inhibit alloreactive T cell activation and lead to immunosuppression of activated T cell. Results: In vitro assay, CTLA4Ig fusion protein inhibited immune response in T cell-specific manner: 1) Human CTLA4Ig inhibited allogeneic stimulation in murine MLR; 2) CTLA4Ig prevented the specific killing activity of CTL. In vivo assay, human CTLA4Ig revealed the capacities to induce alloantigen-specific hyporesponsiveness in mouse model: 1) GVHD was efficiently blocked by dose-dependent manner; 2) Clinical score of EAE was significantly decreased compared to nomal control; 3) The time of skin-graft rejection was not different between CTLA4Ig treated and control group. Conclusion: Human CTLA4Ig suppress the T cell-mediated immune response and efficiently inhibit the EAE, GVHD in mouse model. The mechanism of T cell suppression by human CTLA4Ig fusion protein may be originated from the suppression of activity of cytotoxic T cell. Human CTLA4Ig could not suppress the rejection in mouse skin-graft, this finding suggests that other mechanism except the suppression of cytotoxic T cell may exist on the suppression of graft rejection.

• Korean Journal of Acupuncture
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• 제26권2호
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• pp.27-38
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• 2009

Objectives: Rheumatoid arthritis (RA) is a chronic autoimmune disease, principally characterized by synovial inflammation of the joints. We previously reported the effect of acupuncture for RA, but the mechanism is still unclear. Various factors such as oxidative stress and angiogenesis were involved in the pathogenesis of RA, and recently, it has also been reported that cytokines also play a major role in RA. Thus, we investigated whether acupuncture could induce any changes in the levels of cytokines including vascular endothelial growth factor (VEGF), angiogenin and epidermal growth factor (EGF) as well as erythrocyte sedimentation rate (ESR), c-reactive protein (CRP), and rheumatoid factor (RF) in the sera of RA patients. Methods: The forty three patients who met the American College of Rheumatology (ACR) criteria for RA recruited. The acupuncture group (n=21) underwent 14 sessions of partially individualized acupuncture treatment for 6 weeks, and the control group had no treatment (n=13) over the same periods. We evaluated ESR, CRP and RF. In addition, to find out the mechanism of acupuncture, we assessed the changes of the cytokine activities using protein cytokine array in the sera of the patients. Results: Acupuncture significantly decreased the levels of ESR and CRP, but RF were not changed after 6-week acupuncture treatments. Moreover, acupuncture reduced the levels of VEGF, angiogenin and EGF in the sera of the patients. Interestingly, they were related with angiogenesis, which is an important process in the pathogenesis of RA. The levels of oncostatin, interleukin(IL)-$1{\alpha}$, IL-8, leptin, monocyte chemotactic protein-1, macrophage-derived chemokine, macrophage inflammatory proteins-1, platelet-derived growth factor BB and RANTES were not changed significantly. Conclusions: The effect of acupuncture for reliving RA symptoms can be partially explained by inhibition of angiogenesis factors in the sera of the RA patients.

• 생물정신의학
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• 제2권1호
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• pp.100-106
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• 1995

직접적인 근거를 제시하기는 힘드나 정신장애에서 자가면역적 요소가 병인적으로 중요하다는 단편적인 보고들이 있다. 특히 바이러스 감염은 정신장애를 유발하거나 나중에 정신장애에 대한 소지를 증가시킬 가능성이 높다. 저자들은 최근에 많은 관심을 끌고 있는 C형 간염 항체(이하 anti-HCV)의 양성율이 자가면역적 관점 및 수혈 외에도 성행위 또는 약물의 존자에서 많다는 전파경로상의 특정 때문에 정신과 환자에서 일반 인구군보다 높을 것으로 추정되어 이를 확인해 보고자 본 연구를 시행하였다. 1992년 12월 초부터 1994년 5월 말까지 정신과에 입원한 환자 중에서 무작위로 효소면역측정법 (Abbott HCV EIA kit) 에 의해서 혈청내 anti-HCV를 검사하였으며, anti-HCV 양성 환자와 anti-HCV 음성인 환자를 구분하여 여러 변인별로 비교 분석하였다. 정신과 입원환자 113명중 12명(10.6%) 에서 anti-HCV 양성이었다. anti-HCV 양성자중 간기능검사상 이상이 있는 경우가 50.0% 로서 이중 83.0%는 주정 의존자였으며, 간기능검사상 정상인 환자의 83.3%는 비주정의존자였다. 정신과 진단별 anti-HCV 양성율은 주정의존 환자의 22.2%, 정신증 환자의 2.3% (주로 양극성장애), 신경증(불안장애, 적응장애)환자의 22.2%에서 anti-HCV 양성이 나타났다. 연령, 출생계절, 임파구(%), 간기능 등 변인에 대한 유의한 상관성은 관찰되지 않았다. 결론적으로 정신과 입원환자는 정상 대조군 (3.0%)에 비해 최소한 3.5배 이상 anti-HCV 양성율이 높으므로 (P<0.05), 이에 대한 주의를 환기시킬 필요가 있다.

• Pediatric Infection and Vaccine
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• 제14권2호
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• pp.129-135
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• 2007

목 적 : Kikuchi 병은 고열을 동반한 양성 림프절 비대를 특징으로 하는 아급성 괴사성 림프절염이다. 주로 젊은 여성에게 발생하며 소아에 있어 드물게 보고되고 있다. 병인으로는 바이러스와 연관성, 자가 면역기전 등이 제시되고 있으나 정확히 밝혀지지 않은 상태이다. 최근 저자들은 소아에서 발생한 괴사성 림프절염 5례를 경험하였기에 소아에 있어 Kikuchi 병의 임상적 고찰을 하였다. 방 법 : 2001년 1월부터 2006년 6월까지 경희대학교 소아과에 Kikuchi 병으로 진단 받은 환아 5명을 의무기록을 통해 발생 연령, 성별비, 계절별 발생빈도, 임상증상, 과거력, 검사 소견, 림프절의 발생 부위 및 크기, 방사선학적 소견 등을 조사하였다. 결 과 : 남아가 2명, 여아가 3명이었으며, 평균 연령은 9년 9개월(8년 2개월-12년 6개월)이었다. 주된 증상은 지속되는 발열과 림프선 비대로 병원을 방문하였다. 모든 환자는 항생제 치료를 받았으며, 2명의 환자에게서 발진이 발생하였다. 1례에서 초음파 검사상 Kikuchi 병이 의심되는 괴사성 변화가 관찰되었다. 3례에서 추가적으로 컴퓨터 단층촬영을 실시하였다. 입원 후 절제 생검할 때까지 소요된 시간은 10.2일(7-15일)이었다. 5례 모두 림프절 절제 생검 후 조직 검사상 괴사성 림프절염으로 확진하였다. 결 론 : Kikuchi 병은 진단 전에 불필요한 검사와 항생제 치료를 하며 이로 인해 입원 기간도 길어진다. 이에 저자들은 소아에 있어 Kikuchi 병의 임상 양상을 고찰하였다.

• Tuberculosis and Respiratory Diseases
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• 제59권1호
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• pp.86-92
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• 2005

Goodpasture's syndrome is a disease that is characterized by hemoptysis, anemia, and glomerulonephritis with renal failure. Goodpasture reported a case of a young man who expired as a result of a pulmonary hemorrhage and glomerulonephritis at the recovery phase after an influenza infection in 1919. In 1958, Stanton et al. described a combined case of these two diseases as Goodpasture's syndrome. Since then, antiglomerular basement membrane antibody(anti-GBM Ab) has been confirmed to play an important role in the mechanism of this syndrome, and it was reported that this syndrome was an autoimmune disease. The triad of alveolar hemorrhage, glomerulonephritis and circulating anti-GBM Ab forms the basis of a diagnosis of Goodpasture's syndrome. When patients are affected by disease, the relief of symptoms can be accomplished by eliminating the anti-GBM Ab from the circulatory system through hemodialysis, plasmapheresis and immunoabsorption. However, the patients usually die from a massive pulmonary hemorrhage when the diagnosis or treatment is delayed. The incidence of Goodpasture's syndrome is common in the western world, but it is extremely rare in Korea with only five cases being reported. In three of these cases, pulmonary hemorrhage and renal failure was the initial manifestation. Therefore, hemodialysis or plasmapheresis were absolutely essential treatments. We report a case of Goodpasture's syndrome in Korea with a normal renal function.

• 동의생리병리학회지
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• 제23권5호
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• pp.1106-1115
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• 2009

Mori Ramulus has multiple applications in Korean traditional medicine prescription because it has antioxidant and anti-inflammatory effects by reducing macrophage activities. Yet, no studies on the anti-arthritic activity of EMR (extract of Mori Ramulus) have been reported in vitro and 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. Because collagen-induced arthritis (CIA) is similar to RA in pathological symptoms and immune reactions, there have been several reports concerning RA using CIA mouse model. Here, we investigated the effects of Mori Ramulus on RA using CIA mice. The importance of CD4+ Th1 cells in RA progress was previously indicated and studies further showed that Th17 cells play a prime role in severity of disease. Accordingly, the present study was focused on CIA associated with CD4+ Th1 cells and Th1 7 cells. DBA/1OlaHsd mice were immunized with bovine type II collagen (CII). After a second collagen immunization, mice were treated with EMR once a day for 4 weeks. The severity of arthritis within the paw joints was evaluated by histological assessment of cartilage destruction and pannus formation. Immune cells in peripheral blood mononuclear cells (PBMC), draining lymph node (DLN) and paw joints, cytokine production and gene expression were assessed from CIA mouse using ELISA, FACS and real-time PCR analysis. Administration of EMR significantly suppressed the progression of CIA and inhibited the production of TNF-$\alpha$, IL-6 and IL-17 in the serum. The erosion of cartilage was dramatically reduced in mouse knees after treatment with EMR. In conclusion, our results demonstrate that EMR significantly suppressed the progression of CIA and that this action was mediated by the decreased production of TNF-$\alpha$, IL-6, IL-17 and collagen II-specific antibody in the serum. EMR suppressed Th17 cells and reduced level of IL-6 via B cell suppression, and thus, the levels of autoantibodies produced from B cells were decreased. Furthermore, EMR suppressed NKT cells which directly stimulate B cells and develop imbalance of Th1/Th2 cell. Oral administration of EMR (100 mg/kg or 200 mg/kg) significantly suppressed the progression of CIA, which is comparable to that of methotrexate (MTX, 0.3 mg/kg) used as a positive control. We are currently studying the mechanism underlying the therapeutic role for EMR in CIA mice.

• 근관절건강학회지
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• 제8권1호
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• pp.27-50
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• 2001

Rheumatoid arthritis is a chronic systemic autoimmune disease. Although the joints are the major loci of the disease activity, fatigue is a common extraarticular symptom that exists in all gradations of rheumatoid arthritis. Fatigue is defined as a subjective sense of generalized tiredness or exhaustion and has multiple dimensions. Therefore fatigue is a common and frequent problem for those with rheumatoid arthritis. In fact, 88-100% of individuals with rheumatoid arthritis experience fatigue. Especially the degree of fatigue is higher in women than men with rheumatoid arthritis. Despite the importance of fatigue among the patients with rheumatoid arthritis, the mechanism that leads to fatigue in rheumatoid arthritis is not completely understood. This study was intended to test and validate a model to predict fatigue in women with rheumatoid arthritis. Especially it was intended to identify the direct and indirect effects of the variables of pain, disability, depression, sleep disturbance, morning stiffness, and symptom duration to fatigue. Data were collected by questionnaires including Multidimensional Assesment of Fatigue(Tack, 1991), numeric scale of pain, graphic scale of joints, Ritchie Articular Index, Korean Health Assessment Questionnaire(Bae, et al., 1998), Inventory of Function Status(Tulman, et al., 1991), Center for Epidemiologic Studies-Depression, and Korean Sleep Scale(Oh, et al 1998). The sample consisted of 345 women with a mean duration of rheumatoid arthritis for 10.06 years and a mean age of 49.64 years. SPSS win and Win LISREL were used for the data analysis. Structural equation modeling revealed the overall fit of the model. Pain predicted fatigue directly and indirectly through disability, depression, and sleep disturbance. Disability, sleep disturbance predicted fatigue only directly, while depression only indirectly through disability and sleep disturbance. Also morning stiffness and symptom duration predicted fatigue through disability and depression. All predictors accounted for 65% of the variance of fatigue. Depression, pain, and disability predicted sleep disturbance. Depression had reciprocal relationship with disability and they both were predicted by pain directly and indirectly. In summary, pain, depression, disability, sleep disturbance, morning stiffness, and symptom duration contributed to the fatigue of patients with rheumatoid arthritis. The best predictor of fatigue was pain. This finding indicates that the modification of pain, depression, disability, sleep disturbance, morning stiffness could be nursing intervention for relief or prevention of fatigue.

• Natural Product Sciences
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• 제5권3호
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• pp.113-120
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• 1999

Nitric oxide (NO) is a free radical synthesized from L-arginine by nitric oxide synthase (NOS). It is believed that NO is an important mediator in numerous physiological and inflammatory responses. Particularly, a large amount of NO released from the inducible nitric oxide synthase (iNOS) is mostly associated with inflammatory processes. Overproduction of NO in these processes including sepsis and autoimmune diseases can have deleterious consequences and pathophysiologic relevance. Therefore, for the discovery of new inhibitory agents against iNOS activity, we have evaluated about 100 kinds of natural products after partition into three layers (n-hexane, ethyl acetate and aqueous) from 100% methanol extracts to study inhibitory effects on iNOS activity induced by lipopolysaccharide (LPS) in RAW264.7 cells culture system. As a positive control, curcumin, which is known as an anti-tumor promoter, anti-inflammatory agent as an iNOS inhibitor, was used and showed the dose-dependent inhibitory effect $(IC_{50},\;2.5\;{\mu}g/ml)$. Among tested fractions, the n-hexane fraction of Cimicifuga heracleifolia $(IC_{50}:\;9.65\;{\mu}g/ml)$, Forsythiae fructus $(IC_{50}:\;6.36\;{\mu}g/ml)$, Saposhnikovia divaricata $(IC_{50}:\;5.92\;{\mu}g/ml)$, and the ethyl acetate fraction of Chrysanthemum sibiricum $(IC_{50}:\;2.56\;{\mu}g/ml)$, Gastrodia elata $(IC_{50}:\;3.46\;{\mu}g/ml)$, and the aqueous fraction of Dianthus chinensis $(IC_{50}:\;6.73\;{\mu}g/ml)$, Euonymus alatus $(IC_{50}:\;6.78\;{\mu}g/ml)$, Mechania urticifoloria $(IC_{50}:\;8.01\;{\mu}g/ml)$ showed strong inhibitory activity against LPS-stimulated iNOS. Especially, the ethyl acetate fraction of Chrysanthemum sibiricum $(IC_{50}:\;2.56\;{\mu}g/ml)$, which exhibited the strongest inhibition against iNOS, was fractionated with silica-gel column chromatography. These subfractions exhibited dose-dependent inhibition against iNOS activity in the range of $2.59-5.6\;{\mu}g/ml$ except for fraction No. 3, 4, 5, 6, 8, 9, and 16. Our study shows that Chrysanthemum sibiricum has the strongest inhibitory effect against iNOS activity and has similar effect to curcumin. Therefore, further studies for the identification of active principles from Chrysanthemum sibiricum and investigation for the mechanism of the inhibition of iNOS by active principles will be performed.

• 동의생리병리학회지
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• 제20권3호
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• pp.651-656
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• 2006

Activation of $NF-{\kappa}B$ is known to be a trigger of various cellular disorders including inflammatory and autoimmune diseases such as rheumatoid arthritis. Numerous approaches are ongoing within laboratories to identify potential therapeutic agents which inhibit the $NF-{\kappa}B$ activation. In this study, we have tested the inhibitory effects of five traditional medicines on the activation of $NF-{\kappa}B$ by NIK. Among three medicines which exhibited inhibitory effect on the expression of $NF-{\kappa}B$ repoter plasmid, we investigated further the inhibitory mechanism of Dichroa febrifuga in connection with IKKY activity. Wild type $IKK{\gamma}$ inhibited the $NF-{\kappa}B$ activation by NIK but the C-terminal deletion mutant of IKKY did not show the inhibitory effect, indicating that the C-terminal leucine zipper domain of $NF-{\kappa}B$ is important for the inhibition of $NF-{\kappa}B$ activation. The water extract of Dichroa febrifuga(DFE) also strongly inhibited the $NF-{\kappa}B$ activation by NIK. The inhibitory activity of DFE appeared to be independent of the expression of $IKK{\gamma}$, suggesting that the pathways of inhibition by Dichroa febrifuga and $IKK{\gamma}$ are different. Our results suggest that Dichroa febrifuga can be used as a medicine for inhibition of the $NF-{\kappa}B$ activation in a wide range of cells without relation to the expression of $IKK{\gamma}$.