Effect Of Sinomenine On The Expression Of CD28/CTLA-4 In Rheumatoid Arthritis Patients And It's Suppression On Collagen-induced Arthritis Mouse

Rheumatoid arthritis (RA) is a common (0.36% of Chinese population) chronic inflammatory disease which is characterized by radiographic joint destruction, severe functional deterioration, and work disability (American College of Rheumatology Ad Hoc Committee on Clinical Guidelines, 1996). The investigation about RA immunopathogensis shows that CD4+ T cells act as initiators of RA, by migrating to the affected joints, recognizing peptides derived from processed antigens, and releasing several types of cytokines, such as IFN-γ. Such cytokines enhance the function of other cells, especially macrophages to produce pro-inflammatory cytokines including IL-1β and TNF-α, which induce inflammation response and finally conduce abnormal proliferation of synovium cells, destruction of the joint cartilage and bone.Based on the immunopathogensis theories above, DMARDs are considered as effective drugs to RA patients because they have part of immunosuppressive effect. But a recent investigation found only a few of DMARDs have been unequivocally shown to retard radiographically assessed disease progression. Furthermore, DMARDs can rarely be given for long periods in RA owing to lack of sustained efficacy or to toxicity. Treatments using some new immunity drugs such as TNF-α-mAb, CTLA-4Ig and so on have been shown down-regulate in the development of RA, but the period of therapy is so short that the final conclusion can not be maken. And infection, lymphosarcoma and lupus were reported with patients using these drugs. Therefore, there is a need for new agents with a high ratio of efficafy to toxicity that decrease clinical signs and symptoms of RA, retard disease progressive and improve functional ability and quality of life. Sinomeninm (SN) is an alkaloid isolated from the stem and root of Sinomeninm acutum. Sinomeninm acutum has been used in traditional Chinese medicine to treat various rheumatic diseases for hundreds of years. It has been demonstrated that the effect of SN on rheumatoid arthritis patients is satisfactory. Many reports made it evident that SN has various effects: anti-inflammatory effects, In the 1990s, Liu and collaborators studied the effects of SN in vitro and in vivo and found that SN reduced tumor necrosis factor-α by lipopolysaccharide-treated macrophages in culture. SN also inhibited proliferation of rat synovial fibroblasts stimulated with transforming growth factor-2β or interleukin (IL)-1β and proliferation of lymphocytes. Antiinflammatory properties of SN were also demonstrated in rat models of adjuvant arthritis and antigen-induced arthritis. However, little is known about the mode of action of this herbal medicine on RA patients. Whether the immune suppressive activity of SN might contribute to the therapeutic mode of action of the extract on RA and whether SN in combination with DMARDs has more effective is unknown. In this reseach, we evaluated SN for its effectiveness on two aspects: (1) to investigate whether SN can influence the level of CD28/CTLA-4 on T cells in RA patients after the treatment of SN for two months, and (2) to compare the inhibitory effects of SN on type Ⅱ collagen-induced arthritis (CIA) in mouse.We detected the level of CD3+CD28+ and CD3+CTLA-4+ on PBMCs and SFMCs of 32 RA patients and 12 controls by two-color flow cytometric analysis and found there are some differences between them. There are a faint relationship between the level of these molecules and the clinical activity of the disease in RA patients by the Spearman Correlation analysis, clueing to these molecules not only be concerned with the initiation of autoimmunity, but also affect the development of inflammation. But the correlation coefficient is so low that it can not illuminate the co-stimulatory molecuels are the crucial factors influencing the disease.The level of CD3+CTLA-4+ on PBMCs of RA patients significantly increased after the two months treatment of SN, but the level of CD3+CD28+ was not changed. We speculate there are more negative signs on active T cells, which are inhibited o...