2014-08-012024-05-18https://scholars.lib.ntu.edu.tw/handle/123456789/704938摘要：類風濕性關節炎(rheumatoid arthritis, RA)是一種自體免疫疾病，其致病機轉至今仍未完全清楚，目前已知其病因和遺傳基因及環境因素有關，免疫系統不正常的活化，導致發炎細胞攻擊關節組織而造成慢性關節的發炎與破壞。RA 除可侵犯關節外，亦可能侵犯全身其他器官。若未給予積極治療即可能造成骨骼破壞，目前使用緩解性藥物和免疫抑制劑的治療方式，並無法完全令人滿意。 調節性細胞在抑制自體免疫反應和維持免疫耐受性上扮演重要角色，調節性 T細胞可依表面分子和免疫抑制之機轉區分不同型的調節性 T 細胞 (regulatory T cells, Treg cells)，主要為自然調節性 T 細胞(natural Treg cells)和誘發型調節性 T 細胞(inducible Treg cells)，此外我們最近發現 B 細胞可誘發原始 T 細胞分化為調節性T 細胞，稱 Treg-of-B cells，具有部分經由 IL-10 來抑制 T 細胞增生的能力，Treg-of-B cells 可以減緩小鼠氣喘模式之氣道發炎和過度敏感。除了調節性 T 細胞外，調節性 B 細胞也被發現具有免疫調節的功能，調節性 B 細胞可在發炎環境中被誘發出來。 由於目前治療方師無法在類風濕性關節炎病人重新建立免疫耐受性，提升調節性細胞功能被認為很有治療潛力。在類風濕性關節炎的小鼠模式: 利用膠原蛋白誘發關節炎(collagen-induced arthritis, CIA)中給予 Treg-of-B 細胞或調節性 B 細胞都有報告可以改善關節發炎。 我們在這個計畫中將利用具有調節能力的 B 細胞和 B 細胞所誘發的調節性 T細胞應用到類風濕性關節炎的控制上，其中將分別研究利用試管內培養的方法，免疫抑制機轉的探討，並 CIA 建立動物模式，來研究是否所謂的調節性 B 細胞和Treg-of-B 細胞能夠有效地可以改善類風濕性關節炎的症狀。我們的研究有助於了解 RA 的致病機轉，我們的研究希望可證實調節性細胞對於 RA 病人具有極大的治療潛力。<br> Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease that is characterized by persistent inflammation, swelling, hyperplasia, pannus invasion and destruction of joints. A proposed disease mechanism involves genetic and environmental interaction, resulting lymphocyte abnormal activation with inflammatory cytokine and immune complexes overproduction. Collagen-induced arthritis (CIA) induced by type II collagen has been a well-established mouse model that shares the similarities with human RA. Regulatory cells play an important role in the suppression of autoimmune pathology by induction and maintenance of immunological tolerance. Regulatory T cells (Tregs) can be separated to different populations based on their surface marker expression, including natural or inducible regulatory T cells. We recently have found a group of regulatory T cells induced by B cells (Treg-of-B cells) that could exert a suppressive function on T cell proliferation partially by IL-10. Treg-of-B cells could alleviate airway inflammatory and hyper-responsiveness in a murine model of asthma. In addition to Treg cells, regulatory B cells (Breg cells) have been found to have immunosuppressive function. Breg cells are induced under inflammatory conditions. Since current therapies have failed to promote the reconstruction of immune tolerance in patients with RA. Enhancing the function of regulatory cells components is considered a valuable therapeutic strategy for treating RA. Adoptive transfer of Breg or Treg cells has been demonstrated effective in ameliorating arthritis in CIA model. In our study, we will test the hypothesis that 1) Treg-of-B cells or regulatory B cells have the suppressive ability in vitro through cell-cell contact or anti-inflammatory cytokines IL-10; 2) Adoptive transfer Treg-of-B cells or regulatory B cells can ameliorate CIA by regulating local inflammation, and alleviating the paw swelling. We will further clarify the suppressive function and therapeutic efficacy and mechanism of Treg-of-B and Breg cells in the murine model of CIA. Our study will facilitate more understanding the pathogenesis of RA and will provide a novel therapeutic application of regulatory cells in patients with rheumatoid arthritis.