2015-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/683093摘要：類風濕性關節炎(rheumatoidarthritis,RA)是一種慢性發炎的自體免疫疾病，其致病機轉至今仍未完全清楚，但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滑液膜的發炎與破壞，甚是關節骨侵蝕，除可侵犯關節外，亦可能侵犯全身其他器官。調節性T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(regulatoryTcells,簡稱Tregcells)分為自然調節性T細胞(naturalTregcells,簡稱nTregs)和誘發型調節性T細胞(inducibleTregcells,簡稱iTregs)，除了調節性T細胞外，調節性B細胞產生細胞激素(IL-10)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。利用類風濕性關節炎的小鼠模式:膠原蛋白誘發關節炎(collagen-inducedarthritis，簡稱CIA)，已有研究證實TGF-β誘發之調節性T細胞(TGF-βiTregs)可抑制蝕骨作用和關節股侵蝕。我們先前的研究發現一群新的誘發型調節性T細胞，稱作B細胞誘發之調節性T細胞(Treg-of-Bcells)，本計劃中先建立膠原蛋白誘發關節炎，Treg-of-B細胞帶有lymphocyte activation gene-3 (LAG3)之表面標記，具有分泌IL-10來抑制T細胞增生的能力；此外我們利用BAFF誘發調節性B細胞產生IL-10，我們分別給予(adaptivetransfer)LAG3+Treg-of-B細胞或調節性B細胞，看是否能夠有效地可以改善類風濕性關節炎的症狀與組織切片上之發炎，並且研究是否經由IL-10、LAG3或其他免疫調節之機轉。我們的研究有助於了解類風濕性關節炎的致病機轉，並希望可證實調節性細胞對於類風濕性關節炎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 persistentinflammation, swelling, hyperplasia, pannus invasion and destruction of joints. A proposed diseasemechanism involves genetic and environmental interaction, resulting lymphocytes abnormal activation withinflammatory cytokine and immune complexes over-production. Collagen-induced arthritis (CIA) induced bytype 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 andmaintenance of immunological tolerance. Regulatory T cells (Tregs) can be classified to different populationsbased on their surface marker expression, including natural or inducible regulatory T cells. We recently havefound a group of regulatory T cells induced by B cells (Treg-of-B cells) that express the lymphocyteactivation gene-3 (LAG3) on cell surface and suppress T cell proliferation through IL-10. In addition to Tregcells, regulatory B cells (Breg cells) have been found to have immunosuppressive function through IL-10.Breg cells are induced under inflammatory conditions.Enhancing the function of regulatory cells components is considered a promising therapeutic strategyfor treating RA. Adoptive transfer of Breg or Treg cells (either natural Tregs or TGF-βinducibleTregs)havebeen demonstrated to ameliorate arthritis severity in CIA model. In the current study, we will test thehypothesis that 1) LAG3+Treg-of-B cells have the suppressive ability in vitro through cell-cell contact,anti-inflammatory cytokines IL-10, or surface marker LAG3; 2) Adoptive transfer LAG3+Treg-of-B cells orIL-10-producing regulatory B cells can ameliorate symptoms of CIA (such as paws swelling) by regulatinglocal inflammation in tissue pathology. We will further clarify the suppressive function and therapeuticefficacy of LAG3+Treg-of-B and IL-10-producing Breg cells in the murine model of CIA. Our study willfacilitate more understanding the pathogenesis of RA and will provide a novel therapeutic application ofregulatory cells in patients with RA.