間葉幹細胞應用在類風濕性關節炎動物模式發炎改善之探討

研究背景: 類風濕性關節炎 (Rheumatoid arthritis, RA) 為常見的自體免疫疾病。目前已知許多免疫細胞參與此疾病的病理機制。在疾病初期,T 淋巴細胞被認為是導致疾病發生與影響病程重要因子之一。間葉幹細胞 (Mesenchymal stem cells, MSCs) 為多潛能性幹細胞 (pluripotent stem cells),可由骨髓或其他組織中取得,具有自我更新、繁衍並且可分化成多種不同的細胞與組織。近年許多文獻報告指出間葉幹細胞具有免疫調節的能力。本篇研究希望了解間葉幹細胞在治療類風濕性關節炎動物模式中的應用性。實驗方法: 從小鼠骨髓中培養出間葉幹細胞,確認間葉幹細胞的表面標誌,並在體外培養刺激其分化成骨細胞(osteocytes),軟骨細胞(chondrocytes) 與脂肪細胞 (adipocytes),此外利用在試管內測試間葉幹細胞的免疫抑制功能,更進一步利用牛第二型膠原蛋白建立類風濕性關節炎的動物模式,在疾病進程中,以靜脈注射方式給予間葉幹細胞,用以研究其治療效果。實驗結果: 結果顯示,脾臟中的 T 淋巴球在 anti-CD 3/28 抗體刺激下,與間葉幹細胞共同培養,間葉幹細胞能有效抑制 T 淋巴球分裂增生,確立其免疫調控的功能。給予間葉幹細胞可有效改善類風濕性關節炎動物模式中的發炎反應,降低疾病嚴重程度與細胞浸潤現象 ; 血清中,經過間葉幹細胞治療的小鼠體內所產生的介白素- 1β 濃度較低 ; 膝關節萃取出的蛋白質中,介白素-6 有顯著意義地降低 ; 經間葉幹細胞治療的小鼠脾臟細胞,可產生較高干擾素-γ(interferon-γ)介白素-6 (interleukin-6, IL-6), 介白素-10 (interleukin-10, IL-10)。結論: 本篇實驗結果顯示,間葉幹細胞在體外培養或動物實驗中都可有效調節免疫反應,我們認為間葉幹細胞在類風濕性關節炎的治療中有減緩的效果,未來將進一步研究其參與在此疾病的免疫調控機轉。

關鍵字

間葉幹細胞；類風濕性關節炎

並列摘要

Background: Rheumatoid arthritis (RA) is a common autoimmune disease in the world. A variety of immune cells are involved in pathogenic mechanism and progression of the disease. In the early stage of RA, T lymphocytes are regarded as one of crucial cells in the disease pathogenesis and are related to disease severity. Mesenchymal stem cells (MSCs) are pluripotent stem cells obtained from many tissues. MSCs can self-renew and differentiate into several lineages under stimulations. Recently, more and more studies have demonstrated that MSCs exert the immunoregulatory capacity. In this study, we aimed to examine whether MSCs can have potential therapeutic effect on collagen-induced arthritis (CIA) in rheumatoid arthritis murine model. Methods: We isolated MSCs from bone marrow of DBA/1J mice. MSCs were expanded, characterized by phenotypic analysis, and differentiated into osteocytes, chondrocytes, and adipocytes. Proliferation of T lymphocytes in the absence or presence of MSCs was performed to determine the immunosuppressive function of MSCs in vitro. To investigate the effect of MSCs on CIA animal model, we immunized mice with bovine type II collagen, and injected MSCs intravenously. Results: MSCs efficiently inhibited the anti-CD3/28-induced T cell proliferation and division. These data suggested that MSCs had the regulatory effect on inflammatory immune responses. MSCs administration can reduce the severity of arthritis and cell infiltration. The level of IL -1β was lower in the sera of MSC-treated mice than non MSC-treated group. IL-6 expression in knee protein extraction was decreased after mice receiving MSCs. Furthermore, the lymphocytes of MSC-treated mice secreted higher IFN-γ, IL-6, and IL-10. Conclusions: Our results demonstrated that MSCs could play a modulatory role in the immune responses both in vitro and in vivo. The delivery of MSCs in CIA animal model ameliorated the severity of arthritis. MSCs treatment can be used as a potential therapy for RA. However, further studies are required to clarify the immunoregulatory mechanisms mediated by MSCs treatment.

並列關鍵字

Mesenchymal stem cell ； Rheumatoid arthritis

參考文獻

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Rheumatoid arthritis susceptibility and interleukin 10: a study of two ethnically

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間葉幹細胞應用在類風濕性關節炎動物模式發炎改善之探討

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