B細胞誘導調節性T細胞對關節發炎的免疫調控研究

Abstract

類風溼性關節炎是一主要針對四肢關節的自體免疫疾病，主要在病患關節的滑膜軟骨處有反覆性的發炎，最後導致關節不可逆之腫脹變形，然而目前尚未有完全根治的療法。已知此疾病在免疫致病機轉中，關節周圍浸潤的免疫細胞偏向發炎狀態，這些發炎性物質除了造成關節腫脹，也導致更多免疫細胞浸潤。 在先前的研究已發現，移植誘導型調節性T細胞 (induced regulatory T cells, iTreg) 於膠原蛋白誘導的關節炎(collagen-induced arthritis)小鼠內可改善疾病，因此本研究希望能藉體外培養出由B細胞誘導之調節性T細胞 (Treg-of-B)，改善小鼠的類風濕性關節炎。 本研究的實驗結果發現，B細胞誘導之調節性T細胞，表現和調節性T細胞相似的表面蛋白，例如CD25和LAG3，但不包含Foxp3。在T細胞增生實驗中也證實可藉LAG3分子及分泌抗發炎細胞素IL-10抑制CD4+CD25-T細胞的增生。進一步將這群B細胞誘導之調節性T細胞利用靜脈注射到類風溼性關節炎的小鼠模式中，發現四肢關節在臨床發炎分數有顯著降低；小鼠犧牲後，自脾臟及淋巴結取出的細胞也分泌較多IL-10；而關節組織之發炎性基因IL-6則降低；在小鼠的腳掌組織切片也觀察到移植Treg-of-B細胞的小鼠組別，其細胞浸潤和骨質溶解的程度也較為減緩。 綜合上述，可證實脾臟B細胞誘導調節性T細胞具減輕膠原蛋白誘發之小鼠關節炎的能力，此研究結果也提供未來使用不同誘導型調節性T細胞治療類風溼性關節炎或其他自體免疫疾病的治療潛力。

Rheumatoid arthritis (RA) is an autoimmune disease in which dysregulated immune cells primarily target synovial joints. Despite recent advances in the treatment of RA, including the introduction of biologic therapies and employment of combination disease-modifying antirheumatic drug strategies, remission rates remain suboptimal. Previous studies have demonstrated that the adoptive transfer of induced regulatory T cells (iTreg cells) was effective in treating a murine model of collagen-induced arthritis (CIA). The objective of this study was to develop optimal potential iTreg-based therapy for CIA by adoptively transferring LAG3+ Treg-of-B cells. Our results showed that B-cell-induced Treg-of-B cells expressed LAG3 but not Foxp3 (designated LAG3+ Treg-of-B), and secreted IL-4, IL-10, and TGF-β. Furthermore, LAG3+ Treg-of-B cells suppressed the proliferation of CD4+CD25- responder T cells through both LAG3 and IL-10 production. In the murine CIA model, adoptive transfer of LAG3+ Treg-of-B cells alleviated the joint severity as well as local and systemic inflammation. Treatment with LAG3+ Treg-of-B cells also promoted IL-10 production in lymphocytes isolated from the spleen and draining lymph nodes. Moreover, mice receiving LAG3+ Treg-of-B cell treatment showed significantly less pronounced osteolysis in the hind footpads, which correlated with the downregulation of tartrate-resistant acid phosphatase expression. In conclusion, we identified a novel subset of Treg cells for CIA treatment. This insight may facilitate exploring novel regulatory T-cell-based therapies for human autoimmune diseases.