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標題: | 人類胎盤絨毛膜蛻膜間葉細胞在實驗性自體免疫性腦脊髓炎動物模式療效之評估 The evaluation for the therapeutic effects of human placenta choriodecidual-derived mesenchymal stromal cells (pcMSCs) in experimental autoimmune encephalomyelitis animal model |
作者: | Hsin Li 李昕 |
指導教授: | 林泰元(Thai-Yen Ling) |
關鍵字: | 多發硬性化症,胎盤絨毛膜間葉幹細胞,樹突細胞,實驗性自體免疫性腦脊髓炎,免疫調控, Multiple sclerosis,Placenta choriodecidual-derived mesenchymal stromal cells,Dendritic cells,Experimental autoimmune encephalomyelitis,Immune regulation, |
出版年 : | 2017 |
學位: | 碩士 |
摘要: | 人類的多發性硬化症(Multiple sclerosis, MS)是一種在中樞神經系統引起的慢性發炎反應,伴隨著免疫細胞的浸潤並累積在中樞而造成的自體免疫疾病,它的病灶位於腦和脊髓,包括局部的去髓鞘化和軸突的廣泛性損傷,一般認為T細胞在其中扮演主導性的角色,加上樹突細胞(DC)呈現自身抗原去活化T細胞,去攻擊包覆在神經纖維外的髓鞘,造成感覺或是運動神經功能的異常。目前FDA已經批准許多治療MS的藥物,但是MS還是無法完全治癒。近年來,由於間葉幹細胞(MSCs)已經有許多研究證實具有免疫調節的特性,因此被認為是有潛力的細胞藥物,也應用在自體免疫疾病的臨床治療當中。在我們的實驗室中,分離出人類胎盤絨毛膜蛻膜間葉幹細(placenta-choriodecidual derived mesenchymal stromal cells, pcMSCs),並以無血清的方式進行培養。為了更進一步瞭解pcMSCs在MS這類自體免疫疾病中的應用性,探討對免疫細胞的調控作用,著重在對於DC的影響。首先在in vitro模式中成功建立小鼠骨髓來源的樹突細胞,並發現pcMSCs對於DC的分化以及成熟的過程都具有調節的效果,可能是藉由使COX-2的表現量上升來對樹突細胞的成熟進行抑制。接著為了驗證pcMSCs在in vivo對於樹突細胞的影響,使用了小鼠實驗性自體免疫性腦脊髓炎(EAE)作為動物模型,實驗的結果顯示出給予pcMSCs進行治療的EAE小鼠可以顯著延緩發病的時間之外也可以降低病況的嚴重程度,進一步發現pcMSCs的治療也能有效降低發病當下(disease onset)和急性期(acute phase)中浸潤到脊髓樹突細胞的數量之外,也能降低CD4 T細胞的浸潤,但在脾臟中則是不會觀察到pcMSCs的給予對於樹突細胞和T細胞在比例和活化程度上的影響,代表pcMSCs的治療不會產生全身性的免疫抑制,因此pcMSCs可以成為細胞治療一個有潛力的來源。 Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by chronic inflammation, focal demyelination and widespread damage of axon. Although a wide variety of therapies have been approved by FDA today, there is no cure for MS. So far, many studies have demonstrated mesenchymal stromal cells (MSCs) as a promising source to treat MS, however, the mechanism for the therapeutic effects of MSCs in MS is still unclear. Previously, we have generated a new type of MSCs from the maternal part of human termed placenta by a serum-free selection culture method and named placenta choriodecidual-derived mesenchymal stromal cells (pcMSCs). In order to understand the pathological mechanism of MS and therapeutic effects of pcMSCs, we used myelin oligodendrocyte glycoprotein (MOG)35-55-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice as the animal model to revel the therapeutic mechanism of MSCs for MS treatment in this study. Meanwhile, we also established an in vitro differentiation and maturation assay for mouse bone marrow-derived DCs (m/bmDCs) as well as CFSE proliferation assay for T-cells from mouse spleen to evaluate the immunomodulation potentials of pcMSCs. Different studies have demonstrated that T cells specific for self-antigens mediated pathology in the disease. Moreover, dendritic cells (DCs) have also been reported to critically involve in initiation of immune responses of MS. In this study, we demonstrated that pcMSCs could ameliorate the disease progress of (MOG)35-55-induced EAE mice compared to control. Furthermore, when co-culture of pcMSCs and the progenitor cells of DCs, the results showed that pcMSCs could inhibit the progress of differentiation and maturation of m/bmDCs and both the expression of typical DCs costimulatory molecules (CD80 & CD86), antigen-presenting molecule MHC class II peptides as well as chemokine receptor CCR7 were strongly downregulated. Our data also showed that an upregulation of pcMSCs COX-2 mRNA expression was observed when pcMSCs co-cultured with DCs. Taken together, our findings suggest that the beneficial effects of pcMSCs are likely inhibition not only differentiation process and maturation program of DCs but also proliferation of T cells in vitro, furthermore, pcMSCs treatment in EAE mice can disruption on disease development and progression as a result of reducing the infiltration of DCs and T cells into spinal cord. In conclusion, we provided a distinct perception of modulation from pcMSCs on DCs in EAE model and MS. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20658 |
DOI: | 10.6342/NTU201702033 |
全文授權: | 未授權 |
顯示於系所單位: | 藥理學科所 |
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