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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林泰元(Thai-Yen Ling) | |
dc.contributor.author | Hsin Li | en |
dc.contributor.author | 李昕 | zh_TW |
dc.date.accessioned | 2021-06-08T02:57:23Z | - |
dc.date.copyright | 2017-09-14 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-07-31 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20658 | - |
dc.description.abstract | 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。 | zh_TW |
dc.description.abstract | 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. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T02:57:23Z (GMT). No. of bitstreams: 1 ntu-106-R04443013-1.pdf: 2302366 bytes, checksum: 2a604186e4fae1c3f9a8f67bd792eaf8 (MD5) Previous issue date: 2017 | en |
dc.description.tableofcontents | Contents
中文摘要 iv Abstract v Chapter 1 1 Introduction 1 1.1 Mesenchymal stem/stromal cells (MSCs) 2 1.2 Placenta choriodecidual-derived mesenchymal stromal cells (pcMSCs) 3 1.3 The immunomodulatory effect of MSCs 4 1.4 Demyelinating disease : multiple sclerosis (MS) 5 1.5 Experimental autoimmune encephalomyelitis (EAE) model 8 1.6 The immunopathogenesis of EAE 10 1.7 The role of dendritic cells in multiple sclerosis 12 1.8 Aims of study 14 Materials and methods 15 2.1 Animals 16 2.2 Human placenta choriodecidual-derived mesenchymal stromal/stem cells (pcMSCs) 16 2.3 Murine bone marrow-derived dendritic cells (BMDCs) 17 2.4 Experimental autoimmune encephalomyelitis (EAE) induction 19 2.5 Isolation and preparation of mouse splenocytes 20 2.6 CFSE labeling 21 2.7 Splenocytes proliferation assay 21 2.8 Quantitative real time PCR 22 2.9 Isolation of DCs and T cells from spleen and spinal cord in mice 22 2.10 Flow cytometry analysis 23 Results 25 3.1 Generation of murine bone marrow-derived CD11c+ dendritic cells 26 3.2 pcMSCs inhibit differentiation process of murine bone marrow-derived CD11c+ dendritic cells 26 3.3 pcMSCs inhibit maturation of murine bone marrow-derived CD11c+ dendritic cells 27 3.4 pcMSCs alter the profile of cytokine production mRNA expression in mDCs 28 3.5 Administration of pcMSCs delayed the disease onset and improved the severity of the clinical symptoms in EAE mice 29 3.6 Isolation and evaluation of DCs and T lymphocytes in spleen and spinal cord from EAE mice and pcMSCs-treated EAE mice 30 Discussion and conclusion 33 4.1 The recent advances in our understanding of MSCs administration in EAE model : a comparison between other studies 34 4.2 IL-12p40 acts as antagonistic or agonic role in the regulation of pcMSCs in murine DCs 40 4.3 Conclusion 42 Figures and legends 44 Figure 1. The generation of murine bone marrow-derived CD11c+ dendritic cells. 46 Figure 2. pcMSCs inhibit differentiation of murine bone marrow-derived CD11c+ dendritic cells. 48 Figure 3. pcMSCs inhibit maturation of murine bone marrow-derived CD11c+ dendritic cells. 51 Figure 4. pcMSCs mediate the transcriptional inflammatory cytokine expression of mature CD11c+ dendritic cells may through COX-2 pathway. 53 Figure 5. Administration of pcMSCs delayed the disease onset and alleviated the clinical score in EAE mice. 55 Figure 6. Administration of pcMSCs significantly decrease the number of DCs and T cells infiltration into spinal cord from EAE mice during both the onset and the acute phase of the disease. 57 Figure 7. Administration of pcMSCs did not alter the percentage and phenotype of DCs in spleen from EAE mice during the onset and acute phase of the disease. 59 Figure 8. Administration of pcMSCs did not alter the percentage and phenotype of T cells in spleen from EAE mice during the acute phase of the disease. 61 Table 1. Antibodies for flow cytometry 62 Table 2. Real time PCR human primer sequences 62 Table 3. Real time PCR mouse primer sequences 63 Chapter 6 References 64 | |
dc.language.iso | en | |
dc.title | 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 | zh_TW |
dc.title | The evaluation for the therapeutic effects of human placenta choriodecidual-derived mesenchymal stromal cells (pcMSCs) in experimental autoimmune encephalomyelitis animal model | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 黃彥華(Yen-Hua Huang),林琬琬(Wan-Wan Lin),莊雅惠(Ya-Hui Chuang),朱清良(Ching-Liang Chu) | |
dc.subject.keyword | 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, | zh_TW |
dc.subject.keyword | Multiple sclerosis,Placenta choriodecidual-derived mesenchymal stromal cells,Dendritic cells,Experimental autoimmune encephalomyelitis,Immune regulation, | en |
dc.relation.page | 72 | |
dc.identifier.doi | 10.6342/NTU201702033 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2017-08-01 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥理學研究所 | zh_TW |
顯示於系所單位: | 藥理學科所 |
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ntu-106-1.pdf 目前未授權公開取用 | 2.25 MB | Adobe PDF |
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