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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李建國(Chien-Kuo Lee) | |
| dc.contributor.author | Yu-Tin Lin | en |
| dc.contributor.author | 林于婷 | zh_TW |
| dc.date.accessioned | 2021-06-16T13:13:39Z | - |
| dc.date.available | 2016-09-24 | |
| dc.date.copyright | 2013-09-24 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-07-30 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/61799 | - |
| dc.description.abstract | 樹突細胞 (Dendritic cells, 簡稱DC)是一種存在於人體的特化抗原呈現細胞，它們可分為傳統樹突細胞(cDC) 和漿狀樹突細胞 (pDC)兩種不同的亞群(subsets)，並且在體內扮演免疫和耐受性反應調解者。樹突細胞分佈全身，壽命期短，約3~7天，因此需要持續藉由前驅細胞(progenitors)分化補充。在造血系統中，共同樹突細胞前驅細胞 (common dendritic cell progenitor, CDP)以及共同淋巴前驅細胞 (common lymphoid progenitor, CLP) 均具有分化成樹突細胞的能力。然而，目前的研究中，FMS類酪氨酸激酶3配體 ( FMS Like Tyrosine Kinase 3 Ligand,簡稱Flt3L) 對於樹突細胞發展角色已比較清楚，但巨噬細胞聚落刺激因子 (macrophage-colony stimulating factor,簡稱M-CSF) 如何調節前驅細胞發育成樹突細胞的過程仍尚未完全了解，因此在本論文中，我們將探討巨噬細胞聚落刺激因子影響樹突細胞發育的相關機制。
利用體外培養的方式，我們發現M-CSF 可增加cDC的生成；同時可藉由水壓流體基因傳送(hydrodynamic gene transfer, 簡稱HGT)或靜脈注射途徑中觀察到，M-CSF 會誘導CDP上M-CSFR 的表現量增加，並且增加CDP的生成，因此發育過程能有效生成cDC的因素是藉由增加CDP細胞增生的能力(proliferation)以及減少細胞凋亡(apoptosis)來達成。在TF-1-fms 細胞中(一種血病細胞株，大量表現M-CSFR)，M-CSF的刺激下可活化STAT (Signal transducer and activator of transcription protein) 蛋白，包括STAT1，STAT3蛋白的酪氨酸磷酸化以及活化Akt和M-CSFR。有趣的是，我們使用第一型干擾素(Type I IFNs)訊息傳遞具缺陷的基因突變小鼠Ifnar-/-，Stat1-/-，Stat2m/m，Stat3f/f-MxCre 進行活體實驗時，我們發現M-CSF促進cDC生成的現象受到抑制；同時，使用正常基因型小鼠進行的實驗結果也顯示，若在小鼠體內表現同時表現M-CSF和第一型干擾素， 則可加成cDC的生成。此結果顯示，第一型干擾素可能參與調節M-CSF影響cDC的發育機制。 在篩選對M-CSFR的抑制劑研究中，我們找到Dasatinib是最具有效能和最具有特異性的抑制劑。它抑制TF-1-fms 細胞株和cDC細胞分裂的IC50分別為42 nM and 11 nM。Dasatinib抑制cDC的生成更勝於目前對於M-CSFR最有效的藥物GW2580。此外，體外骨髓細胞和活體實驗中，Dasatinib也會抑制M-CSF誘導前驅細胞CDP的生成以及cDC的發育。以上實驗結果證實，M-CSF促使cDC的發育過程主要透過兩種機制，即透過CDP增生及分化成cDC以及增加cDC細胞自身複製。整體而言，STAT1，STAT2，STAT3 以及第一型干擾素對M-CSF 誘導cDC的發育扮演正向調節者(positive regulator)的角色。而Dasatinib抑制M-CSF 訊息傳遞以及cDC的生成能力，可作為新穎的工具來治療如牛皮癬、動脈粥狀硬化以及發炎性腸道等和cDC過多或活化的相關疾病。 | zh_TW |
| dc.description.abstract | Dendritic cells (DCs) are specialized antigen-presenting cells and are essential mediators of immunity and tolerance. DCs distribute throughout the body and are continuously replenished by hematopoietic progenitors. While the requirement of Flt3L (FL) for DC development is well characterized, the mechanisms of the involvement of M-CSF in the regulation of DC development and homeostasis are still not fully understood.
In vitro treatment of M-CSF increased expansion of cDC and not pDC. M-CSF-dependent enhancement of cDC was also observed in vivo following hydrodynamic gene transfer (HGT) or cytokine injection via intravenous route. M-CSF induced M-CSFR expression on common dendritic cell progenitors (CDP) and increased their expansion by enhancing survival and proliferation of CDPs and differentiation into cDCs. M-CSF signaling activated STAT proteins, including STAT1 and STAT3 by tyrosine phosphorylation in addition to Akt and M-CSFR in TF1-fms, an erythroleukemia cell line, expressing c-fms. Interestingly, M-CSF-dependent cDC generation was reduced in the absence of IFNAR1, STAT1 and STAT3 in vivo. Moreover, M-CSF synergized with IFNα to promote cDC development in vivo, suggesting that IFN-I may be involved in the M-CSF-dependent DC development. In the screening of specific inhibitor for M-CSFR, we have identified dasatinib, a multiple tyrosine kinase inhibitor, as the most potent and selective drag. The IC50 for inhibiting proliferation of TF-1 fms and DC development is 42nM and 11 nM, respectively. The latter is even better than GW2580, the most potent inhibitor for M-CSFR by far. In addition, dasatinib also specifically blocked M-CSF-induced CDP expansion and cDC development from BM in vitro and in vivo. Taken together, M-CSF enhances the development mainly cDC, mainly through, at least two different mechanisms, namely CDP expansion/ differentiation and cDC proliferation. Moreover, STAT1, STAT2, STAT3, and IFN-I may positively regulate M-CSF-dependent cDC development. The ability of Dasatinib to inhibit M-CSFR signaling and M-CSF-dependent cDC development provide a novel tool to treat cDC–associated diseases, including psoriasis, atherosclerosis and inflammatory bowel diseases. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T13:13:39Z (GMT). No. of bitstreams: 1 ntu-102-R00449003-1.pdf: 2802548 bytes, checksum: 565b69d0b6a8d92d08fc3146e6b0650b (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | Table of Contents
口試委員會審定書 誌謝 中文摘要…………………………………………………………….…..……………….i Abstract…………………………………………………………………………iii Abbreviations………………………………………………………………………v Table of contents………………………………………………………..………vii List of figures……………………………………………………………………………x List of tables………………………………………………………………………...…xii Chapter I Introduction…………………………………..………....……………….1 1.1 DC subsets …………………………………...……………………………..2 1.2 DC progenitors……......................……………..……………………………3 1.3 Cytokines in DC development………………………………...….……….……4 1.4 Role of Type I IFNs in HSC homeostasis………..………….…….......………6 1.5 Type I IFN-mediated signaling………………………………………….……7 1.6 M-CSF signaling……………………………………………………………7 1.7 M-CSFR inhibitors…………………………………….…………….……….…8 Chapter II Materials and Methods………………………...…………..…………10 2.1 Mice……………………………………….…….……………..…..........…11 2.2 Cell lines and reagents……………………………...…..…………..…….…11 2.3 In vitro DC cultures………….…………………………………...….…11 2.4 Preparation of Hu M-CSF…………………………………………..……12 2.5 Ex vivo analysis of progenitors population……………………………..……12 2.6 Ex vivo analysis of DC, myeloid, T and B and NKT subsets…………..13 2.7 Hydrodynamic gene teansfer (HGT)………….………………………13 2.8 Bioassay for cytokine-dependent proliferation……….……14 2.9 In vitro and in vivo inhibitor treatment……………………….….…….14 2.10 Proliferation and apoptosis assay……………………………………….14 2.11 Western blotting analysis…………………………………………………… 15 2.12 Primers ……………………………………………………………........15 2.13 Antibodies………………………………………………………………16 2.14 Chemicals and Regents……………………………………………………17 Chapter III Results…………………………..……………………………….……...19 3.1 M-CSF enhances DC development in vitro and in vivo……………….…20 3.2 M-CSF enhances CDP expansion in vivo………………………………...21 3.3 M-CSF activates STAT1, STAT2 and STAT3 in TF-1-fms cell line …...22 3.4 M-CSF-dependent cDC generation was reduced in the absence of IFNAR1, STAT1 and STAT3 in vitro and in vivo………………………………...22 3.5 Identification and characterization of M-CSFR inhibitors……………….23 3.6 Inhibitory effect of dasatinib on activation of M-CSFR downstream signaling molecules…………………..………………………………...23 3.7 Dasatinib specifically blocked M-CSF-induced CDP expansion and cDC development in vitro and in vivo……………..…………………….….24 3.8 GW2580 blocked M-CSF-induced CDP expansion and cDC development in vivo………………………………………….……….………………25 3.9 M-CSF cytokine enhances DC development in vivo……………………..25 Chapter IV Discussion………………………….……………………………………26 4.1 CDPs is the progenitor of M-CSF-dependent cDC development…………..27 4.2 The detailed mechanism of IFN-I involved in the M-CSF-dependent DC development remains to be determined…………………………………...29 4.3 M-CSFR signaling and inhibitors effect on primary CDP by ICS for pM-CSFR, pSTAT3 and pSTAT1……………………….……………….30 4.4 Dasatinib provide a novel tool to treat cDC–associated diseases…………..30 Figures…………..……………...………………………………………...…...…..33 Tables…………………………………………………………………..………..73 References…………..…………………………………..……………….........…..76 List of figures Figure 1. M-CSF enhances DC development in vitro.……………..…….……... 36 Figure 2. M-CSF enhances cDC development in vivo…………….…………….37 Figure 3. M-CSF also enhances macrophage expansion in the BM and spleen in vivo.………………………………………………………………………………..39 Figure 4. The effect of M-CSF on NK and NKT cells………………….…………..41 Figure 5. The effect of M-CSF on T and B lymphocytes……………………..…….43 Figure 6. M-CSF induces CDP expansion in the BM and increases M-CSFR expression in vitro………………………….………………………...…………....45 Figure 7. M-CSF increases proliferation of cDCs and CDPs……………….…….46 Figure 8. M-CSF decreases apoptosis of BM CDP and sorted CDP………….……...47 Figure 9. M-CSF enhances cDC differentiation from CDP………………………48 Figure 10. M-CSF activates STAT1, STAT2 and STAT3………..…..………..…..49 Figure11. Efect of STAT1 and STAT3 in M-CSF-dependent- cDC development in vitro……………………….……………………….……………………………... 51 Figure 12. Impaired M-CSF-dependent- cDC development in vitro in the absent of IFNAR1. ………………………….…………………….…..…………………..52 Figure 13. Impaired M-CSF-dependent development of cDC and CDP in Stat1-/-, Stat2m/m, Stat3-/- and Ifnar1-/- mice in vivo……………………………………..…...54 Figure 14. IFN-I enhances M-CSF–dependent cDC development in vivo………..…56 Figure 15. Identification and characterization of M-CSFR inhibitors……...………57 Figure 16. Inhibitory effect of dasatinib on activation of M-CSFR downstream signaling molecules………………………………………………..…………….……58 Figure 17. Dasatinib blocks M-CSF –dependent cDC development in vitro….…60 Figure 18. Dasatinib blocks FL –dependent cDC development in vitro…………....61 Figure 19. Dasatinib blocks M-CSF-dependent CDP expansion in the BM in vitro…………………………………………………...…………………….………63 Figure 20. Dasatinib blocks M-CSF-dependent expression of cDC in vivo………65 Figure 21. Dasatinib blocks M-CSF-dependent expansion of CDP in vivo……..…..67 Figure 22. GW2580 blocks M-CSF-dependent expression of cDC in vivo………....69 Figure 23. GW2580 blocks M-CSF-dependent expansion of CDP in vivo............…71 Figure 24. M-CSF cytokine enhances DC development in vivo……………72 List of Tables Table 1. A table of summary of IC50 of different inhibitions on the inhibition of TF1-fms, NFS-60 and Ba/f3-Flt3 is shown………………………………..……...……74 Table 2. A table of summary of IC50 of different inhibitions on the inhibition of M-CSF-dependent cDC development is shown. ……………………...……...…...……74 Table 3. A table of summary of IC50 of different inhibitions on the inhibition of FL-dependent cDC development is shown…………………….………...……………..74 Table 4. The effect of cytokine receptor or ligand knockout mice on DC development.75 | |
| dc.language.iso | en | |
| dc.title | 第一型干擾素訊息在巨噬細胞聚落刺激因子依賴性樹突細胞發育過程中所扮演角色之研究 | zh_TW |
| dc.title | Effects of Type I Interferon Signals on M-CSF-dependent Dendritic Cell Development | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 嚴仲陽(Jeffrey J.Y. Yen),林國儀(Kuo-I?Lin) | |
| dc.subject.keyword | 干擾素,巨噬細胞聚落刺激因子,樹突細胞, | zh_TW |
| dc.subject.keyword | interferon,M-CSF,dendritic cell, | en |
| dc.relation.page | 88 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2013-07-30 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 免疫學研究所 | zh_TW |
| 顯示於系所單位： | 免疫學研究所 | |
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