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研究生:趙雅萱
研究生(外文):Ya-Hsuan Chao
論文名稱:發展抗磷脂質症候群之免疫治療策略
論文名稱(外文):Development of immunotherapy strategies for antiphospholipid syndrome
指導教授:林季千
口試委員:林民昆李孟修何尚哲林士超
口試日期:2021-01-27
學位類別:博士
校院名稱:國立中興大學
系所名稱:生物醫學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2021
畢業學年度:109
語文別:中文
論文頁數:90
中文關鍵詞:抗磷脂症候群β2醣蛋白IDNA疫苗免疫調節天然物
外文關鍵詞:Antiphospholipid syndromeβ2-glycoprotein IDNA vaccineImmunomodulatorynatural products
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抗磷脂症候群是一種全身性免疫疾病,其臨床特徵主要為血栓形成與反覆流產。雖然現行治療策略能減緩病況,但長期使用仍具有潛在之副作用且皆無法根除病灶。此次研究目的為尋找新的抗磷脂症候群免疫治療策略,我們從建立β2醣蛋白I誘導抗磷脂症候群小鼠模式,並利用此模式探討DNA疫苗與天然物柚皮素、SF10-6於治療抗磷脂症候群免疫調節功效。首先,在抗磷脂症候群小鼠觀察到血小板減少、延長部份凝血活酵素時間、以及過度產生anti-β2-GPI抗體、影響體內Th1與Th17 mRNA表現量增加、並造成妊娠後胎兒流失比例增加。我們成功利用β2醣蛋白I誘導抗磷脂症候群小鼠,且此小鼠模式可做為抗磷脂症候群研究模式。進一步我們測試β2-GPI DNA疫苗、FK506單獨或合併治療於抗磷脂症候群小鼠模式。根據實驗結果β2-GPI DNA疫苗合併FK506治療可以增加血小板、縮短部份凝血活酵素時間和減少胎兒流失的百分比。而在離體實驗中脾臟T細胞藉由β2-GPI刺激後,抑制IFN-γ和IL-17A的分泌,反之增加Treg細胞和IL-10分泌。我們的結果證明了β2-GPI DNA疫苗合併FK506具有治療抗磷脂症候群小鼠的效果。最後,我們也評估海洋軟珊瑚萃取物SF10-6與柚皮素於治療抗磷脂症候群免疫調節功效。根據結果SF10-6抑制Th1、Th2與Th17細胞比例,而柚皮素抑制anti-β2-GPI抗體的產生。總的來說,我們建立具有抗磷脂症候群臨床特徵的小鼠模式,並提供β2-GPI DNA疫苗合併FK506作為抗磷脂症候群小鼠模式的治療方法,雖然SF10-6與柚皮素具有免疫調節功效,但是兩者無法減少血栓形成與反覆流產。在未來我們將藉由改善DNA疫苗設計,並使用此次研究的免疫療法策略和抗磷脂症候群小鼠模式,探討其他潛在天然物進而達到更有效的治療抗磷脂症候群。
Antiphospholipid syndrome is a systemic immune disease characterized by thrombosis and recurrent pregnancy loss. Although current treatment options can alleviate the condition, there could be side effects for long-term treatments where none of them can eradicate the disease. The goal of this study was to find new immunotherapy strategies for antiphospholipid syndrome. In this study, we started with establishment of a β2 glycoprotein I-induced antiphospholipid syndrome mouse model, by which we explore the immunomodulatory and the therapeutic effects of DNA vaccines and natural products, naringenin and SF10-6, in antiphospholipid syndrome therapy. Mice with antiphospholipid syndrome exhibit elevated platelet count, prolonged activated partial thromboplastin time, and increased rate of fetal loss due to the excessive produvtion of anti-β2-GPI autoantibody as well as Th1-, Th17- skewed but not Th2 and Treg responses. With such a mouse antiphospholipid syndrome model, we tested the therapeutic effects of β2-GPI DNA vaccine with or with out combinational treatments of an immunosuppressant, FK506. We found that β2-GPI DNA vaccine combined with FK506 could increase platelet counts, shorten activated partial thromboplastin time, and lower the percentage of fetal loss. After the challenge of β2-GPI antigen on splenic T cells from APS mice ex vivo, our DNA vaccine remedy inhibited the IFN-γ and IL-17A cytokine prouductions, and conversely increased the Treg cell numbers and IL-10, suggesting the therapeutic effect of β2-GPI DNA vaccine combined with FK506 treatment for antiphospholipid syndrome. Subsequently, we employed a marine soft coral extract, SF10-6, and naringenin to treat the antiphospholipid syndrome. Our data show that SF10-6 inhibited the ratio of Th1, Th2, Th17, and naringenin repressed the production of anti-β2-GPI antibody. Taken together, we established a mouse model with clinical features of antiphospholipid syndrome which can be treated by β2-GPI DNA vaccine combined FK506 and accessed for poteintial immunomodulatory functions or therapeutic effects of natural products. In the future, new treatment for APS might be avalible by improving the design of DNA vaccines and searching other poteintial natural products with our immunotherapy strategies and the APS animal model presented in this study.
目次
摘要 i
Abstract ii
目次 iii
表目次 v
圖目次 vi
第一章、緒論 1
第一節、抗磷脂質症候群(antiphospholipid syndrome, APS) 1
第二節、APS的疾病生理機制(Pathophysiological mechanisms in APS) 1
第三節、APS的分類(Type of APS) 2
第四節、APS的治療(Treartment of APS) 3
第五節、APS動物模式(APS animal model) 4
第二章、研究動機與策略 7
第一節、建立β2-GPI誘導APS動物模式 7
一、 APS與β2-GPI關係 7
二、 β2-GPI與自體T細胞之關係 7
三、 建立β2-GPI誘導APS動物模式研究策略 8
第二節、發展DNA疫苗於APS之免疫調節功效 9
一、 抗自體免疫疾病之免疫耐受性DNA疫苗發展現況 9
二、 β2-GPI作為治療標的 9
三、 DNA疫苗結合FK506的功效 10
四、 發展DNA疫苗於β2-GPI誘導APS動物模式 10
第三節、天然物於免疫調節功效 12
一、 植物天然物 12
二、 柚皮素之生物活性 12
三、 海洋天然物 13
四、 珊瑚萃取物之生物活性 13
五、 隔板葉形軟珊瑚(L. crassum) 萃取物SF10-6 14
六、 探討天然物於β2-GPI誘導APS動物模式之免疫調節 15
第三章、實驗方法 17
第四章、實驗結果 25
第一節、 建立β2-GPI誘導APS動物模式 25
一、 APS小鼠抗磷脂症候群的臨床表現 25
二、 APS小鼠血液中anti-β2-GPI IgG表現 25
三、 APS小鼠血液中不同白血球的比例 25
四、 APS小鼠脾臟T細胞亞群的影響 26
第二節、 發展DNA疫苗於APS之免疫調節功效 27
一、 β2-GPI DNA疫苗對APS臨床表現的影響 27
二、 β2-GPI DNA疫苗和FK506的合併治療對APS表現的影響 27
三、 β2-GPI DNA疫苗和FK506合併治療對β2-GPI特異性T細胞增殖和細胞因子的影響 27
四、 β2-GPI DNA疫苗和FK506合併治療對β2-GPI特異性調節性T細胞比例和抗發炎細胞因子的影響 28
第三節、天然物於APS小鼠模式之免疫調節功效 29
一、 Naringenin改善APS小鼠抗磷脂症候群的臨床表現 29
二、 Naringenin抑制APS小鼠血液中anti-β2-GPI IgG表現 29
三、 Naringenin對APS小鼠血液不同種類白血球的影響 29
四、 Naringenin對β2-GPI特異性T細胞亞群的影響 30
五、 SF10-6對APS小鼠臨床表現的影響 30
六、 SF10-6不影響APS小鼠血液中anti-β2-GPI IgG表現與不同白血球百分比 30
七、 SF10-6對β2-GPI特異性T細胞亞群的影響 31
第五章、討論 32
參考書目 36
附錄 80
一、 補充資料 80
二、 實驗材料 85
三、 已發表論文 89
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