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  1. NTU Theses and Dissertations Repository
  2. 醫學院
  3. 牙醫專業學院
  4. 口腔生物科學研究所
請用此 Handle URI 來引用此文件: http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/10501
標題: 藉由抑制PI3K P110δ的活化途徑來研究對B-1細胞和狼瘡小鼠的影響
Targeting PI3K P110δ Pathway to Interfere B-1 Cells Functions and Decrease Activity of Murine Lupus
作者: Szu-Ying Chen
陳思縈
指導教授: 江伯倫(Bor-Luen Chiang)
關鍵字: 全身紅斑性狼瘡,PI3Ks,p110δ,B-1細胞,IL-10,NZB/W F1小鼠,
Systemic lupus erythematosus,PI3Ks,p110δ,B-1cells,IL-10,NZB/W F1,
出版年 : 2010
學位: 碩士
摘要: 全身紅斑性狼瘡是一全身性自體免疫疾病,其致病機轉是多因子的,包含遺傳基因、性荷爾蒙、環境及許多異常之免疫因素。其中B細胞過度活化被認為在狼瘡的致病機轉中扮演一個重要的角色,而其中B-1細胞又被認為與自體抗體的發生有關。先前研究顯示移除腹腔之B-1細胞,可以有效改善疾病的惡化。然而,這些方式可能產生後續不良的副作用。p110δ是PI3Ks家族中具白血球專一性之催化性次單元,已被證實可去除成熟之B細胞,特別是marginal zone B細胞和B-1細胞之族群。因此本研究想藉由一專一性抑制p110δ之藥物IC87114抑制p110δ的作用,來干擾全身紅斑性狼瘡NZB/W F1小鼠腹腔中過度活化之B-1細胞的數量,以緩解疾病的發展,並且研究此抑制劑在生物體內與體外的作用。首先在細胞實驗裡,我們發現使用高、低劑量的IC87114可以降低脾臟細胞、B-1與B-2細胞的增生作用,亦可降低腹腔細胞與B-1細胞分泌IL-10的能力;而更進一步使用高、低劑量的IC87114對Balb/c小鼠進行腹腔注射後,發現小鼠不論腹腔和脾臟中B、T細胞的數量與活化程度皆不受影響,但高劑量的IC87114對小鼠腹腔細胞的增生具有抑制作用。而在狼瘡小鼠的動物實驗中,我們在小鼠第二個月開始腹腔注射IC87114,可以發現小鼠在第四個月齡,低劑量的IC87114與wortmannin治療組和發病組相比較,其血清中anti-ss/dsDNA IgG自體抗體有顯著性的降低。綜合以上實驗結果可以發現,p110δ抑制劑確實可以有效抑制B細胞在增生與分泌IL-10上之功能,但並不會影響小鼠體內免疫細胞之數量、活化程度,以及免疫細胞的族群分布。而相關研究應用在狼瘡小鼠模式上也可證實早期給予p110δ抑制劑干擾可以有效降低小鼠體內自體抗體的表現,顯示針對PI3Ks中p110δ途徑對紅斑性狼瘡的治療是具有潛力的,若可以進一步研究p110δ在維持B-1細胞族群的重要性與相關機轉,也有助於闡明治療其他與B-1細胞相關之疾病,例如特定的黑色素瘤、淋巴瘤、及白血病等。
Systemic lupus erythematosus is an autoimmune disease caused by multiple pathogenic factors, such as genetic, hormone, environmental, and different abnormal immune components. Hyperreactivity of B cells, expecially B-1 cells, has been suggested to play a critical role in the development of autoantibodies. Previous studies have illustrated that depravation of B-1 cells was profitable to alleviate the disease aggravation. However, these approaches might result in subsequent unfavorable side-effects. P110δ, a leukocyte-specific catalytic subunit of PI3Ks, are proved to be able to abrogate the maturation of B cell lineages, especially the marginal zone B cell and B-1 cell populations. In this study, we plan to apply IC87114, a highly selective inhibitor of P110δ, to interfere the development of B-1 cells in murine NZB/W F1 model. Furthermore, we also studied the effect of IC87114 on B-1 cells both in vitro and in vivo. First, we found IC87114 could decrease the proliferation of splenocytes, B-1 and B-2 cells in dose-dependent response. The drug could also reduce IL-10 production of peritoneal resident cells and B-1 cells. Next, we treated Balb/c mice with IC87114 by peritoneal injection, the population and the activated level of B cells and T cells were not affected, but the proliferation of peritoneal washout cells were decreased. In murine lupus model, we treated NZB/W F1 mice with IC87114 since 2-months by peritoneal injection. Compared to the control group, we found the anti-ss/ds DNA IgG was decreased significantly in the low dose of IC87114 group. In summary, the P110δ inhibitor can suppress the proliferation and cytokine production of B cells effectively, but it did not affect the population, percentage and the activated manners of immune cells in vivo. In the lupus model, the auto-antibodies are decreased, supporting the notion that the p110δ inhibitor might be a potential therapeutic agent for SLE. Moreover, the evidence that PI3Ks are critical for the maintenance of B-1 cell populations might shed light on future exploring the potential treatment of other diseases associated with B-1 cells, such as certain melanoma, lymphoma, or leukemia.
URI: http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/10501
全文授權: 同意授權(全球公開)
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