跳到主要內容

臺灣博碩士論文加值系統

(44.200.169.3) 您好!臺灣時間:2022/12/05 19:00
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

: 
twitterline
研究生:傅立岡
研究生(外文):Li-Kang Fu
論文名稱:探討奇任醇對於免疫細胞的調控與氣喘小鼠呼吸道發炎之影響
論文名稱(外文):Study on the modulatory effects of kirenol on the immune effector cells and airway inflammation in a murine model of asthma
指導教授:李岳倫李岳倫引用關係
指導教授(外文):Yueh-Lun Lee
口試委員:楊曜旭王靜瓊
口試委員(外文):Yao-Hsu YangChing-Chiung Wang
口試日期:2017-07-10
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:醫學科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:60
中文關鍵詞:過敏性氣喘樹突狀細胞T細胞奇任醇
外文關鍵詞:atopic asthmadendritic cellT cellkirenol
相關次數:
  • 被引用被引用:0
  • 點閱點閱:70
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
過敏性氣喘是一種由 Th2 細胞所造成的慢性發炎疾病。過敏性氣喘具有的特 徵包括 Th2 細胞激素分泌增加、肺部的嗜酸性紅血球浸潤和肥大細胞分泌發炎介質,而這些因素會導致呼吸道平滑肌收縮與發炎反應。奇任醇為一種具有免疫抑制和抗發炎特性的二萜類化合物。在本篇研究中,我們探討奇任醇在免疫細胞中所呈現的免疫調節功能,並進一步研究奇任醇在氣喘小鼠中抗過敏的效果。在 此我們利用骨髓衍生之樹突細胞和純化的 CD4+ T 細胞來瞭解奇任醇是否可以經由改變樹突細胞調節 T 細胞的能力或直接抑制 T 細胞的活化與分化。實驗結果
顯示奇任醇對於經脂多醣刺激的樹突細胞其活化與功能上並沒有影響。然而奇任 醇可以直接抑制活化的 CD4+ T 細胞其增殖與細胞激素的分泌。在動物實驗中,藉由口服給予奇任醇,以雞白蛋白致敏和激發的小鼠血清中,對雞白蛋白具專一性的免疫球蛋白 IgE 顯著減少,在氣道高反應的情形也有明顯的降低,改善了呼吸道的發炎反應。此外,奇任醇治療後小鼠肺沖洗液與脾臟細胞培養之上清液中,Th2 細胞激素(IL-4、IL-5 和 IL-13)與趨化激素皆有顯著的減少。值得注意的是,
我們發現奇任醇的治療可以誘導雞白蛋白專一性 T 細胞的細胞凋亡。綜合以上結果顯示,奇任醇可以直接抑制 Th2 細胞的活化,具有治療 Th2 誘導之過敏性氣喘的潛力。在治療過敏性氣喘方面,我們認為未來可利用奇任醇做為一種抗過敏 的輔助藥物。
Atopic asthma is a chronic inflammatory disease caused by Th2 cells. The features of this allergic disease include increasing Th2 cytokines production, eosinophils infiltration in the lung, and the release of inflammatory mediators by mast cells, which result in airway smooth muscle constriction and airway inflammation. Kirenol is a
diterpenoid compound which has immune-suppressive and anti-inflammatory activities. In this study, we explored the immunomodulatory actions of kirenol on immune cells and further investigated the anti-allergic effects of kirenol in asthmatic mice. Therefore, bone-marrow-derived dendritic cells (DCs) and purified CD4+ T cell were used to clarify whether kirenol exerts an immunomodulatory effects through altering the ability of DCs to regulate T cells or directly inhibiting T-cell activation and differentiation. The data showed that kirenol had no effects on lipopolysaccharide-stimulated DC’s activation and function. However, kirenol directly suppressed activated CD4+ T-cell proliferation and cytokine production. In animal experiments, oral administration of kirenol to ovalbumin (OVA)-sensitized and
-challenged mice decreased serum OVA-specific IgE production, attenuated the airway hyper-responsiveness, and alleviated airway inflammation. Additionally, the
levels of Th2-type cytokines (IL-4, IL-5, and IL-13) and chemokines in bronchoalveolar lavage fluid and the culture supernatant of splenocytes significantly
reduced in kirenol-treated mice. Notably, we found that kirenol treatment induced OVA-specific T-cell apoptosis. Taken together, these findings suggest that kirenol
possess therapeutic potential against Th2-mediated allergic asthma via direct inhibition of Th2-cell activation. Herein, we provide a potential use of kirenol as an anti-allergic adjuvant to treat allergic asthma.
致謝………………………………………………………………………1
中文摘要………………………………………………………………3
英文摘要…………………………………………………………………4
第一章 緒論……………………………………………………………5
1.過敏性氣喘簡介………………………………………………………6
2.過敏性氣喘的致病機轉………………………………………………6
3.樹突細胞和T 細胞與過敏性氣喘之關聯……………………………7
4.氣喘的治療方法………………………………………………………7
5.奇任醇(kirenol)的簡介………………………………………………8
6.奇任醇的生理及免疫功能……………………………………………8
第二章 探討奇任醇調控樹突細胞與CD4+T 細胞的活化與分化能力
…………………………………………………………………………11
研究動機與目的………………………………………………………12
研究材料與方法
1.奇任醇的來源及處理………………………………………………13
2.實驗動物來源………………………………………………………13
3.骨髓衍生性樹突細胞之培養………………………………………13
4. CD4+T 細胞之純化………………………………………………13
5.細胞存活率試驗……………………………………………………13
6.細胞激素的測量……………………………………………………14
7.表面分子表現之測量………………………………………………14
8.混和淋巴細胞反應…………………………………………………15
9. CD4+T 細胞分裂增生能力之測量…………………………………15
10. T 細胞之細胞凋亡試驗…………………………………………16
11.統計方法……………………………………………………………16
研究結果
1.奇任醇對樹突細胞存活率之影響…………………………………17
2.奇任醇對於樹突細胞的活化或成熟沒有影響……………………17
3.奇任醇對於樹突細胞對CD4+T 細胞的細胞增殖反應沒有影響…18
4.奇任醇對CD4+T 細胞存活率的影響………………………………18
5.奇任醇明顯直接抑制了CD4+T 細胞的活化與分化………………18
第三章 探討奇任醇在氣喘動物模式中的治療效果…………………20
研究動機與目的………………………………………………………21
研究材料與方法
1.過敏性氣喘動物模式之建立與治療………………………………22
2.對OVA 具專一性之抗體測定………………………………………22
3.呼吸阻力之測試……………………………………………………23
4.肺沖洗液中細胞分類計算…………………………………………24
5.細胞激素及趨化激素之測量………………………………………24
6.肺組織切片染色........................................24
7.脾臟細胞對OVA 抗原專一性增殖反應之測試……………………25
8.脾臟CD4+T 細胞之細胞凋亡試驗…………………………………25
9.統計方法……………………………………………………………26
研究結果
1.奇任醇顯著降低氣喘小鼠血清中IgE 的產量……………………27
2.奇任醇顯著降低氣喘模式小鼠之呼吸道阻力……………………27
3.奇任醇治療後明顯抑制小鼠肺部發炎細胞聚集並改善肺組織之病
理情形…………………………………………………………………27
4.奇任醇治療顯著降低氣喘小鼠肺部及脾臟細胞Th2 型細胞激素之
產量……………………………………………………………………28
5.奇任醇顯著抑制氣喘小鼠脾臟之細胞增殖反應…………………28
第四章 討論…………………………………………………………30
第五章 結論與未來方向……………………………………………34
圖表……………………………………………………………………36
參考文獻………………………………………………………………57
1. Lambrecht BN, Hammad H: The immunology of asthma. Nat Immunol 2015,
16:45-56.
2. Fehrenbach H, Wagner C, Wegmann M: Airway remodeling in asthma: what
really matters. Cell Tissue Res 2017, 367:551-569.
3. Anandan C, Nurmatov U, van Schayck OC, Sheikh A: Is the prevalence of
asthma declining? Systematic review of epidemiological studies. Allergy 2010,
65:152-167.
4. Grant EN, Wagner R, Weiss KB: Observations on emerging patterns of asthma
in our society. J Allergy Clin Immunol 1999, 104:S1-9.
5. Loftus PA, Wise SK: Epidemiology of asthma. Curr Opin Otolaryngol Head
Neck Surg 2016, 24:245-249.
6. Masoli M, Fabian D, Holt S, Beasley R, Global Initiative for Asthma P: The
global burden of asthma: executive summary of the GINA Dissemination
Committee report. Allergy 2004, 59:469-478.
7. Plantinga M, Guilliams M, Vanheerswynghels M, Deswarte K, Branco-Madeira
F, Toussaint W, Vanhoutte L, Neyt K, Killeen N, Malissen B, et al: Conventional
and monocyte-derived CD11b(+) dendritic cells initiate and maintain T helper
2 cell-mediated immunity to house dust mite allergen. Immunity 2013,
38:322-335.
8. Lloyd CM, Hessel EM: Functions of T cells in asthma: more than just T(H)2
cells. Nat Rev Immunol 2010, 10:838-848.
9. Deo SS, Mistry KJ, Kakade AM, Niphadkar PV: Role played by Th2 type
cytokines in IgE mediated allergy and asthma. Lung India 2010, 27:66-71.
10. Jin C, Shelburne CP, Li G, Potts EN, Riebe KJ, Sempowski GD, Foster WM,
Abraham SN: Particulate allergens potentiate allergic asthma in mice through
sustained IgE-mediated mast cell activation. J Clin Invest 2011, 121:941-955.
11. Hall S, Agrawal DK: Key mediators in the immunopathogenesis of allergic
asthma. Int Immunopharmacol 2014, 23:316-329.
12. Collin M, McGovern N, Haniffa M: Human dendritic cell subsets. Immunology
2013, 140:22-30.
13. Hammer GE, Ma A: Molecular control of steady-state dendritic cell
maturation and immune homeostasis. Annu Rev Immunol 2013, 31:743-791.
14. Na H, Cho M, Chung Y: Regulation of Th2 Cell Immunity by Dendritic Cells.
Immune Netw 2016, 16:1-12.
15. Hansbro PM, Kim RY, Starkey MR, Donovan C, Dua K, Mayall JR, Liu G, Hansbro
NG, Simpson JL, Wood LG, et al: Mechanisms and treatments for severe,
steroid-resistant allergic airway disease and asthma. Immunol Rev 2017,
278:41-62.
16. Alangari AA: Corticosteroids in the treatment of acute asthma. Ann Thorac
Med 2014, 9:187-192.
17. Stevenson DD, Hankammer MA, Mathison DA, Christiansen SC, Simon RA:
Aspirin desensitization treatment of aspirin-sensitive patients with
rhinosinusitis-asthma: long-term outcomes. J Allergy Clin Immunol 1996,
98:751-758.
18. Soar J, Guideline Development G: Emergency treatment of anaphylaxis in
adults: concise guidance. Clin Med (Lond) 2009, 9:181-185.
19. Lommatzsch M, Geissler K, Bergmann KC, Virchow JC: [IgE and Anti-IgE in
Asthma: A Chequered History]. Pneumologie 2017, 71:398-405.
20. Kepil Ozdemir S, Bavbek S: Prospects for new and emerging therapeutics in
severe asthma: the role of biologics. Expert Rev Respir Med 2017, 11:505-512.
21. Bosnjak B, Stelzmueller B, Erb KJ, Epstein MM: Treatment of allergic asthma:
modulation of Th2 cells and their responses. Respir Res 2011, 12:114.
22. Yang YL, Pan YQ, He BS, Zhong TY: Regulatory T cells and Th1/Th2 in
peripheral blood and their roles in asthmatic children. Transl Pediatr 2013,
2:27-33.
23. Zhu J, Liu X, Wang W, Ouyang X, Zheng W, Wang Q: Altered expression of
regulatory T and Th17 cells in murine bronchial asthma. Exp Ther Med 2017,
14:714-722.
24. Hong YH, Weng LW, Chang CC, Hsu HF, Wang CP, Wang SW, Houng JY: Antiinflammatory
effects of Siegesbeckia orientalis ethanol extract in in vitro and
in vivo models. Biomed Res Int 2014, 2014:329712.
25. Qian R, Zhang C, Fu H: [Study on therapeutic mechanism of anti-rheumatism
action of herba siegesbeckiae]. Zhongguo Zhong Xi Yi Jie He Za Zhi 2000,
20:192-195.
26. Sun HX, Wang H: Immunosuppressive activity of the ethanol extract of
Siegesbeckia orientalis on the immune responses to ovalbumin in mice. Chem
Biodivers 2006, 3:754-761.
27. Wang ZM, Zhu SG, Wu ZW, Lu Y, Fu HZ, Qian RQ: Kirenol upregulates nuclear
annexin-1 which interacts with NF-kappaB to attenuate synovial inflammation
of collagen-induced arthritis in rats. J Ethnopharmacol 2011, 137:774-782.
28. Lu Y, Xiao J, Wu ZW, Wang ZM, Hu J, Fu HZ, Chen YY, Qian RQ: Kirenol exerts a
potent anti-arthritic effect in collagen-induced arthritis by modifying the T
cells balance. Phytomedicine 2012, 19:882-889.
29. Xiao J, Yang R, Yang L, Fan X, Liu W, Deng W: Kirenol attenuates experimental
autoimmune encephalomyelitis by inhibiting differentiation of Th1 and th17
cells and inducing apoptosis of effector T cells. Sci Rep 2015, 5:9022.
30. Hwang WJ, Park EJ, Jang CH, Han SW, Oh GJ, Kim NS, Kim HM: Inhibitory effect
of immunoglobulin E production by jin-deuk-chal (Siegesbeckia orientalis).
Immunopharmacol Immunotoxicol 2001, 23:555-563.
31. Lu Y, Qian R, Xiao J, Xu D, Fu H, Chen Y: Kirenol, a compound from Herba
Siegesbeckiae, induces apoptosis in human chronic myeloid leukemia K562
cells. Pharmazie 2014, 69:148-153.
32. Kim MB, Song Y, Hwang JK: Kirenol stimulates osteoblast differentiation
through activation of the BMP and Wnt/beta-catenin signaling pathways in
MC3T3-E1 cells. Fitoterapia 2014, 98:59-65.
33. Xiang Y, Zhang H, Fan CQ, Yue JM: Novel diterpenoids and diterpenoid
glycosides from Siegesbeckia orientalis. J Nat Prod 2004, 67:1517-1521.
34. Wang J, Duan H, Wang Y, Pan B, Gao C, Gai C, Wu Q, Fu H: ent-Strobane and
ent-Pimarane Diterpenoids from Siegesbeckia pubescens. J Nat Prod 2017,
80:19-29.
35. Bui TT, Piao CH, Kim SM, Song CH, Shin HS, Lee CH, Chai OH: Citrus tachibana
Leaves Ethanol Extract Alleviates Airway Inflammation by the Modulation of
Th1/Th2 Imbalance via Inhibiting NF-kappaB Signaling and Histamine
Secretion in a Mouse Model of Allergic Asthma. J Med Food 2017.
36. Moitra S, Datta A, Mondal S, Hazra I, Faruk SMO, Das PK, Basu AK, Tripathi SK,
Chaudhuri S: Modulation of regulatory T cells by intranasal allergen
immunotherapy in an experimental rat model of airway allergy. Int
Immunopharmacol 2017, 47:9-19.
37. Broeren CP, Wauben MH, Lucassen MA, Van Meurs M, Van Kooten PJ, Boog
CJ, Claassen E, Van Eden W: Activated rat T cells synthesize and express
functional major histocompatibility class II antigens. Immunology 1995,
84:193-201.
38. Xiao Y, Deng T, Shang Z, Wang D: Adiponectin inhibits oxidization-induced
differentiation of T helper cells through inhibiting costimulatory CD40 and
CD80. Braz J Med Biol Res 2017, 50:e6227.
39. Li H, Shao S, Cai J, Burner D, Lu L, Chen Q, Minev B, Ma W: Artificial human
antigen presenting cells are superior to dendritic cells at inducing cytotoxic T
cell responses. Immunology 2017.
40. Hatam LJ, Devoti JA, Rosenthal DW, Lam F, Abramson AL, Steinberg BM,
Bonagura VR: Immune suppression in premalignant respiratory papillomas:
enriched functional CD4+Foxp3+ regulatory T cells and PD-1/PD-L1/L2
expression. Clin Cancer Res 2012, 18:1925-1935.
41. Li F, Wang Y, Lin L, Wang J, Xiao H, Li J, Peng X, Dai H, Li L: Mast Cell-Derived
Exosomes Promote Th2 Cell Differentiation via OX40L-OX40 Ligation. J
Immunol Res 2016, 2016:3623898.
42. Srivastava KD, Dunkin D, Liu C, Yang N, Miller RL, Sampson HA, Li XM: Effect of
Antiasthma Simplified Herbal Medicine Intervention on neutrophil
predominant airway inflammation in a ragweed sensitized murine asthma
model. Ann Allergy Asthma Immunol 2014, 112:339-347 e331-332.
43. Piao CH, Bui TT, Song CH, Shin HS, Shon DH, Chai OH: Trigonella foenumgraecum
alleviates airway inflammation of allergic asthma in ovalbumininduced
mouse model. Biochem Biophys Res Commun 2017, 482:1284-1288.
44. Boor PP, Metselaar HJ, Mancham S, Tilanus HW, Kusters JG, Kwekkeboom J:
Prednisolone suppresses the function and promotes apoptosis of
plasmacytoid dendritic cells. Am J Transplant 2006, 6:2332-2341.
45. Lanza L, Scudeletti M, Puppo F, Bosco O, Peirano L, Filaci G, Fecarotta E, Vidali
G, Indiveri F: Prednisone increases apoptosis in in vitro activated human
peripheral blood T lymphocytes. Clin Exp Immunol 1996, 103:482-490.
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關期刊