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系統識別號 U0026-1507201418241000
論文名稱(中文) 第六介白素在過敏性氣喘所扮演的角色
論文名稱(英文) The role of interleukin-6 in allergic asthma
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 102
學期 2
出版年 103
研究生(中文) 林嬿琳
研究生(英文) Yen-Lin Lin
學號 s58961379
學位類別 博士
語文別 中文
論文頁數 109頁
口試委員 指導教授-王志堯
召集委員-謝奇璋
召集委員-葉才明
召集委員-林秋烽
口試委員-林清淵
口試委員-洪志興
中文關鍵字 過敏性氣喘  第六介白素  歐洲塵蟎  呼吸道發炎  樹突細胞 
英文關鍵字 Allergic asthma  Interleukin-6  Dermatophagoides pteronyssinus  Airway inflammation  Dendritic cells 
學科別分類
中文摘要 目的 過敏性氣喘主要為過敏原所引起的慢性呼吸道疾病,伴隨呼吸道發炎、呼吸道過度反應、可逆性呼吸道阻塞及呼吸道重組。研究顯示過敏性氣喘的免疫病理機制為過敏原誘發第二型輔助型T 細胞的活化,產生大量細胞激素如第四介白素interleukin-4 (IL-4)、IL-5和IL-13,引起以抗體immunoglobulin E (IgE) 及嗜伊性球所媒介的呼吸道發炎及呼吸道過度反應。然而,研究指出過敏原所引起的呼吸道發炎及呼吸道過度反應也可由第十七型輔助型T 細胞引起嗜中性球的浸潤所造成。文獻指出樹突細胞dendritic cells (DCs) 在受抗原刺激時所製造的IL-6 對於第二型及第十七型輔助型T細胞的分化是不可或缺的細胞激素,然而,IL-6 在過敏性氣喘的角色及IL-6 是否能影響樹突細胞的發育及功能仍不清楚。因此,本研究第一部分將探討IL-6 在過敏性氣喘的動物模式中所扮演的角色。第二部分則假設內生性IL-6能影響DCs的分化及功能和其誘發小鼠呼吸道發炎及呼吸道過度反應的能力。第三部分則分析利用IL-6接收器單株抗體 (tocilizumab) 阻斷IL-6的訊息傳遞時,是否能影響過敏性氣喘患者DCs的分化及功能。

方法 在本研究第一部分,我們首先利用兩種不同致敏的動物模式誘發小鼠呼吸道發炎及呼吸道過度反應,藉偵測呼吸道阻力、肺泡沖洗液中細胞種類及總數及細胞激素和血清抗體的含量,分析正常小鼠及IL-6基因剔除小鼠呼吸道發炎的情形及呼吸道過度反應是否有所不同。在鼻腔intranasal 致敏的動物模式中,以連續十天從小鼠鼻腔內滴入歐洲塵蟎Dermatophagoides pteronyssinus (Der p) 的方式誘發小鼠呼吸道發炎及呼吸道過度反應。在腹腔intraperitoneal 致敏的動物模式中,從小鼠腹腔注射佐劑氫氧化鋁乳化後的Der p致敏小鼠,每週一次共三次,第四週則從氣管滴入Der p引發小鼠呼吸道發炎及呼吸道過度反應。第二部分: 分析正常小鼠及IL-6基因剔除小鼠骨髓分化產生的CD11c+ DC的數目及其功能。此外,將正常小鼠和IL-6基因剔除小鼠骨髓分化產生的CD11c+ DCs,先以Der p刺激後,再用adoptive transfer的方式將CD11c+ DCs從呼吸道給予正常小鼠,十天後,再從接受CD11c+ DCs的正常小鼠鼻腔內滴入Der p引發其呼吸道發炎及呼吸道過度反應,藉此比較正常小鼠和IL-6基因剔除小鼠的CD11c+ DCs誘發呼吸道發炎及呼吸道過度反應的能力是否不同。第三部分: 以人類重組蛋白GM-CSF和IL-4刺激正常人及過敏性氣喘患者的週邊單核球使其分化成未成熟的DCs (medium-DCs),有些單核球還給予tocilizumab阻斷IL-6的訊息傳遞,產生tocilizumab-DCs。以Der p刺激medium-DCs和tocilizumab-DCs後,分析medium-DCs和tocilizumab-DCs 表現CD1a、CD11c、HLA-DR和CD86及誘導第二型輔助型T細胞分化的能力是否不同。

結果 第一部分: 在intranasal 及intraperitoneal 的致敏動物模式中,跟正常小鼠相比,氣道過度反應、浸潤於肺部的淋巴球、嗜酸性球及嗜中性球、還有肺泡沖洗液中促發炎的細胞激素與趨化素chemokines如TNF-、IL-4、IL-17、CCL17和CCL11的含量於IL-6基因剔除小鼠都顯著降低。Der p特異性IgG1 於IL-6基因剔除小鼠也顯著減少。在intranasal及intraperitoneal的動物模式中,與正常小鼠相比,Der p特異性IL-4、IL-5、IL-13和IL-17於IL-6基因剔除小鼠也顯著降低。此外,IL-6基因剔除小鼠肺部的CD4+CD25+調節性T細胞Foxp3的表現和抑制CD4+CD25- T 細胞增生的能力並沒有受到影響,但正常小鼠在肺部發炎的情形下,其肺部的CD4+CD25+調節性T細胞Foxp3的表現和抑制CD4+CD25- T 細胞增生的能力則顯著降低。第二部分: 與IL-6基因剔除小鼠相比,正常小鼠骨髓能培育較多的CD11c+ DCs。從IL-6基因剔除小鼠骨髓所培育的CD11c+ DCs,其吞噬beads的能力顯著降低,分別以脂多醣lipopolysaccharide、TNF-和Der p刺激IL-6基因剔除小鼠骨髓所培育的CD11c+ DCs時,其MHC class II和CD86的表現都沒有增加,也無法誘發第二型與第十七型輔助型T細胞的分化。此外,從IL-6基因剔除小鼠骨髓培育的CD11c+ DCs,先以Der p刺激後,再用adoptive transfer的方式將其從小鼠呼吸道給予正常小鼠,並無法誘發小鼠呼吸道發炎及呼吸道過度反應。第三部分: 來自正常人及過敏性氣喘患者的週邊單核球分化為DCs時,不論有無給予tocilizumab或Der p刺激,對於CD1a和CD11c的表現並無影響。但過敏性患者的tocilizumab-DCs在 Der p的刺激下,與medium-DCs相比,其HLA-DR及CD86的表現顯著降低,也較無法引起第二型輔助型T細胞的分化。

結論 從IL-6基因剔除小鼠可知,IL-6在Der p引起的過敏性氣喘小鼠模式中扮演致病性的角色。過敏原引起的IL-6可以藉由誘發第二型與第十七型輔助型T細胞的分化和抑制CD4+CD25+調節性T細胞的功能導致擴大呼吸道發炎及呼吸道過度反應。而內生性的IL-6對於DCs的吞噬能力、成熟、活化naïve CD4+ T細胞的能力及誘發以第二型與第十七型輔助型T細胞所媒介的呼吸道發炎及呼吸道過度反應中扮演不可或缺的角色。因此,阻斷IL-6的訊息傳遞或許可以提供將來臨床上治療過敏性氣喘的另一種參考。
英文摘要 Objective: Allergic asthma is a chronic disease characterized with allergen-induced airway inflammation, airway hyperreactivity (AHR), reversible airway obstruction, and airway remodeling. Previous researches have indicated that the immunopathogenesis of allergic asthma is due to predominant differentiation and activation of interleukin (IL)-4-, IL-5-, and IL-13-producing T helper (Th) 2 cells, which result in immunoglobulin (Ig)E- and eosinophil-mediated airway inflammation and AHR. However, recent studies also show that Th17 cells result in neutrophil-mediated airway inflammation and AHR. IL-6, a pleiotropic inflammatory cytokine secreted by antigen-stimulated dendritic cells (DCs), is essential for development of Th2 and Th17 cells, but its roles in allergic asthma and in DC differentiation and function remain unclear. Therefore, the first part of this study is to explore the role of IL-6 in animal models of allergic asthma and the influence of IL-6 on Th differentiation and function of CD4+CD25+ regulatory T (Treg) cells. In the second part, we hypothesize that IL-6 affects DC differentiation and function and their ability to induce airway inflammation and AHR. The third part of this study is to investigate the effect of blockade of IL-6 signaling on DC differentiation and function in allergic asthmatics.

Methods: In the first part of this study, we used two sensitization protocols of mouse models of allergic asthma to examine the role of IL-6 in Dermatophagoides pteronyssinus (Der p)-induced airway inflammation and AHR. In the intranasal model, wild-type (WT) and IL-6 knockout (KO) mice were intranasally instilled of Der p daily for 10 days. In the intraperitoneal model, WT and IL-6 KO mice were intraperitoneally sensitized with Der p emulsified in aluminum hydroxide and intratracheally challenged with Der p. We analyzed airway resistance, cell influx and cytokine production in bronchoalveolar lavage fluid (BALF), Ig production, Th differentiation, and suppressive function of CD4+CD25+ Treg cells of Der p-sensitized and -challenged WT and IL-6 KO mice. Part II: We detected percentages and function of CD11c+ DCs generated from bone marrow (BM) of WT and IL-6 KO mice. Der p-loaded CD11c+ bone marrow-derived DCs (BMDCs) from WT and IL-6 KO mice were adoptively transferred into naïve WT mice via intratracheal route, respectively. Then, recipient mice were intranasally challenged with Der p to induce airway inflammation and AHR. Part III: Peripheral blood monocytes, collected from non-atopic controls and Der p-sensitive, allergic asthmatics, were differentiated into DCs by incubation with recombinant human (rh) GM-CSF and rhIL-4. During this differentiation phase, monocytes were also treated in the absence (medium-DCs) and presence of tocilizumab (tocilizumab-DCs). Upon Der p stimulation, CD1a, CD11c, human histocompatibility leukocyte antigen (HLA)-DR, and CD86 expression, and ability to induce Th2 differentiation were compared between medium-DCs and tocilizumab-DCs.

Results: In Part I, as compared to Der p-sensitized and -challenged WT mice, AHR, recruited lymphocytes, eosinophils, neutrophils, and levels of tumor necrosis factor (TNF)-, IL-4, IL-17, CCL17, and CCL11 significantly decreased in the airway of Der p-sensitized and -challenged IL-6 KO mice in the intranasal and intraperitoneal models. Levels of Der p-specific IgG1, IL-4, IL-5, IL-13, and IL-17 also markedly reduced in Der p-sensitized and -challenged IL-6 KO mice. However, as compared to Der p-sensitized and -challenged WT mice, significantly increased Foxp3 expression on CD4+CD25+ Treg cells was observed in Der p-sensitized and -challenged IL-6 KO mice. Moreover, lung CD4+CD25+ Treg cells of Der p-sensitized and -challenged IL-6 KO mice also had better capability in inhibiting CD4+CD25- T cell proliferation than that of Der p-exposed WT mice. Part II: We found that there was higher frequency of CD11c+ DCs generated from WT BM than that from IL-6 KO BM. Further exploration of BMDCs from IL-6 KO mice revealed that they had weaker activity of phagocytosis and lower MHC class II and CD86 expression in response to LPS, TNF-a, and Der p stimulation than those of WT BMDCs. Der p-loaded CD11c+ BMDCs from IL-6 KO mice failed to induce Th2 and Th17 differentiation. Moreover, adoptive transfer of Der p-loaded BMDCs from IL-6 KO mice also showed a functional defect in their inability to trigger airway inflammation and AHR in recipient mice. Part III: Tocilizumab had no influence on CD1a and CD11c expression on monocyte-derived DCs in non-atopic controls and allergic asthmatics. Upon Der p stimulation, HLA-DR and CD86 expression on tocilizumab-DCs were significantly lower than those on medium-DCs in allergic asthmatics. Moreover, tocilizumab-DCs had poor capacity for eliciting Th2 polarization as compared to medium-DCs in allergic asthmatics.

Conclusion: IL-6 plays a central role in the pathogenesis of allergic asthma. IL-6 can induce Th2 and Th17 differentiation and inhibit function of CD4+CD25+ Treg cells to trigger and amplify airway inflammation and AHR. IL-6 signaling in DCs is essential for their uptake of allergens, maturation, activation of naïve CD4+ T cells, and initiation of Th2 and Th17-mediated airway inflammation and AHR in allergic asthma, thus providing a new potential target for treating patients with allergic asthma.

論文目次 中文摘要 I
Abstract IV
Acknowlegement VII
Contents IX
List of Figures XIII
Abbreviations XV
Chapter 1-Introduction 1
I. Introduction
I.1 The prevalence of asthma 2
I.2 The allergenicity of house dust mite 3
II. The immunopathology of allergic asthma 4
II.1 DCs 5
II.2 Th2 cells 6
II.3 Th17 cells 9
II.4 Treg cells 11
III. The role of IL-6 in allergic asthma 13
IV. The treatment of asthma 15
Chapter 2-Study specific aims 17
1. Specific aim A: To investigate the role of IL-6 in Der p-induced airway inflammation and AHR in mouse models of allergic asthma 18
2. Specific aim B: To verify the role of IL-6 in DC differentiation and function 20
3. Specific aim C: To study the influence of IL-6 signaling blockade on differentiation and function of human monocyte-derived DCs (MoDCs) 22
Chapter 3-Materials and Methods 24
1. Mice 25
2. Preparation of Der p 25
3. Animal models of inducing allergic inflammation 25
4. Invasive measurement of AHR 26
5. Cell infiltration and cytokine levels in BALF 26
6. Ig quantification 26
7. Lung histology and immunohistochemistry 27
8. Isolation of mouse lung cells 28
9. LLN cell restimulation 28
10. CD4+CD25- T cell stimulation and suppressive function of CD4+CD25+ Treg cells 28
11. BMDC generation and functional assay 29
12. Th differentiation 30
13. CD11c+ BMDC transfer and challenge procedure 31
14. Study subjects 31
15. Generation of human DCs and naïve CD4+ T cell priming 32
16. Statistics 33
Chapter 4-Results 35
Part A: To investigate the role of IL-6 in Der p-induced airway inflammation and AHR in mouse models of allergic asthma 36
IL-6 is involved in Der p-induced AHR and airway inflammation in the i.n. model 36
The influence of IL-6 on Th differentiation and function of CD4+CD25+ Treg cells in Der p-induced airway inflammation 37
IL-6 is essential for Der p-induced AHR and airway inflammation in the i.p. model 38
Summary 39
Part B: To verify the role of IL-6 in DC differentiation and function 40
The influence of IL-6 on DC development and function 40
IL-6 is required for DC-induced airway inflammation and AHR 41
Summary 43
Part C: To study the influence of IL-6 signaling blockade on differentiation and function of human MoDCs 43
The effect of IL-6 signaling blockade on human MoDC differentiation and function 43
Summary 45
Chapter 5-Dissussion 46
1. AHR and airway inflammation are greatly alleviated in Der p-sensitized and -challenged IL-6 KO mice 47
2. The development of Der p-specific Th2 and Th17 responses in mouse models of allergic asthma depends on IL-6 49
3. IL-6 is required for DC-induced airway inflammation and AHR 50
4. Der p-loaded DCs differentiated from peripheral monocytes with IL-6 receptor- blockade were defective in inducing Th2 responses 51
Future work 54
Chapter 7-References 92
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