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研究生： 林宜平
Lin, I-Ping
論文名稱： 大腸桿菌減毒素LTS61K在過敏原誘導小鼠氣喘模式中免疫調節的角色
The immunomodulatory effect of Escherichia coli heat-labile enterotoxoid (LTS61K) on allergen-induced mouse model of asthma
指導教授： 王志堯
Wang, Jiu-Yao
學位類別： 碩士
Master
系所名稱： 醫學院 - 微生物及免疫學研究所
Department of Microbiology & Immunology
論文出版年： 2010
畢業學年度： 98
語文別： 中文
論文頁數： 88
中文關鍵詞： 塵螨 、LTS61K 、樹狀細胞
外文關鍵詞： Der p, LTS61K, dendritic cells
相關次數： 點閱：159  下載：1 
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    • 根據世界衛生組織調查統計，過敏性氣喘病人數目在近10年來有逐年增加的趨勢。過敏性氣喘為一種呼吸道慢性發炎疾病，病人會有嗜酸性白血球大量浸潤到呼吸道、呼吸道黏液大量分泌、及呼吸道過度反應等TH2類型免疫反應的症狀產生。但為何病患對於空氣中無害的過敏原，如屋塵螨 (Der p)、花粉等，會引起不正常免疫反應的原因仍不清楚。大腸桿菌分泌的熱不穩定腸毒素 (Escherichia coli heat-labile enterotoxin, LT)因其能有效活化免疫系統，所以製造出許多減毒素，作為疫苗研發上的佐劑，以增強免疫系統對於特定抗原的免疫反應。本研究假設黏膜佐劑LTS61K能透過影響樹狀細胞功能，調節小鼠體內免疫反應，進而達到治療及預防小鼠對於屋塵螨引起的呼吸道發炎。將LTS61K或是LTS61K和屋塵螨混合 (LTS61K/Der p)後，在誘導老鼠對塵螨過敏之前(預防性流程)或之後(治療性流程)，利用鼻腔給予方式送入老鼠體內，犧牲後評估肺部及全身性免疫反應。實驗結果發現，不管是預防或是治療性流程，給予LTS61K或LTS61K/Der p的老鼠，其肺泡沖洗液中細胞浸潤數目、TH2-type細胞激素分泌量、呼吸道過度反應的現象，和控制組相比皆明顯降低，由組織切片結果也可以發現給予LTS61K或LTS61K/Der p後，老鼠氣管管壁周圍、肺泡細胞區域細胞浸潤數目及支氣管黏膜細胞受損情形均顯著改善。此外，LTS61K/Der p處理的老鼠，其血清及肺泡沖洗液中，具塵螨專一性IgA濃度明顯比其他處理組別高。利用LTS61K/Der p刺激DC2.4細胞株及自小鼠骨髓分化的樹狀細胞 (BMDCs)，都能增加細胞分泌發炎性細胞激素IL-6及TNF-，但LTS61K刺激的BMDCs，發育成成熟細胞數目減少，IL-6及TNF-分泌量也會降低。此外，LTS61K刺激的BMDCs能藉由抑制NF-B入核，進一步抑制BMDCs因Der p刺激而導致細胞成熟的現象。利用adoptive transfer方式，將LTS61K或LTS61K/Der p處理後DC2.4 細胞株，或相同處理後的BMDCs，灌送入老鼠肺部，和送入單獨Der p處理樹狀細胞的老鼠相比，其肺泡沖洗液中細胞浸潤數目、TH2-type細胞激素分泌量、呼吸道過度反應的現象以及肺部發炎情形均明顯改善。而血清中及肺泡沖洗液內，具塵螨專一性的IgA濃度有上升情形。總結以上實驗結果，LTS61K能藉由影響樹狀細胞成熟及細胞激素分泌，和過敏原混合後也能促進具抗原專一性IgA的分泌量，進而影響老鼠對於塵螨所引起的不正常免疫反應，達到治療以及預防老鼠對於塵螨的過敏現象。

    Pathologic type 2 T cell immune responses to environmental allergens, such as eosinophil infiltration, increased mucus production and airway hyperresponsiveness (AHR), are the major hallmarks in allergic asthmatics. The pathogenesis for these aerosol allergens, like house dust mites, pollens, induced deviate immune response is still unclear. Escherichia coli heat-labile enterotoxin (LT) with different mutant forms has been used as adjuvants for vaccines due to its ability to enhance immune response to specific antigen in vivo. Our study hypothesis is that LTS61K or LTS61K mixed with Der p (LTS61K/Der p) can modulate dendritic cells (DCs) s’ functions thus alleviate allergen-induced airway inflammation. Two protocols (i.e. preventive and therapeutic protocol) were designed to evaluate the effects of LTS61K in allergen-induced murine model of asthma. Both intranasal inoculations with LTS61K or LTS61K/Der p decreased allergen-induced airway inflammation and alleviated systemic TH2-type immune response. In addition, bronchoalveolar lavage (BAL) fluids and sera from LTS61K/Der p treated mice have higher concentrations of Der p-specific IgA than those of other groups. In the in vitro study, bone marrow-derived dendritic cells (BMDCs) and DC cell line, DC2.4 cells stimulated with LTS61K/Der p both secreted pro-inflammation cytokines IL-6 and TNF-. In contrast, after LTS61K treatment, only BMDCs decreased production of IL-6 and TNF- as well as decreased maturation. Futhermore, we found that pre-treatment BMDC with LTS61K inhibited Der p-induced NF-B translacation which might explain the delayed maturation and decreased productions of IL-6 and TNF- in LTS61K pre-treated BMDCs. Intratracheally adoptive transferred with LTS61K- or LTS61K/Der p-primed DC2.4 cells or BMDCS into Der p-sensitized mice decreased inflammatory cells infiltration and TH2-type chemokines in BAL fluids and alleviated airway inflammation. In conclusion, our results show that LTS61K may influence DCs maturation and its cytokine production. On the other hands, LTS61K/Der p may induce more Der p-specific IgA production to decrease allergic TH2 cytokine responses and alleviate airway inflammation in murine model of asthma. These finding suggested that LTS61K may have clinical application as an immune-modulator effect on the diseases of allergy and asthma.

    目錄 第一章 緒論 1 第一節 研究背景 1 第二節 研究目的 4 第二章 文獻探討 5 第一節 過敏性氣喘的免疫致病機制 5 第二節 樹狀細胞與過敏性氣喘 8 第三節 大腸桿菌熱不穩定腸毒素 (LT) 10 第三章 研究假說與實驗設計 12 第一節 研究假說 12 第二節 實驗設計 13 第四章 材料與方法 16 第一節 實驗材料 16 第二節 實驗方法 21 第五章 研究結果 30 第一節 利用鼻腔投藥方式給予LTS61K或LTS61K/Der p，對於小鼠因塵螨引起呼吸道發炎的治療結果 30 第二節 於引起小鼠對塵螨產生過敏反應前，利用鼻腔投藥方式給予LTS61K或LTS61K/Der p，對於小鼠呼吸道發炎的預防現象 32 第三節 LTS61K增加樹狀細胞株DC2.4細胞分泌發炎性cytokines 35 第四節 LTS61K及 LTS61K/Der p處理後DC2.4細胞能減緩老鼠呼吸道發炎現象 36 第五節 LTS61K藉由抑制NF-B進入細胞核，進而抑制BMDC的成熟 37 第六節 LTS61K或LTS61K/Der p處理後BMDC，能抑制小鼠呼吸道發炎現象 39 第六章 討論 42 第一節 LTS61K佐劑及免疫調節功能 42 第二節 IgA 與過敏性氣喘 46 圖目錄 Fig.1 In vivo animal study model. 54 Fig.2 Intranasal treatments of LTS61K or LTS61K/Der p significant decrease the BALF total cell number in Der p-sensitized mice. 55 Fig.3 Intranasal treatment of LTS61K or LTS61K/Der p decrease TH2-type cytokines in BALF from Der p-sensitized mice. 56 Fig.4 Intranasal treatment LTS61K or LTS61K/Der p does not decrease the proliferation of splenocytes in Der p-sensitized mice. 57 Fig.5 Intranasal treatment LTS61K or LTS61K/Der p alleviate systemic TH2-immune response to specific antigen in Der p-sensitized mice. 58 Fig.6 Intranasal treatment LTS61K or LTS61K/Der p alleviate AHR in Der p-sensitized mice. 59 Fig.7 Intranasal treatment of LTS61K and LTS61K/Der p decreased airway inflammation in Der p-sensitized mice. 60 Fig.8 Intranasal treatment LTS61K/ Der p increase systemic and local Der p-specific IgA. 61 Fig.9 Serum total or antigen-specific IgE are not different between each groups. 62 Fig.10 Intranasal treatment LTS61K/ Der p increase systemic Der p-specific IgG1. 63 Fig.11 Intranasal pre-treatment LTS61K or LTS61K/Der p decrease the BALF total cell number in Der p-sensitized mice. 64 Fig.12 Intranasal pre-treatment of LTS61K or mixed Der p decrease TH2-type cytokines in BAL fluids from Der p-sensitized mice. 65 Fig.13 Intranasal pre-treatment LTS61K or LTS61K/Der p does not decrease the proliferation of splenocytes in Der p-sensitized mice. 66 Fig.14 Intranasal pre-treatment LTS61K or LTS61K/Der p alleviates systemic TH2-immune response to specific antigen in Der p-sensitized mice. 67 Fig.15 Intranasal pre-treatment LTS61K or LTS61K/Der p prevent Der p-sensitized mice from AHR. 68 Fig.16 Intranasal pre-treatment of LTS61K and LTS61K/Der p prevent mice airway inflammation from Der p. 69 Fig.17 Intranasal pre-treatment LTS61K/ Der p increase systemic and local Der p-specific IgA. 70 Fig.18 Serum total or antigen-specific IgE are not different between each groups. 71 Fig.19 Intranasal pre-treatment LTS61K/ Der p increase systemic Der p-specific IgG1 and IgG2a. 72 Fig.20 LTS61K or LTS61K/Der p stimulates DC2.4 cells to secrets pro-inflammatory cytokines IL-6 and TNF-. 73 Fig.21 LTS61K or LTS61K/Der p-primed DC2.4 cells do not decrease BALF total cell count in Der p-treatment mice. 74 Fig.22 LTS61K or LTS61K/Der p primed-DC2.4 cells decrease TH2-type cytokine in Der p-treatment mice. 75 Fig.23 LTS61K or LTS61K/Der p–primed DC2.4 cells alleviate AHR in Der p-treatment mice. 76 Fig.24 LTS61K or LTS61K/Der p–primed DC2.4 cells alleviate airway inflammation. 77 Fig.25 LTS61K/Der p–primed DC2.4 cells do not influence antibody production in mice. 78 Fig.26 DC2.4 cell and BMDC surface markers MHC classⅡ、CD80 and CD86 expression level. 79 Fig.27 LTS61K inhibit BMDC maturation. 80 Fig.28 BMDC treat with LTS61K decreased the production of pro-inflammation cytokines IL-6 and TNF-. 81 Fig.29 LTS61K inhibit Der p- or LPS-stimulated BMDC maturation by decreased NF-B translocation. 82 Fig.30 Adoptive transferred LTS61K-primed BMDCs decrease total cell count in BALF from Der p-treatment mice. 83 Fig.31 Adoptive transferred LTS61K-primed BMDCs decrease TH2-type cytokines in BALF from Der p-treatment mice. 84 Fig.32 LTS61K- or LTS61K/Der p-primed BMDCs alleviate AHR in Der p-treatment mice. 85 Fig.33 LTS61K or LTS61K/Der p–primed BMDCs alleviate airway inflammation. 86 Fig.34 Adoptive transferred LTS61K/Der p-primed BMDCs increase systemic and local Der p-specific IgA production in Der p-treatment mice. 87

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