• 系統編號 RN9511-2128
• 計畫中文名稱 細胞激素的基因療法在過敏氣喘疾病上的應用
• 計畫英文名稱 The Application of Cytokine Genes in Gene Therapy of Allergic Asthma
• 主管機關 -- • 計畫編號 NSC93-2314-B038-019
• 執行機構 臺北醫學大學微免學科
• 本期期間 9308 ~ 9407
• 報告頁數 7 頁 • 使用語言 中文
• 研究人員 李岳倫; 江伯倫 lee, Yueh-Luen; Chiang, Bor-Luen
• 中文關鍵字 --
• 英文關鍵字 --
• 中文摘要
從 1970 年代以來，許多報告都指出，全世界氣喘病的罹患率持續在增加，病情轉趨嚴重，住院率和死亡率也隨著增高，台灣地區也不例 外。在氣喘病人身上可觀察到幾項特徵：包括血液中的 IgE 增加，體內第二型 T 輔助細胞(Th2)數目增加，氣管聚集大量的嗜伊紅性白血球 細胞(eosinophilia)以及發炎媒介物的產生。過去對氣喘疾病的治療大部分偏重於抑制氣管的發炎現象和舒緩氣管的收縮程度，而吸入性類 固醇的使用為目前對於氣喘症狀控制和肺功能的改善最有效的方法；但是類固醇的使用只能抑制發炎現象，對氣喘仍無法根治，而且對於 人體仍有潛在的副作用，所以病人除了儘量避免接觸過敏原外，要徹底治療氣喘疾病，目前治療方法為減敏療法。減敏治療必須持續幾年 的治療，此種耗時並且需要大量純化過敏原的治療方式並不是最理想的治療方法。基於此，其病因的探討和研發過敏氣喘新治療的方法則 刻不容緩。目前已經知道細胞激素 IL-12 會促進 T 細胞分化為 Th1 輔助細胞，使其產生大量的 Th1 型細胞激素 IFN-gamma 以及 IL-2，並 抑制 Th2 型細胞激素 IL-4 以及 IL-5 的分泌。多年前我們實驗室就已經開始將 IL-12 應用到過敏氣喘動物的治療，在對於將 IL-12 蛋白質以 及 IL-12 基因治療氣管發炎的小鼠上皆獲得不錯的成績。目前，則更進一步將具有單一鏈的 IL-12 融合基因之腺病毒載體送到有氣喘症狀 的小鼠肺部，來治療其氣管發炎的現象，而初步的研究成果令人滿意。
• 英文摘要
The frequency of allergic diseases such as asthma and allergic rhinitis has increased rapidly during the past decade. Allergic asthma is characterized by airway hyperresponsiveness(AHR) to specific and nonspecific stimuli with elevated serum IgE levels and eosinophilic inflammation. Thus far, a broad range of therapeutic strategies is now under development. Although the topical glucocorticoids are now considered the cornerstone of therapy in the management of allergic diseases, many patients continue treatment with glucocorticoids despite the onset of serious adverse effects and poor
clinical response. Immunotherapy, the intradermal injection of small but gradually increasing amounts of allergen, has been used as an effective treatment for allergic diseases. However, injection of allergen involves the risk of induction of mild and sometimes severe anaphylactic reactions.
Allergic asthma is thought to be regulated by Th2 cells, thus inhibiting Th2 response or developing Th1 cells is a promising mode of
intervention.IL-12 is a heterodimeric cytokine, which strongly promotes the differentiation of naïve CD4+ T cells to the type-1 Th1 phenotype and suppresses the expression of Th2 cytokines. Preliminary data have demonstrated that IL-12 is a good candidate for the cytokine treatment of allergic diseases. In mice with ovalbumin-induced asthma, the local administration of IL-12-expressing adenovirus (Ad-IL-12) into the lungs significantly prevented the development of AHR, abrogated airway eosinophilia, and inhibited type-2 cytokine production. Recently, a novel cytokine, IL-27, is discovered and drives rapid clonal expansion of mouse naive T cells. It also strongly synergizes with IL-12 to trigger IFN-gamma production of naïve CD4+ T cells. Thus, these immunoregulatory properties of IL-27 will lead to its therapeutic use in allergic asthma. In general, the aims of our study are as follow: First year: Construction of recombinant IL-27-expressing adenovirus (Ad-IL-27) and investigation the biological effects of recombinant IL-27 in vitro. Second year: Combination of Ad-IL-12 and Ad-IL-27 will be used to apply the DNA vaccine or gene therapy in a murine asthma model in vivo. In summary, our project might shed light further understanding the regulatory mechanisms and designing immunotherapy for atopic diseases.
