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細胞激素 -10 及細胞激素 -12 的基因療法在過敏氣喘疾病上的應用

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(1)

目前已經知道主導氣喘發炎反應的主要原因是因為體內多量的第二型 T 輔助細胞 (Th2) 產生的細胞激素 IL-4 、 IL-5 以及 IL-13 所造成。一個活化的 T 細胞分化成第一型或第 二型 T 輔助細胞是受到許多因子的調控,其中最重要的就是細胞激素的影響。為了評 估表現細胞激素 -10 ( interleukin-10,IL-10 )及細胞激素 -12 ( IL-12 )的腺病毒載體 對過敏氣喘造成的免疫調控影響,我們將能表現 IL-10 及 IL-12 蛋白質的腺病毒載體 (A d-IL-10,Ad-IL-12) 送到有氣喘發病的小鼠肺部,來評估其治療氣管發炎的效果。經由比 較單獨使用及合併使用的結果,可知合併低劑量 Ad-IL-10 和 Ad-IL-12 的治療,可更明 顯抑制 Th2 免疫反應;包括更有效的降低呼吸道阻力的產生,抑制 IL-4 、 IL-5 的表現

,尤其可以明顯減少發炎介質 eotaxin 的分泌量,但 Th1 型細胞激素 IFN-γ 並無明顯的 增加,所以細胞激素 IL-12 和 IL-10 的合併治療可為未來發展的新方向。

為了評估能表現 IL-10 及 IL-12 的樹突細胞對於 T 細胞增殖和分化的影響以及是否可做 為治療過敏氣喘疾病的工具,我們以帶有 IL-10 及 IL-12 基因之腺病毒載體感染的樹突 細胞與純化出的 CD4+ T 細胞一起培養,來定義和分析此特殊 T 細胞 ? 的特性。研究結 果顯示,在低劑量 Ad-IL-10 合併高劑量 Ad-IL-12 的作用下, T 細胞傾向分化成調節型 T 細胞並透過其所分泌的 IL-10 來抑制作用 T 細胞的增殖反應。此外,在合併高劑量 A d-IL-10 和高劑量 Ad-IL-12 或高劑量 Ad-IL-10 及低劑量 Ad-IL-12 作用下培養出來的 T 細胞反而不透過 IL-10 來執行抑制作用的功能,我們相信這些結果可做為未來發展以樹 突細胞來治療或預防氣喘疾病上重要的評估和參考。

細胞激素 -10 及細胞激素 -12 的基因療法在過敏 氣喘疾病上的應用

(2)

Asthma is a chronic disease characterized by airway inflammation, airway hyperresponsiveness (A HR) and reversible airway obstruction. It causes by the dysregulated production of cytokines secret ed by the allergen-specific type 2 T helper (Th2) cells. To an effort to enhance the efficacy of gene t herapy, our studies were attempted to address the therapeutic effect of IL-10 and IL-12-expressing a denovirus for asthma treatment. The cytokines-expressing adenoviruses (Ad-IL-12, Ad-IL-10) were prepared and applied in an established murine model of ovalbumin (OVA)-induced asthma. The dat a showed that combination of Ad-IL-12 and Ad-IL-10 could get a synergistic effect and inhibit the development of airway symptoms in OVA-sensitized mice. In addition, such regulation from Ad-I L-12 and Ad-IL-10 might not through an IFN-γ dependent pathway. These data suggested that IL-1 2 combined with IL-10 might be a novel therapeutic approaches for asthma treatment.

To investigate the regulatory mechanism of dendritic cells ( DC ) in the area of CD4+ T cell-po larization, we generated co-transfect DCs with different doses of adenoviral vectors encoding for I L-12 ( Ad-IL-12 ) and IL-10 ( Ad-IL-10 ) . In the absence of IL-2 support, low dose of Ad-I L-10 combined with high dose of Ad-IL-12 pushed T cells to develop regulatory T cells ( Treg cel ls ) that suppressed the proliferation of effector T cells by IL-10. Interestingly, in the same cultur e condition, high dose of Ad-IL-10 and Ad-IL-12 or high dose of Ad-IL-10 combined with low dos e of Ad-IL-12 induced a Treg cell population that performed the suppressive function by cell-cell c ontact. It is believed that this study makes us further understand the regulatory roles of IL-12 and I L-10, and ultimately results in dendritic cells-based vaccines to prevent and treat atopic asthma.

The Application of Interleukin-10 and

Interleukin-12 in Gene Therapy of Allergic Asthma

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