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

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(Ad-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Ad-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。

關鍵字

細胞激素-10 ；細胞激素-12 ；第一型T輔助細胞；第二型T輔助細胞；調節型T細胞；樹突細胞；氣喘

並列摘要

Asthma is a chronic disease characterized by airway inflammation, airway hyperresponsiveness (AHR) and reversible airway obstruction. It causes by the dysregulated production of cytokines secreted by the allergen-specific type 2 T helper (Th2) cells. To an effort to enhance the efficacy of gene therapy, our studies were attempted to address the therapeutic effect of IL-10 and IL-12-expressing adenovirus 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 data 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-IL-12 and Ad-IL-10 might not through an IFN-γ dependent pathway. These data suggested that IL-12 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-polarization, we generated co-transfect DCs with different doses of adenoviral vectors encoding for IL-12（Ad-IL-12）and IL-10（Ad-IL-10）. In the absence of IL-2 support, low dose of Ad-IL-10 combined with high dose of Ad-IL-12 pushed T cells to develop regulatory T cells（Treg cells） that suppressed the proliferation of effector T cells by IL-10. Interestingly, in the same culture condition, high dose of Ad-IL-10 and Ad-IL-12 or high dose of Ad-IL-10 combined with low dose of Ad-IL-12 induced a Treg cell population that performed the suppressive function by cell-cell contact. It is believed that this study makes us further understand the regulatory roles of IL-12 and IL-10, and ultimately results in dendritic cells-based vaccines to prevent and treat atopic asthma.

並列關鍵字

IL-10 ； IL-12 ； Th1 ； Th2 ； regulatory T cell ； dendritic cell ； asthma

參考文獻

Grunig, G., Corry, D. B., et al. (1997). Interleukin-10 is a natural suppressor of cytokine production and inflammation in a murine model of allergic bronchopulmonary aspergillosis. J Exp Med 185: 1089-1099. Kuipers, H., Heirman, C., et al. (2004). Dendritic cells retrovirally overexpressing IL-12 induce strong Th1 responses to inhaled antigen in the lung but fail to revert established Th2 sensitization. J Leukoc Biol 76: 1028-1038. Oh J.W., Seroogy, C. M., et al. (2002). CD4 T helper cells engineered to produce IL-10 reverse allergen-induced airway hyperreactivity and inflammation. J Allergy Clin Immunol(110): 460-468. Stock, P., Akbari, O., et al. (2004). Induction of T helper type 1–like regulatory cells that express Foxp3 and protect against airway hyper-reactivity. Nat Immunol 5: 1149-1156. Van Scott, M. R., Justice, J. P., et al. (2000). IL-10 reduces Th2 cytokine production and eosinophilia but augments airway reactivity in allergic mice. Am J Physiol Lung Cell Mol Physiol 278: L667-L674. Ye, Y. L., Huang, W. C., et al. (2002). Interleukin-12 inhibits eptaxin secretion of cultured promary ling cells and alleviates airway inflammation in vivo. Cytokine 19: 76-84 Ye, Y. L., Lee, Y. L., et al. (2004). Dendritic cells modulated by cytokine-expressing adenoviruses alleviate eosinophilia and airway hyperresponsiveness in an animal model of asthma. J Allergy Clin Immunol 114: 88-96.

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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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