探討Interleukin-10及Interleukin-22於原發性膽道硬化症的免疫調節作用

Study on the Immunoregulatory Effects of Interleukin-10 and Interleukin-22 on Primary Biliary Cirrhosis

薛郁馨(Yu-Hsin Hsueh)

指導教授 ： 莊雅惠

國立臺灣大學/醫學院/醫學檢驗暨生物技術學研究所/碩士(2014年)

https://doi.org/10.6342/NTU.2014.00212

摘要

IL-10 family cytokine對於保護組織、避免組織因為感染及發炎反應而受到破壞相當重要。其中IL-10可抑制發炎反應並且也可抑制肝纖維化的發生。而IL-22則是對於上皮組織的平衡、修復以及傷口癒合相當重要。目前的研究顯示IL-10及IL-22在免疫反應的調控上皆扮演了重要的角色，特別是在肝臟的發炎反應中，兩者皆可有效的減緩肝臟的發炎反應。IL-10及IL-22對於許多不同的自體免疫疾病亦有抑制的效果。原發性膽道硬化症 (Primary Biliary Cirrhosis，PBC) 為一種因免疫反應引起肝內小膽管的發炎及損壞的肝臟自體免疫疾病，導致慢性膽汁鬱積，最終會造成肝纖維化與肝硬化。本研究探討IL-10及IL-22對於肝臟自體免疫疾病 PBC的影響。由於AAV (adeno-associated virus)僅會引起輕微的發炎反應，且可長久的表達其所攜帶的基因，因此可作為良好的載體。我們利用攜帶IL-10及IL-22基因的AAV以尾靜脈注射方式打入以2-OA-OVA/α-GalCer致敏的PBC小鼠體內，觀察PBC小鼠的自體抗體、肝臟單核細胞浸潤及病理變化。我們發現給予IL-10的PBC小鼠肝臟中的B cells數量下降、Foxp3+ CD4 T cells的數量上升，肝臟中的granulomas數目及MMP-9的表現降低。而給予IL-22的PBC小鼠肝臟單核細胞數顯著下降，尤其是T cells及B cells。IL-10 也許可透過降低B cells的數目及增加肝臟中Tregs的數量以減緩PBC的發炎反應，或透過降低granulomas的形成及減少MMP-9的表現以抑制fibrosis。而IL-22則可減緩PBC所引起的肝臟發炎細胞浸潤，特別是T cells及B cells。因此IL-10及IL-22均會降低肝臟自體免疫疾病PBC的發炎反應。

關鍵字

IL-10 ； IL-22 ； 原發性膽道硬化症 ； 自體免疫疾病 ； AAV

並列摘要

IL-10 family cytokines are essential for the prevention of tissue damage caused by excessive inflammatory responses as well as maintaining the homeostasis of tissue epithelial layers. IL-10 is an anti-inflammatory and anti-fibrotic cytokine. IL-22 preserves tissue integrity with enhanced wound-healing and tissue repair activities. Both IL-10 and IL-22 are important in controlling the inflammatory response, especially in hepatitis. In addition IL-10 and IL-22 also have the protective effects in the variety of autoimmune diseases. Primary biliary cirrhosis (PBC) is a liver autoimmune disease, characterized by the immune mediated infiltration and destruction of the bile duct, which leads to cholestasis, fibrosis, and finally, cirrhosis. Our specific aim is to investigate the effects of IL-10 and IL-22 on the regulation of PBC. Because of the minute immune response and the long-term expression of the gene, adeno-associated virus (AAV) is a good vector for gene transfer. In this study, mouse IL-10 and IL-22 expressing AAV were injected to 2-OA-OVA/α-GC immunized mice and PBC features including serum anti-mitochondrial antibodies (AMA) titer, liver mononuclear cells infiltration and the histopathology in these cytokine expressed mice were then examined. Our results showed that administration of IL-10 decreased B cells but increased Foxp3+ CD4 T cells in the liver of 2-OA-OVA/α-GC immunized PBC mice. Moreover, reduced granulomas and MMP-9 expression were observed in the liver of IL-10 injected PBC mice. IL-22 administration reduced the liver mononuclear cells, especially T cells and B cells in 2-OA-OVA/α-GC immunized PBC mice. These results suggested that IL-10 in PBC might inhibit liver inflammation by decreasing B cells and increasing Foxp3+ regulatory T cells. In addition, IL-10 may suppress liver fibrosis by reducing the granulomas formation and MMP-9 expression. IL-22 could ameliorate liver inflammation by decreasing T cell and B cell infiltration in PBC mice. Taken together, our study demonstrated the down-regulatory effects of IL-10 and IL-22 on PBC.

並列關鍵字

IL-10 ； IL-22 ； primary biliary cirrhosis ； autoimmune disease ； AAV

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