2017-08-012024-05-16https://scholars.lib.ntu.edu.tw/handle/123456789/667277摘要：纖維化是因肝臟慢性損傷使針狀肝細胞外基質逐步積累之結果。因為沒有適當的動 物模式，目前對於免疫媒介疾病造成的肝纖維化仍不清楚。IL-22是IL-10家族的細 胞激素，先前研究已知IL-22在感染或毒性物質造成的肝臟發炎及肝纖維化的病人或 動物模式中具有調控的功能，然而IL-22在免疫媒介之肝臟發炎及纖維化的角色則未 知。我們根據人類肝臟自體免疫疾病原發性膽道硬化症(primary biliary cirrhosis; PBC) 發展一個獨特的自體免疫膽管炎及肝纖維化的動物模式用以探討肝臟慢性發炎及纖 維化的免疫機轉以及評估新的治療方法。小鼠注射似PBC自體抗原的2-OA-OVA加 上a-galactosylceramide (2-OA-OVA/a-GalCer)後產生類似PBC的症狀，包括血清中高 量抗粒線體抗體及肝臟門脈區淋巴球浸潤及發炎、肉芽腫產生、膽管破壞及肝纖維 化。在此研究計劃中，我們將利用此小鼠模式探討IL-22在免疫媒介肝纖維化的角色 及機轉。一、探討IL-22對2-OA-OVA/a-GalCer致敏的小鼠疾病的影響。二、探討 IL-22影響自體免疫膽管炎及肝纖維化之作用機轉。是否透過調控型T細胞或IL-10， 是否影響肝細胞及星狀細胞分泌的chemokine的量，或是自體免疫膽管炎小鼠的T cells表現IL-22 receptor，因此IL-22直接影響T cell功能。三、我們將探討IL-22在 疾病治療之可能性。藉此研究，我們將可釐清IL-22在免疫媒介肝纖維化之作用。此 外，這研究結果將提供以重組IL-22或IL-22抑制劑的策略為免疫媒介疾病例如PBC 的免疫治療的新契機。<br> Abstract: Liver fibrosis is a leading cause of morbidity and mortality. It should be regarded as a wound-healing response to chronic liver injury due to infectious, toxic, metabolic, or autoimmune causes, which may eventually result in cirrhosis and hepatic failure. Cytokines play an important role in the regulation of inflammatory responses and fibrosis. IL-22, an IL-10 family member and secreted by Th17 cells, has been reported to regulate liver inflammation and liver fibrosis in patients or mouse models of fibrosis due to infectious and toxic causes. However, the roles of IL-22 in immune-mediated liver inflammation and liver fibrosis remained obscure. We have developed a unique system of mouse autoimmune cholangitis and liver fibrosis for the understanding of immunological mechanisms involved in the development of chronic liver inflammation, fibrosis, and for the assessment of new treatments. The model was established based upon human liver autoimmune disease, primary biliary cirrhosis, by immunizing mice with xenobiotics 2-OA-OVA and a-galactosylceramide (a-GalCer). Such mice develop high titer of autoantibodies and autoimmune cholangitis with a significant increase in lymphocyte recruitment, portal inflammation, bile duct damage, granulomas, and fibrosis. In the current application, we will investigate the effects and underlying mechanism of IL-22 on the autoimmune cholangitis and liver fibrosis by 2-OA-OVA/a-GalCer immunized mouse model.Specific Aim 1. To define the effects of IL-22 in autoimmune cholangitis and liver fibrosis. Specific Aim 2. To elucidate the underlying mechanism how IL-22 affects autoimmune cholangitis and liver fibrosisAim 2.1 To determine whether IL-22 induces regulatory T cells and/or anti-inflammatory IL-10 in autoimmune cholangitis and liver fibrosis.Aim 2.2 To determine whether IL-22 decreases chemokines which lead to decrease the recruitment of immune cells to liver.Aim 2.3 To determine whether T cells in 2-OA-OVA/a-GalCer immunized mice expressed IL-22 receptor and whether IL-22 inhibits IFN-y production of T cells.Specific Aim 3. To determine the potential therapeutic relevance and underlying mechanism of IL-22 in autoimmune cholangitis and liver fibrosis.By this study, we will clarify the roles and mechanisms of IL-22 in the regulation of immune mediated liver inflammation and liver fibrosis. In addition, the results of this study will provide an immunotherapy strategy, such as treatment with IL-22 or IL-22 inhibitors, for immune mediated liver diseases such as primary biliary cirrhosis.肝纖維化免疫媒介肝發炎原發性膽道硬化症小鼠模式IL-22Liver fibrosisimmune-mediated liver inflammationprimary biliary cirrhosismouse modelIL-22