2017-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/658172摘要：發炎性腸炎(inflammatory bowel disease 簡稱IBD)包括克隆氏症(Crohn’s disease)和潰瘍性腸炎(ulcerative colitis)是慢性腸胃道發炎之重要疾病，許多因素與發炎性腸炎之發病有關，包括基因遺傳、環境因素、腸胃微生物相異常、與廣泛免疫失調。異常活化的免疫第一型(TH1，IFN-γ為代表之細胞激素)與第十七型(TH17，IL-17 為代表性細胞激素)反應為發炎性腸炎的重要特徵之一。最近的研究顯示抗原誘發之調節性T 細胞(regulatory T cells)可預防或治療發炎性腸炎，我們最近的研究發現由B 細胞誘發調節性T 細胞(Treg-of-B cells)表面分子為lymphocyteactivation gene-3 (LAG3)且分泌IL-10 具有免疫調節功能，並發現Treg-of-B 細胞對於氣喘與類風濕性關節炎小鼠模式有顯著療效。我們利用免疫缺損(severe combined immunodeficiency 簡稱SCID)小鼠轉移輸入CD4+CD45RBhigh T cells 來誘發小鼠發炎性腸炎，我們假設(1) LAG3+Treg-of-B 細胞可預防或治療小鼠實驗性腸炎；(2) LAG3+ Treg-of-B 細胞經由抑制TH1 與TH17反應達成治療小鼠實驗性腸炎之效果，我們於本計劃中先經由體外實驗證實LAG3+Treg-of-B細胞的免疫抑制功能及其機轉，接著我們將LAG3+Treg-of-B 細胞用於發展中與已發病之發炎性腸炎小鼠，我們將探討LAG3+Treg-of-B 細胞抑制TH1 與TH17 反應之免疫機轉，我們將利用IL-10 基因剔除小鼠、anti-TGFβ 抗體and anti-LAG3 抗體，體內與體外實驗來證實LAG3+Treg-of-B 免疫抑制功能來自於IL-10、TGF-β、或LAG3。本研究將有助於對於發炎性腸炎致病機轉的了解，以及發展細胞免疫療法治療自體免疫疾病的臨床應用。<br> Abstract: Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a chronicinflammatory condition of the gastrointestinal (GI) tract. Multiple factors are involved in the pathogenesis ofIBS, including gene susceptibility, environmental changes, abnormal GI microbiota and a broadlydysregulated immune response. Dysregulated activation of TH1 and TH17 (IL-23/IL-17 axis) response wasshown to be characteristic in IBD. Recent studies have showed that antigen specific induced regulatory T(Treg) cells not only could prevent colitis but also might become a therapy for IBD. We have found a groupof regulatory T cells induced by B cells (Treg-of-B cells) that express the lymphocyte activation gene-3(LAG3) on cell surface and suppress T cell proliferation through IL-10. We have documented that Treg-of-Bcells could alleviate local or systemic inflammatory of asthma and collagen-induced arthritis in mice. We usea well-characterized animal model of IBD by the transfer of predominantly naïve CD4+CD45RBhigh T cellsinto syngeneic immunodeficient mice. We hypothesize that (1) adoptive transfer LAG3+ Treg-of-B cells canprevent or ameliorate clinical status and intestinal inflammatory pathology in mice with experimental colitis;(2) LAG3+ Treg-of-B cells could suppress TH1 and TH17 immune response in mice with experimental colitis.In the current project, we plan to investigate the suppressive effect and surface marker of Treg-of-B cells invitro. We then investigate the suppressive function of LAG3+Treg-of-B cells in mice with established anddeveloping colitis, and the mechanism of suppression function of LAG3+Treg-of-B cells to TH17 and/or TH1response. We will use IL10 -/- mice, anti-TGFβ antibodies and anti-LAG3 antibodies to document themechanism of Treg-of-B cells mediated immune suppression through LAG3, IL-10, or TGF-β in vitro and invivo. Our study will facilitate more understanding the pathogenesis of IBD and will provide a noveltherapeutic potential for the clinical application of regulatory cells in patients with IBD.發炎性腸炎調節性T 細胞TH17 免疫反應實驗性腸炎inflammatory bowel diseasesregulatory T cellsTH17experimental colitis