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標題: | 治療動脈粥狀硬化的未來展望:寄生蟲感染及第二型免疫反應 Possible future therapeutic for atherosclerosis: Helminth infection and type 2 immunity |
作者: | 陳言亭 Yen-Ting Chen |
指導教授: | 林建達 Jian-Da Lin |
關鍵字: | 動脈粥狀硬化,NOD2 基因,鼠鞭蟲,多型性螺旋線蟲,第二型免疫反應,寄生蟲感染, atherosclerosis,Nod2-/-,Trichuris muris,Heligmosomoides polygyrus,type 2 immunity,helminth infection, |
出版年 : | 2023 |
學位: | 碩士 |
摘要: | 第一型免疫反應及慢性發炎與動脈粥狀硬化的進程息息相關,而近期的臨床目標在於透過增加第二型免疫反應以降低發炎症狀來促進斑塊消退。核苷酸結合寡聚域蛋白質2 (NOD2) 受體能偵測細菌或其產物以刺激免疫反應。根據先前研究指出,Nod2-/-小鼠有腸道菌相失衡及較少的第二型免疫反應等現象,然而腸道菌群失衡,動脈粥狀硬化疾病進程及第一/二型免疫反應之間的相關機制仍待探究,因此本研究將探討腸道菌群失調是否能促進動脈粥狀硬化的進展,而增加第二型免疫反應是否能治療疾病。本研究預期透過鼠鞭蟲 (T. muris) 及多型性螺旋線蟲 (H. polygyrus) 腸道寄生蟲的感染能抑制發炎反應使斑塊消退。我們建立了高參數免疫分析圖譜,透過光譜式流式細胞分析技術可同時分析組織中35種免疫細胞標記,並在疾病進展及逆轉期間長期對野生型 (WT) 及Nod2-/-小鼠的血液進行免疫細胞群分析。結果顯示,淋巴細胞在兩種基因型小鼠中的表現量有顯著差異,在疾病進程中Ly6C+/Ly6C-單核球、樹突細胞、γ/δ T細胞及effector memory CD4/CD8 T細胞顯著增加,而CD25+ CD4 T細胞則降低其表現。此外,經過寄生蟲感染後的動脈粥狀硬化小鼠發現腹腔組織中的M2巨噬細胞、CD25+ ST2+調節性T細胞、先天性淋巴細胞2及活化的CD4/CD8 T細胞群擴增。最後,透過切片定量斑塊大小,我們成功利用寄生蟲感染誘導動脈粥狀硬化小鼠主動脈弓的斑塊消退,且證實了斑塊消退依賴於NOD2基因的存在。因此,由本實驗結果顯示,基於強烈第二型免疫反應的生成,寄生蟲感染將成為未來治療動脈粥狀硬化的潛在策略。 Type 1 immune responses and chronic inflammation are always associated with atherosclerosis progression. A recent clinical goal aims to promote plaque regression by reducing inflammation that may be correlated with the increase of type 2 immunity. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is the bacterial sensor to stimulate immune responses, and previous studies have indicated Nod2-/- mice present gut dysbiosis and reduced type 2 immunity. However, the relationships between gut dysbiosis, atherosclerosis progression, and type 1/2 immune responses remain elusive. Here, we aim to interrogate whether gut dysbiosis can promote atherosclerosis progression and whether the inflammatory phenotypes can be reversed by increasing type 2 immunity. We hypothesized that the gastrointestinal helminth infection, Trichuris muris (T. muris) and Heligmosomoides polygyrus (H. polygyrus), can resolve inflammation and induce plaque regression. Currently, the powerful immune profiling panel is built up to analyze the 35 immune markers simultaneously by spectral flow cytometry. We longitudinally perform immune profiling on the blood of wild-type (WT) and Nod2-/- mice during atherosclerosis progression and regression. The significant differences of B cells and CD4 T cells were observed in both genotypes of mice. We show that Ly6C+/Ly6C- monocytes, dendritic cells, γ/δ T cells, and effector memory CD4/CD8 T cells increase in the blood, while CD25+ CD4 T cells decrease during atherogenesis progression. Notably, strong type 2 immune responses were induced by helminth-infected atherosclerotic mice and may induce plaque regression, as evidenced by the expansion of M2 macrophages, CD25+ ST2+ regulatory T cells, type 2 innate lymphoid cells, and activated CD4/CD8 T cells in peritoneal cavity tissue. Plaque regression in the aortic root of atherosclerotic mice was observed with helminth treatments, as confirmed through quantitative analysis. Additionally, our study reveals that plaque regression is NOD2-dependent. Overall, our results suggest promising strategies by helminth treatments for future therapeutics in atherosclerosis. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/90463 |
DOI: | 10.6342/NTU202303056 |
全文授權: | 同意授權(限校園內公開) |
顯示於系所單位: | 生化科技學系 |
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