2010-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/643152摘要：自體免疫疾病的發生是受多重因子所調控的過程，涉及到免疫系統許多組成的失調，包括了適應性（adaptive）以及先天性（innate）免疫系統的缺失。相較於適應性免疫，先天性免疫在自體免疫疾病致病機轉上所扮演的角色仍未被完整的探討。研究顯示先天性免疫系統的活化即使在沒有適應性免疫細胞的協助下也可直接的造成標的器官的受損。Galectins是屬於β-galactoside結合醣蛋白家族成員之一。研究顯示Galectins可經由調控免疫細胞的功能進而在免疫反應中扮演著重要的角色。這些研究顯示了醣免疫學及先天性免疫力在感染原激發發炎反應上可能扮演著重要角色，同時這可能與引起自體免疫疾病之發炎性反應與產生自體免疫疾病有密切關係。之前研究證實,外源性galectin-1能直接引起T細胞和淋巴細胞的死亡,然而內生性galectin-3卻能抑制T細胞的死亡。Galectin-3參與呼吸道以及自體免疫疾病的發炎性免疫反應。然而,galectins在T細胞活化以及細胞凋亡上面所扮演的角色目前仍舊不是很清楚。在我們初步的實驗結果中，我們證實galectin-1,3,4和9的表現能藉由利用抗CD3和抗CD28單株抗體去活化T細胞所提高。由自galectin-3基因缺損的老鼠體內分離出來的T細胞對於CD3和抗CD28單株抗體活化T細胞的刺激具有較強的增生反應。同時galectin-3基因缺損的老鼠對於collagen抗體所誘發的關節炎具較嚴重的反應，顯示出galectin-3在T細胞活化扮演著重要的角色。在這研究計畫中，我們想去研究galectins在控調T細胞反應與自體免疫疾病的角色。我們將探討galectins參與T細胞活化，分化和凋亡的的訊息傳導路徑。我們將進一步研究由galectins誘發T細胞活化與死亡的分子機制。為了去研究這個主題，我們將進一步利用siRNAs 進行galectins-knock down的研究；並利用galectins基因缺陷的老鼠在自體免疫疾病小鼠動物模式中探討。這個研究將有助我們瞭解galectins在控調T細胞反應與自體免疫疾病的角色，進而應用在發展治療人類自體免疫疾病上。<br> Abstract: Autoimmune diseases are multi-factorial processes involving dysregulation of multiple components of the immune system including the adaptive and the innate immune system. Compared to adaptive immunity, the role of innate immunity in the pathogenesis of autoimmune diseases is not well being elucidated yet. It has been shown that activation of the innate immune system can directly damage the target organ even without the help of adaptive immune cells.Galectins are a family of animal lectins with affinity for beta-galactosides. Current research indicates that galectins play important roles in the immune response through regulating the homeostasis and functions of the immune cells. All these results indicate that the glycol-immunology and innate immunity may play important role in triggering inflammatory reaction in response to infectious agents; and it may contribute to the development of autoimmune diseases via interaction with endogenous ligand.Previous studies demonstrated that extracellular galectin-1 and –3 directly induces death of T cells and thymocytes, while intracellular galectin-3 blocks T cell death. Galectin-3 has been implicated in the inflammatory immune response in airway inflammation and autoimmune diseases. In our preliminary results, we have demonstrated that expression of galectin-1, 3, 4 and 9 is upregulated when T cells are activated by anti-CD3 and anti-CD28. T cells from galectin-3 knock mice demonstrated enhanced T cell proliferation to stimulation with anti-CD3 and anti-CD28. Moreover, there were enhanced collagen Ab-induced arthrititis in galectin-3 knock out mice, indicating galectin-3 play an important role in T cell activation and apoptosis.In this project, we attempt to investigate role of galectins in regulating T cell activation and development of autoimmune diseases. We will study the mechanisms of galectins-induced T cell activation, differentiation and apoptosis. In order to explore the regulation of T cell activation, differentiation and apoptosis by galectins, we will further investigate the intracellular signaling pathway modulated by galectins. Role of galectins in T cell immune responses will also be further addressed with siRNAs, and galectins-knock out mice in autoimmune disease animal models. This will further help us to understand the role glactins in autoimmunity, and targeting glactins may become a novel strategy for the treatment of autoimmune diseases in the future.galectinsT 細胞活化細胞凋亡galectinsT cellactivationapoptosis