AdvmICOSIg阻斷ICOS共刺激通路對(duì)MLD-STZ誘導(dǎo)的T1D的治療作用
發(fā)布時(shí)間：2018-08-07 13:57
【摘要】：一、研究背景和目的 1型糖尿病(Type 1 Diabetes，T1D)是由自身免疫紊亂引起的糖尿病，其發(fā)病過(guò)程表現(xiàn)為兩個(gè)階段：首先是多種因素引起炎癥因子的分泌，，導(dǎo)致局部淋巴細(xì)胞浸潤(rùn)，引起胰腺炎；隨后發(fā)展為自身耐受被打破，活化后的CD4~+T和CD8~+T細(xì)胞攻擊自身β細(xì)胞，引起β細(xì)胞大部分死亡，導(dǎo)致胰島素分泌不足，血糖濃度過(guò)高而引起糖尿病。T細(xì)胞對(duì)β細(xì)胞的特異性殺傷是T1D發(fā)生的直接原因。 T細(xì)胞活化機(jī)制方面的研究發(fā)現(xiàn)T細(xì)胞的有效活化和效應(yīng)發(fā)揮需要共刺激信號(hào)，缺乏共刺激信號(hào)的抗原刺激引起免疫耐受。針對(duì)已知的幾種共刺激分子(CD28、CD40L、CTLA-4等)的研究數(shù)據(jù)表明，缺乏共刺激分子或用適當(dāng)?shù)氖侄巫钄喙泊碳ば盘?hào)途徑，T細(xì)胞不能有效的活化和增殖。鑒于共刺激分子對(duì)免疫應(yīng)答中的重要影響，其在自身免疫性糖尿病中的作用吸引了研究者的興趣。其中Arreaza，G．A等和Balasa，B等分別用CD28和CD40L阻斷性單抗治療NOD小鼠自發(fā)產(chǎn)生的糖尿病，發(fā)現(xiàn)這些試劑對(duì)防止2-4周大的NOD小鼠發(fā)生胰腺炎和IDDM糖尿病有效，但對(duì)5-7周大的小鼠無(wú)效。這些結(jié)果提示當(dāng)T1D表現(xiàn)出臨床癥狀時(shí)，CD28、CD40L等提供的共刺激信號(hào)并不重要，在維持著T細(xì)胞的殺傷效應(yīng)上，存在其他的共刺激途徑。 近年來(lái)，有關(guān)T細(xì)胞活化共刺激信號(hào)的研究取得了許多新進(jìn)展。明確了B7-1／B7-2—CD28／CTLA-4和CD40L-CD40共刺激信號(hào)通路在激發(fā)初始T細(xì)胞活化中的主導(dǎo)地位，同時(shí)也發(fā)現(xiàn)，大部分效應(yīng)性CD8~+和CD4~+T細(xì)胞的功能發(fā)揮和維持，以及記憶性T細(xì)胞發(fā)生再次應(yīng)答不依賴這兩條共刺激信號(hào)通路，體內(nèi)還存在其它共刺激信號(hào)通路。這些共刺激信號(hào)在T細(xì)胞應(yīng)答的不同時(shí)空階段，對(duì)T細(xì)胞的功能和效應(yīng)發(fā)揮著各自不同的調(diào)節(jié)作用。聯(lián)系到T1D發(fā)病時(shí)的特點(diǎn)，此時(shí)體內(nèi)已經(jīng)存在大量活化后的T細(xì)胞，干預(yù)上述共刺激途徑的局限性可能在于上述這些共刺激途徑只在初始T細(xì)胞的活化階段上發(fā)揮重要作用，而在記憶和效應(yīng)T細(xì)胞的功能發(fā)揮和維持階段上可能存在其他的途徑。最近，ICOS-B7h信號(hào)通路在調(diào)節(jié)記憶性和效應(yīng)性T細(xì)胞功能、維持外周耐受方面的重要意義引起我們極大的關(guān)注。
[Abstract]:Background and objective Type 1 diabetes mellitus (Type 1 diabetes mellitus T1D) is caused by autoimmune disorders. The process is characterized by two stages: first, a variety of factors cause the secretion of inflammatory factors, leading to local lymphocytic infiltration, causing pancreatitis, and then the development of self-tolerance is broken, The activated CD4T and CD8T cells attacked their own 尾 cells, resulting in the death of most of the 尾 cells and the deficiency of insulin secretion. The specific cytotoxicity of T cells to 尾 cells caused by excessive blood glucose concentration is the direct cause of T 1D. The mechanism of T cell activation It has been found that the effective activation and effect of T cells require costimulatory signals. Antigen stimulation that lacks costimulatory signals causes immune tolerance. The data of several known costimulatory molecules (CD28, CD40L, CTLA-4, etc.) indicate that the lack of costimulatory molecules or blocking of costimulatory signaling pathway by appropriate means can not effectively activate and proliferate T cells. The role of costimulatory molecules in autoimmune diabetes has attracted the interest of researchers due to their important role in immune response. Among them, Arreazaer G.A and BalasaHB were used to treat spontaneously produced diabetes in NOD mice with CD28 and CD40L blocking monoclonal antibodies, respectively. It was found that these reagents were effective in preventing pancreatitis and IDDM diabetes in NOD mice aged 2-4 weeks, but not in 5-7 week-old mice. These results suggest that when T1D shows clinical symptoms, the costimulatory signal provided by CD28, CD40L and so on is not important, and there are other co-stimulatory pathways in maintaining the killing effect of T cells. In recent years, many new advances have been made in the study of T cell activation costimulatory signal. The dominant role of B7-1/B7-2-CD28/CTLA-4 and CD40L-CD40 costimulatory signaling pathway in stimulating the activation of primary T cells was clarified. At the same time, it was found that most of the effectual CD8 ~ and CD4 ~ T cells function and maintained. The memory T cell response was independent of these two costimulatory signaling pathways, and there were other co-stimulatory signaling pathways in vivo. These costimulatory signals play different roles in regulating the function and effect of T cells at different time and space stages of T cell response. In connection with the characteristics of T1D, there are already a large number of activated T cells in vivo. The limitation of interfering with these co-stimulation pathways may be that these co-stimulation pathways only play an important role in the activation stage of the initial T cells. There may be other pathways in the functioning and maintenance of memory and effector T cells. Recently, the importance of ICOS-B7h signaling pathway in regulating memory and effectual T cell function and maintaining peripheral tolerance has aroused great concern.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2006
【分類號(hào)】：R587.1;R392
本文編號(hào)：2170237
[Abstract]:Background and objective Type 1 diabetes mellitus (Type 1 diabetes mellitus T1D) is caused by autoimmune disorders. The process is characterized by two stages: first, a variety of factors cause the secretion of inflammatory factors, leading to local lymphocytic infiltration, causing pancreatitis, and then the development of self-tolerance is broken, The activated CD4T and CD8T cells attacked their own 尾 cells, resulting in the death of most of the 尾 cells and the deficiency of insulin secretion. The specific cytotoxicity of T cells to 尾 cells caused by excessive blood glucose concentration is the direct cause of T 1D. The mechanism of T cell activation It has been found that the effective activation and effect of T cells require costimulatory signals. Antigen stimulation that lacks costimulatory signals causes immune tolerance. The data of several known costimulatory molecules (CD28, CD40L, CTLA-4, etc.) indicate that the lack of costimulatory molecules or blocking of costimulatory signaling pathway by appropriate means can not effectively activate and proliferate T cells. The role of costimulatory molecules in autoimmune diabetes has attracted the interest of researchers due to their important role in immune response. Among them, Arreazaer G.A and BalasaHB were used to treat spontaneously produced diabetes in NOD mice with CD28 and CD40L blocking monoclonal antibodies, respectively. It was found that these reagents were effective in preventing pancreatitis and IDDM diabetes in NOD mice aged 2-4 weeks, but not in 5-7 week-old mice. These results suggest that when T1D shows clinical symptoms, the costimulatory signal provided by CD28, CD40L and so on is not important, and there are other co-stimulatory pathways in maintaining the killing effect of T cells. In recent years, many new advances have been made in the study of T cell activation costimulatory signal. The dominant role of B7-1/B7-2-CD28/CTLA-4 and CD40L-CD40 costimulatory signaling pathway in stimulating the activation of primary T cells was clarified. At the same time, it was found that most of the effectual CD8 ~ and CD4 ~ T cells function and maintained. The memory T cell response was independent of these two costimulatory signaling pathways, and there were other co-stimulatory signaling pathways in vivo. These costimulatory signals play different roles in regulating the function and effect of T cells at different time and space stages of T cell response. In connection with the characteristics of T1D, there are already a large number of activated T cells in vivo. The limitation of interfering with these co-stimulation pathways may be that these co-stimulation pathways only play an important role in the activation stage of the initial T cells. There may be other pathways in the functioning and maintenance of memory and effector T cells. Recently, the importance of ICOS-B7h signaling pathway in regulating memory and effectual T cell function and maintaining peripheral tolerance has aroused great concern.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2006
【分類號(hào)】：R587.1;R392
【參考文獻(xiàn)】
相關(guān)期刊論文 前1條
1 侯寧寧,董硯虎,于國(guó)慶;NOD小鼠口服胰島素誘導(dǎo)免疫耐受機(jī)制探討[J];中華內(nèi)分泌代謝雜志;2002年01期
本文編號(hào)：2170237
本文鏈接：http://sikaile.net/yixuelunwen/binglixuelunwen/2170237.html
最近更新
教材專著
