AdvmICOSIg阻断ICOS共刺激通路对MLD-STZ诱导的T1D的治疗作用
发布时间：2018-08-07 13:57
【摘要】：一、研究背景和目的 1型糖尿病(Type 1 Diabetes，T1D)是由自身免疫紊乱引起的糖尿病，其发病过程表现为两个阶段：首先是多种因素引起炎症因子的分泌，，导致局部淋巴细胞浸润，引起胰腺炎；随后发展为自身耐受被打破，活化后的CD4~+T和CD8~+T细胞攻击自身β细胞，引起β细胞大部分死亡，导致胰岛素分泌不足，血糖浓度过高而引起糖尿病。T细胞对β细胞的特异性杀伤是T1D发生的直接原因。 T细胞活化机制方面的研究发现T细胞的有效活化和效应发挥需要共刺激信号，缺乏共刺激信号的抗原刺激引起免疫耐受。针对已知的几种共刺激分子(CD28、CD40L、CTLA-4等)的研究数据表明，缺乏共刺激分子或用适当的手段阻断共刺激信号途径，T细胞不能有效的活化和增殖。鉴于共刺激分子对免疫应答中的重要影响，其在自身免疫性糖尿病中的作用吸引了研究者的兴趣。其中Arreaza，G．A等和Balasa，B等分别用CD28和CD40L阻断性单抗治疗NOD小鼠自发产生的糖尿病，发现这些试剂对防止2-4周大的NOD小鼠发生胰腺炎和IDDM糖尿病有效，但对5-7周大的小鼠无效。这些结果提示当T1D表现出临床症状时，CD28、CD40L等提供的共刺激信号并不重要，在维持着T细胞的杀伤效应上，存在其他的共刺激途径。 近年来，有关T细胞活化共刺激信号的研究取得了许多新进展。明确了B7-1／B7-2—CD28／CTLA-4和CD40L-CD40共刺激信号通路在激发初始T细胞活化中的主导地位，同时也发现，大部分效应性CD8~+和CD4~+T细胞的功能发挥和维持，以及记忆性T细胞发生再次应答不依赖这两条共刺激信号通路，体内还存在其它共刺激信号通路。这些共刺激信号在T细胞应答的不同时空阶段，对T细胞的功能和效应发挥着各自不同的调节作用。联系到T1D发病时的特点，此时体内已经存在大量活化后的T细胞，干预上述共刺激途径的局限性可能在于上述这些共刺激途径只在初始T细胞的活化阶段上发挥重要作用，而在记忆和效应T细胞的功能发挥和维持阶段上可能存在其他的途径。最近，ICOS-B7h信号通路在调节记忆性和效应性T细胞功能、维持外周耐受方面的重要意义引起我们极大的关注。
[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.
【学位授予单位】：第三军医大学
【学位级别】：博士
【学位授予年份】：2006
【分类号】：R587.1;R392
本文编号：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.
【学位授予单位】：第三军医大学
【学位级别】：博士
【学位授予年份】：2006
【分类号】：R587.1;R392
【参考文献】
相关期刊论文 前1条
1 侯宁宁,董砚虎,于国庆;NOD小鼠口服胰岛素诱导免疫耐受机制探讨[J];中华内分泌代谢杂志;2002年01期
本文编号：2170237
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