T-cell mechanisms of B-cell destruction

在1型糖尿病患者中，由于免疫系统错误地攻击并摧毁了b细胞，导致胰腺b细胞产生胰岛素的能力不足，就好像它们是入侵的感染一样。自体免疫破坏b细胞的复发也会在整个胰腺或胰岛细胞移植后发生，并可能在将来移植其他工程胰岛素产生细胞时发生。这个项目的重点是更好地了解b细胞是如何被免疫系统杀死的，并测试保护β细胞免受这些机制影响的方法。由于无法对糖尿病患者的胰腺进行研究（特别是活检），因此大部分拟议的工作将在非肥胖糖尿病小鼠（NOD）的b细胞中进行，这是目前最好的1型糖尿病小鼠模型。从文献中可以清楚地看出，在细胞毒性T淋巴细胞（CTL）中发现的一种称为穿孔素的分子是免疫系统对抗b细胞的主要机制，如果不是主要机制的话。因此，我们将尝试更好地理解b细胞与穿孔素之间的相互作用，并最终设计出穿孔素介导细胞死亡的方法。同样清楚的是，除了穿孔蛋白之外，还有其他机制可以导致b细胞死亡，该项目也将致力于发现这些机制和阻止它们的新方法。通过添加保护性基因或使用转基因敲除技术去除有害基因，NOD小鼠中的β细胞将免受穿孔素或其他机制的影响。可以系统地添加或删除与细胞死亡有关的基因，并使用NOD小鼠模型对每种方案进行测试。1型糖尿病患者b细胞发生的细胞死亡过程称为细胞凋亡。细胞凋亡是所有类型细胞死亡的一般机制。细胞凋亡和穿孔素生物学方面的专家是该项目的重要成员，为将细胞死亡研究的最新进展转化为糖尿病提供了机会。本研究涉及JDRF感兴趣的几个特定研究领域。它的重点是预防b细胞死亡的个体1型糖尿病患者接受胰岛移植。它可能在未来适用于保护已分化为b细胞的干细胞或前体细胞，甚至设计预防糖尿病发展的策略。

In type 1 diabetes the body becomes deficient in insulin production from pancreatic b cells because the immune system mistakenly attacks and destroys b cells as if they were an invading infection. Recurrence of autoimmune destruction of b cells also occurs following transplantation of whole pancreas or islet cells and may occur in the future when other engineered insulin producing cells are transplanted. The focus of this program is to better understand how b cells are killed by the immune system and to test ways of protecting beta cells from these mechanisms. Because of the inaccessibility of the pancreas to study (particularly biopsy) in humans with diabetes, much of the proposed work will be carried out in b cells derived from non-obese diabetic (NOD) mice, the best available mouse model of type 1 diabetes. It is clear from the literature that a molecule called perforin found in cytoxic T lymphocytes (CTL) is a major, if not the major, mechanism the immune system uses against b cells. For this reason we will try to better understand the interaction between b cells and perforin and ultimately design ways of them from perforin-mediated cell death. It is equally clear that there are other mechanisms besides perforin that can cause b cell death and the program will also address discovery of these mechanisms and new ways to block them. Beta cells in NOD mice will be protected from perforin or other mechanisms by the addition of protective genes or removal of harmful genes using transgenic knockout technology. Addition or removal of genes involved in cell death can be done systematically and each protocol tested using NOD mouse model. The process of cell death that b cell undergo in type 1 diabetes is called apoptosis. Apoptosis is a general mechanism by which cells of all types die. Experts in the biology of apoptosis and perforin are important members of the program, providing the opportunity to translate the latest advances in cell death research to diabetes. This research addresses several of the specific research areas of interest to JDRF. It focuses on the prevention of b cell death in individuals with type 1 diabetes receiving islet transplants. It may be applicable in the future to protection of stem or precursor cells that have been differentiated into b cells or even to devising strategies to prevent the development of diabetes.