Project 3: Epitope Selection in Type 1 Diabetes

项目 3：1 型糖尿病的表位选择

• 批准号: 9151390
• 负责人: JOHN W KAPPLER
• 金额: $ 39.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-08 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9151390
• 关键词: Agonist; Antigens; Appearance; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Back; Beta Cell; Binding; CD4 Positive T Lymphocytes; CHGA gene; Cells; Chromogranin A; Collaborations; Data; Development; Disease; Engineering; Epitopes; Eragrostis; Female; Genes; Genetic; Genetic Polymorphism; Goals; Human; Immune; Immune system; Immunization; Inbred NOD Mice; Incidence; Infection; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Knowledge; Lead; Major Histocompatibility Complex Gene; Modification; Monitor; Mus; Mutation; Organ; Pancreas; Patients; Peptides; Peripheral; Proteins; Regulatory T-Lymphocyte; Research; Risk; Self Tolerance; Specificity; Staging; Structure of beta Cell of islet; T-Lymphocyte; Testing; Thymus Gland; Tissues; Work; abstracting; anergy; beef; central tolerance; diabetic; diabetogenic; fighting; nuclease; peripheral tolerance; prevent; receptor; risk variant; vector

Project Summary/Abstract – Project 3 Type-1 diabetes (T1D) is a serious autoimmune disease, whose incidence has been steadily increasing in recent years. It results from an immune attack on the pancreas by the patients T cells that selectively eliminates the insulin-producing beta cells that reside in the organs Islets of Langerhans eventually. The risk of developing T1D is tied to both environmental and genetic factors. The main genetic factor is tied to the polymorphisms in the genes encoding Class II molecules within the major histocompatibility gene complex (MHCII). The usual function of MHCII molecules is usually to capture antigenic peptides derived from foreign proteins for presentation to and activation of CD4+ T cells in order direct these cells fight off infections. Since MHCII molecules can also capture and present peptides derived the host's own protein, the immune system has developed an elaborate two stage mechanism for preventing these self-peptides from inducing an autoimmune response against the hosts on tissues. The first stage involves a pre-check of CD4+ T cells in the thymus early in their development eliminating T cell whose antigen recognizing receptor (TCR) can engage an MHCII molecule containing a self-peptide. The second stage involves a set of regulatory T cells in the peripheral organs to deal with T cells that have somehow escaped the thymic pre-check. However, under the right conditions some of CD4+ T cells specific for certain peptides derived from pancreatic islet proteins sneak through both of these filters to cause T1D. The main objective of Project 3 is to determine why the T cells specific some pancreatic peptides are deleted in the thymus, while others are not, and to see if this information can be used to beef up the peripheral regulatory T cells to prevent the activation of the escapees. In Project 3 our main hypothesis is that the thymic escapees recognize peptides that bind poorly in the thymus to the relevant MHCII risk alleles and therefore break through the thymic first filter. We will test this hypothesis by altering the expression of various pancreatic peptides in the thymus to see what effect this has on the appearance of CD4+ T cells of those specificities. We will also test the idea that by engineering the relevant peptide to bind better to the MHCII risk alleles we can create a “super agonist” that can be used to delete pathogenic T cells or to boost the activity of the peripheral regulatory T cells to prevent the activation of the pathogenic ones.

项目摘要/摘要 - 项目3 1型糖尿病（T1D）是一种严重的自身免疫性疾病，其事件一直稳定 近年来增加。它是由患者T细胞对胰腺的免疫攻击引起的 有选择地消除了存在于机器人胰岛的产生胰岛素的β细胞 兰格汉斯最终。发展T1D的风险与环境和遗传因素均息息相关。 主要的遗传因素与编码II类分子的基因中的多态性有关 主要的组织相容性基因复合物（MHCII）。 MHCII分子的通常功能通常是捕获从 外国蛋白质以呈现和激活CD4+ T细胞的激活，以便将这些细胞抗击 感染。由于MHCII分子也可以捕获并呈现Petides衍生出宿主自己的 蛋白质，免疫系统开发了一种精心的两级机制，以防止这些机制 来自组织上宿主的自肽诱导自身免疫反应。第一阶段 涉及在胸腺中早期检查CD4+ T细胞的前检查，从而消除了T细胞Who的T细胞 抗原识别受体（TCR）可以参与含有自肽的MHCII分子。这 第二阶段涉及外围器官中的一组调节性T细胞，以处理具有的T细胞 不知何故逃脱了胸腺预检查。但是，在正确的条件下，一些CD4+ T细胞 针对源自胰岛胰岛蛋白的某些宠物，这两个过滤器潜入 引起T1D。项目3的主要目的是确定为什么T细胞特定于某些 胰腺pet在百里香中被删除，而其他胰腺则没有，并且查看此信息是否可以 用于加强外围调节T细胞以防止逃生者的激活。 在项目3中，我们的主要假设是胸腺逃避者识别肽结合不佳的肽 相关MHCII的胸腺风险等位基因，因此突破了胸腺第一过滤器。我们 将通过改变胸腺中各种胰胡椒粉的表达来检验这一假设 这对这些特异性的CD4+ T细胞的外观有何影响。我们还将测试 通过工程化相关肽以更好地绑定到MHCII风险等位基因，我们可以创建一个 可用于删除致病性T细胞或增强周围活性的“超级激动剂” 调节性T细胞以防止致病性的细胞激活。