Hybrid Peptides as Autoantigens for Diabetogenic CD4 T Cells

摘要 这一竞争性的更新应用是继续我们对杂交胰岛素肽(HIPS)作为 自身免疫性糖尿病中自身反应性CD4T细胞的新表位。在这段非常富有成效的时期，我们 已经确定由胰岛素C肽和其他β细胞颗粒蛋白形成的HIPS是 NOD小鼠胰腺中大量的自身反应性CD4T细胞可用于 诱导抗原特异性耐受，也存在于人胰岛和1型患者的PBMC中 糖尿病(T1D)。我们在奖项的下一阶段的目标将是表征新的胰岛素(INS)B- 在NOD小鼠和人类受试者中，链状髋关节和T细胞对这些髋关节起反应。我们假设 研究较多的胰岛素B链肽B：9-23的抗原性是由于 B：9-23和其他颗粒蛋白的裂解多肽产物的序列。追求的理由是 这些研究是基于初步数据表明，包含B9-23序列的B链HIP是 胰岛素反应性T细胞克隆的强烈激动剂以及对这些HIP有反应的T细胞可以在 NOD小鼠的多克隆T细胞群。我们在下一个项目阶段的目标是(1)调查 B链HIP反应性T细胞在疾病发病机制中的作用；(2)决定是否可以耐受 胰岛素B链HIPS偶联生物可降解纳米粒诱导的自发性NOD模型 疾病和胰岛移植；以及(3)调查B链HIP反应性CD4T细胞在 人类T1D，并开发含有B链髋关节的新人类四聚体。B链髋关节将提供 了解胰腺β细胞抗原的自身免疫反应的进一步工具，以及 特别是胰岛素反应性T细胞在疾病过程中的作用。我们预测这些研究 将导致不仅用于跟踪与疾病相关的T细胞的试剂的产生，而且还将用于开发和 扩大抗原特异性治疗的途径。

Abstract This competing renewal application is to continue our studies on the role of hybrid insulin peptides (HIPs) as neo-epitopes for autoreactive CD4 T cells in autoimmune diabetes. During this very productive period we have established that HIPs formed from insulin C-peptide and other β-cell granule proteins are antigens for large numbers of autoreactive CD4 T cells in the pancreas of NOD mice, can be used in strategies to induce antigen-specific tolerance, and are also present in human islets and PBMC of patients with type 1 diabetes (T1D). Our objective in the next period of the award will be to characterize new insulin (Ins) B- chain HIPs and T cells reactive to these HIPs, in both NOD mice and human subjects. We hypothesize that antigenicity of the much studied insulin B chain peptide, B:9-23, is due to hybrid peptide formation between sequences of B:9-23 and cleavage peptide products of other granule proteins. The rationale for pursuing these studies is based on preliminary data indicating that B-chain HIPs containing B9-23 sequences are strong agonists for insulin-reactive T cell clones and that T cells reactive to these HIPs can be identified in the polyclonal T cell population of NOD mice. Our aims for this next project period are to (1) investigate the role of B-chain HIP-reactive T cells in disease pathogenesis; (2) determine whether tolerance can be induced with insulin B-chain HIPs coupled to biodegradable nanoparticles in NOD models of spontaneous disease and islet transplantation; and (3) investigate the presence of B-chain HIP-reactive CD4 T cells in human T1D and develop new human tetramers containing B-chain HIPs. The B-chain HIPs will provide further tools for understanding the autoimmune response to pancreatic β-cell antigens in general, and specifically the contribution of insulin-reactive T cells to the disease process. We predict that these studies will lead to generation of reagents not only for tracking disease-relevant T cells, but also for developing and expanding approaches to antigen-specific therapy.