1型糖尿病是由胰腺β细胞损伤所导致的血糖稳态失调，β细胞的损伤是由CD4 T细胞和CD8 T细胞特异性识别众多致糖尿病性自身抗原表位所介导。使用静脉注射ECDI固定的同系脾细胞交叉连接多种糖尿病性抗原/表位（Ag-SP）诱导T细胞抗原特异性免疫耐受，结果表明表位扩展在非肥胖糖尿病小鼠的1型糖尿病病理过程中扮演重要角色。Ag-SP与完整的胰岛素偶联，或者与InsB（9-23）或InsB（15-23）偶联能够保护4-6周龄非肥胖糖尿病小鼠，防止其最终发展成临床糖尿病，降低胰岛的免疫细胞浸润，并以抗原特异性的方式阻断调节性T细胞依赖性的启发式抗原特异性迟发型超敏反应（DTH response）。但与GAD65（509-528），GAD65(524-543)或IGRP（206-214）偶联却无此效应； InsB（9-23）的外部胰岛素表位对疾病晚期阶段的病理机制十分重要；在诱导耐受的过程中，调节性T细胞是使用Ag-SP有效治疗所必须的。然而，在19-21周龄非肥胖糖尿病小鼠的耐受性诱导可仅通过Ins-SP有效完成，提示InsB（9-23）是一个起始的表位结构域，但在疾病发展过程中对胰岛素表位的自身免疫应答和InsB（9-23）的出现不一致。总之，我们的数据表明Ag-SP耐受能够阻止与免疫抑制及可溶性抗原诱导的过敏性休克相关的潜在的副作用，对长期保护非肥胖糖尿病鼠1型糖尿病发生发展具有有效的治疗作用。此外，这些结果还提示1型糖尿病的慢性病理机制与功能性表位扩展相关，在疾病的始发阶段与表位和胰岛素B链9-23区应答相关，而进展明显的疾病与表位和胰岛素的应答相关，有别于始发阶段的B链9-23区应答。

 Pathogenesis of NOD diabetes is initiated by reactivity to the insulin B chain 9-23 epitope and involves functional epitope spreading.
Type 1 diabetes (T1D) is mediated by destruction of pancreatic β-cells by CD4 and CD8 T cells specific for epitopes on numerous diabetogenic autoantigens resulting in loss of glucose homeostasis. Employing antigen-specific tolerance induced by i.v. administration of syngeneic splenocytes ECDI cross-linked to various diabetogenic antigens/epitopes (Ag-SP), we show that epitope spreading plays a functional role in the pathogenesis of T1D in NOD mice. Specifically, Ag-SP coupled with intact insulin, Ins B(9-23) or Ins B(15-23), but not GAD65(509-528), GAD65(524-543) or IGRP(206-214), protected 4-6 week old NOD mice from the eventual development of clinical disease; infiltration of immune cells to the pancreatic islets; and blocked the induction of DTH responses in a Treg-dependent, antigen-specific manner. However, tolerance induction in 19-21 week old NOD mice was effectively accomplished only by Ins-SP, suggesting Ins B(9-23) is a dominant initiating epitope, but autoimmune responses to insulin epitope(s) distinct from Ins B(9-23) emerge during disease progression.