Altered B:9-23 insulin, when administered intranasally with cholera toxin adjuvant, suppresses the expression of insulin autoantibodies and prevents diabetes
Altered B:9-23 insulin, when administered intranasally with cholera toxin adjuvant, suppresses the expression of insulin autoantibodies and prevents diabetes
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DOI：
10.4049/jimmunol.179.4.2082
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发表时间：
2007-08-15
影响因子：
4.4
通讯作者：
Eguchi, Katsumi
中科院分区：
文献类型：
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作者：
Kobayashi, Masakazu;Abiru, Norio;Eguchi, Katsumi
胰岛素多肽B：9-23是I型糖尿病的主要自身抗原，含有两个不同的CD4表位(B：9-16和B：13-23)。两个表位之一B：13-23与CTL表位(B：15-23)重叠。在这项研究中，我们报告了通过13：16和19位氨基酸替换(与丙氨酸一起)(A16，19位改变的肽配体)或截断肽(B：9-21)的C末端氨基酸来消除13：9-23肽的CTL表位，这两种方法都没有刺激胰岛素13：15-23反应性CD8 T细胞的增殖，当与有效的粘膜佐剂毒素(CT)联合使用时，对糖尿病有显著的鼻腔诱导抑制作用。鼻腔注射A16，19可消除自发的胰岛素自身抗体，显著抑制胰岛素炎症，缓解高血糖，并防止进展为糖尿病。鼻腔注射国产B：9-23/CT或B：11-23/CT可显著增强胰岛素自身抗体的表达，并显著增加胰岛素炎症的严重程度，但不能预防糖尿病。我们目前的研究表明，去除13：9-23肽的CTL表位对于粘膜诱导的糖尿病预防至关重要。A16，19改变的多肽配体，而不是其他天然的胰岛素多肽，抑制与糖尿病保护和缓解相关的胰岛素自身抗体。
Insulin peptide B:9-23 is a major autoantigen in type I diabetes that contains two distinct CD4 epitopes (B:9-16 and B:13-23). One of the two epitopes, B:13-23, overlaps with a CTL epitope (B:15-23). In this study, we report that the elimination of the CTL epitope from the 13:9-23 peptide by amino acid substitution (with alanine) at positions 13:16 and 19 (A16,19 altered peptide ligand) or truncation of the C-terminal amino acids from the peptide (B:9-21), neither of which stimulated the proliferation of insulin 13:15-23 reactive CD8 T cells, provided significant intranasally induced suppression of diabetes when coadministered with a potent mucosal adjuvant cholera toxin (CT). Intranasal treatment with A16,19 resulted in the elimination of spontaneous insulin autoantibodies, significant inhibition of insulitis and remission from hyperglycemia, and prevented the progression to diabetes. Intranasal administration of native B:9-23/CT or B:11-23/CT resulted in a significant enhancement of insulin autoantibody expression and severity of insulitis and failed to prevent diabetes. Our present study indicates that elimination of the CTL epitope from the 13:9-23 peptide was critically important for mucosally induced diabetes prevention. The A16,19 altered peptide ligand, but not other native insulin peptides, suppresses insulin autoantibodies associated with protection from and remission of diabetes.