Protection of nonobese diabetic mice from diabetes by intranasal or subcutaneous administration of insulin peptide B-(9-23)
Protection of nonobese diabetic mice from diabetes by intranasal or subcutaneous administration of insulin peptide B-(9-23)
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DOI：
10.1073/pnas.93.2.956
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发表时间：
1996-01-23
影响因子：
11.1
通讯作者：
Wegmann, DR
中科院分区：
文献类型：
--
作者：
Daniel, D;Wegmann, DR
观察到显性I型糖尿病通常先于胰岛素自身抗体的出现，以及对生物繁殖糖尿病易感性（BB-DP）大鼠、非肥胖糖尿病小鼠（NOD）小鼠和人类受试者预防性给予胰岛素可预防糖尿病的报道表明，对胰岛素的免疫反应参与了β细胞破坏的过程。我们最近报道了从NOD小鼠中分离的胰岛浸润细胞富含胰岛素特异性T细胞，胰岛素特异性T细胞克隆能够过继转移糖尿病，并且存在于B链残基9-23上的表位似乎在这种自发反应中占主导地位。在本报告中描述的实验中，我们对312个独立分离的胰岛素特异性T细胞克隆的表位特异性进行了测定，发现B-(9-23)占主导地位，93%的克隆对该肽具有特异性，其余克隆对A链残基7-21上的表位具有特异性。在这些观察的基础上，我们确定了皮下或鼻内给药B-(9-23)对NOD小鼠糖尿病发病率的影响。本研究的结果表明，与给予对照肽破伤风毒素的小鼠相比，皮下和鼻内给予B-(9-23)可显著延缓糖尿病的发病，并降低糖尿病的发病率。这种保护作用与B-(9-23)处理小鼠中t细胞对B-(9-23)的增殖反应降低有关。
The observation that overt type I diabetes is often preceded by the appearance of insulin autoantibodies and the reports that prophylactic administration of insulin to biobreeding diabetes-prone (BB-DP) rats, nonobese diabetic (NOD) mice, and human subjects results in protection from diabetes suggest that an immune response to insulin is involved in the process of beta cell destruction. We have recently reported that islet-infiltrating cells isolated from NOD mice are enriched for insulin-specific T cells, that insulin-specific T cell clones are capable of adoptive transfer of diabetes, and that epitopes present on residues 9-23 of the B chain appear to be dominant in this spontaneous response. In the experiments described in this report, the epitope specificity of 312 independently isolated insulin-specific T cell clones was determined and B-(9-23) was found to be dominant, with 93% of the clones exhibiting specificity toward this peptide and the remainder to an epitope on residues 7-21 of the A chain. On the basis of these observations, the effect of either subcutaneous or intranasal administration of B-(9-23) on the incidence of diabetes in NOD mice was determined. The results presented here indicate that both subcutaneous and intranasal administration of B-(9-23) resulted in a marked delay in the onset and a decrease in the incidence of diabetes relative to mice given the control peptide, tetanus toxin-(830-843). This protective effect is associated with reduced T-cell proliferative response to B-(9-23) in B-(9-23)-treated mice.