Protease-resistant human GAD-derived altered peptide ligands decrease TNF-α and IL-17 production in peripheral blood cells from patients with type 1 diabetes mellitus
Protease-resistant human GAD-derived altered peptide ligands decrease TNF-α and IL-17 production in peripheral blood cells from patients with type 1 diabetes mellitus
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DOI：
10.1016/j.molimm.2009.05.007
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发表时间：
2009-08-01
影响因子：
3.6
通讯作者：
Burster, Timo
中科院分区：
文献类型：
--
作者：
Boehm, Bernhard O.;Rosinger, Silke;Burster, Timo
谷氨酸脱羧酶65（GAD）和胰岛素原是驱动自身反应性T细胞的主要糖尿病相关自身抗原。改变的肽配体（APL）已被提议作为用于修饰自身免疫反应的试剂。在这里，我们已经制备了GAD衍生的蛋白酶抗性APL（prAPL）的切割位点定向修饰。产生的prAPL对溶酶体和血清蛋白酶具有抗性，与HLA-DRB 1（.）并且在血清中具有延长的半衰期。GAD衍生的prAPL显着降低GAD特异性人T细胞克隆的促炎细胞因子的分泌。同样地，当用GAD和GAD衍生的prAPL刺激时，I型糖尿病（T1 D）患者外周血淋巴细胞产生IL-17、TNF-α和分泌IL-6减少。0401减轻了GAD反应性人Th 17细胞的应答。设计特异性免疫调节蛋白酶抗性改变肽配体的策略为治疗干预的新途径提供了基础。(C)2009爱思唯尔有限公司版权所有。
Glutamic acid decarboxylase 65 (GAD) and proinsulin are major diabetes-associated autoantigens that drive autoreactive T cells. Altered peptide ligands (APL) have been proposed as reagents for the modification of autoimmune reactions. Here, we have prepared GAD-derived protease-resistant APL (prAPL) by cleavage site-directed modification. The resulting prAPL are resistant to lysosomal and serum proteases, bind with high-affinity to HLA-DRB1(.)0401 and have a prolonged half-life in the serum. GAD-derived prAPL significantly decreased the secretion of proinflammatory cytokines by a GAD-specific human T cell clone. Likewise, the production of IL-17, TNF-alpha, and secretion of IL-6 by peripheral blood lymphocytes from patients with type I diabetes mellitus (T1D) was reduced, when stimulated with both GAD and GAD-derived prAPL Thus, prAPL with high affinity for HLA-DRB1(.)0401 mitigate the response of GAD-reactive human Th17 cells. The strategy of designing specific immunomodulatory protease-resistant altered peptide ligands provides the basis for novel avenues of therapeutic intervention. (C) 2009 Elsevier Ltd. All rights reserved.