Prevention of diabetes by manipulation of anti-IGRP autoimmunity:: high efficiency of a low-affinity peptide
Prevention of diabetes by manipulation of anti-IGRP autoimmunity:: high efficiency of a low-affinity peptide
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DOI：
10.1038/nm1250
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发表时间：
2005-06-01
期刊：
影响因子：
82.9
通讯作者：
Santamaria, P
中科院分区：
文献类型：
--
作者：
Han, BY;Serra, P;Santamaria, P
抗原疗法对于预防自身免疫有很大希望。然而，大多数临床试验都失败了，这表明指导治疗选择的原则仍然不明确。在这里，我们检查了CD8+T细胞改变的肽配体的抗糖尿病特性，这些配体识别胰岛特异性葡萄糖6-磷酸酶催化亚基相关蛋白（IGRP（206-214））的表位，IGRP（206-214）是自身免疫性糖尿病中普遍存在的自身反应性T细胞群体。我们发现，非肥胖糖尿病小鼠中的胰岛相关 CD8(+) T 细胞可识别大量 IGRP 表位，并且这些细胞在旨在诱导 IGRP(206-214) 特异性耐受的方案的结果中发挥作用。靶向 IGRP(206-214) 反应性 T 细胞的配体可预防疾病，但仅限于不产生低亲和力克隆型的剂量。值得注意的是，IGRP（206-214）反应性T细胞库的接近完全耗尽增强了次显性特异性的募集，并且没有减弱糖尿病的发生。因此，在促进非致病性、低亲和力克隆型占据靶器官淋巴细胞生态位的条件下，自身免疫肽疗法最有效。
Antigen therapy may hold great promise for the prevention of autoimmunity; however, most clinical trials have failed, suggesting that the principles guiding the choice of treatment remain ill defined. Here, we examine the antidiabetogenic properties of altered peptide ligands of CD8(+) T cells recognizing an epitope of islet-specific glucose-6-phosphatase catalytic subunit - related protein (IGRP(206-214)), a prevalent population of autoreactive T cells in autoimmune diabetes. We show that islet-associated CD8(+) T cells in nonobese diabetic mice recognize numerous IGRP epitopes, and that these cells have a role in the outcome of protocols designed to induce IGRP(206-214)-specific tolerance. Ligands targeting IGRP(206-214)-reactive T cells prevented disease, but only at doses that spared low-avidity clonotypes. Notably, near complete depletion of the IGRP(206-214)-reactive T-cell pool enhanced the recruitment of subdominant specificities and did not blunt diabetogenesis. Thus, peptide therapy in autoimmunity is most effective under conditions that foster occupation of the target organ lymphocyte niche by nonpathogenic, low-avidity clonotypes.