CD8+ T lymphocytes specific for glutamic acid decarboxylase 90-98 epitope mediate diabetes in NOD SCID mouse.
CD8+ T lymphocytes specific for glutamic acid decarboxylase 90-98 epitope mediate diabetes in NOD SCID mouse.
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DOI：
10.1016/j.molimm.2007.01.008
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发表时间：
2007-04
影响因子：
3.6
通讯作者：
S. Sévère;A. Gauvrit;A. Vu;J. Bach
中科院分区：
文献类型：
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作者：
S. Sévère;A. Gauvrit;A. Vu;J. Bach
在过去的十年中，谷氨酸脱羧酶(GAD)被认为是一种关键的β细胞自身抗原，与NOD小鼠和人类的1型糖尿病有关。近年来，广泛性AD的发病机制仍存在争议。在NOD小鼠中，以前的一些研究支持GAD特异性CD_4~+T细胞的调节作用，到目前为止还没有发现GAD特异性的糖尿病致病CD_8~+T细胞，这否定了GAD在β细胞损伤中的重要性。在NOD模型中，我们使用编码GAD的质粒免疫来识别相关的GAD CD8+T细胞表位(GAD90-98)，这是一种依赖于体内处理来自自身抗原蛋白的多肽的方案。在NOD幼稚雌性小鼠胰腺淋巴结中，在侵袭性胰腺炎早期(4~8周龄)检测到识别GAD90-98肽的CD8+T细胞，提示CD8+T细胞在疾病的第一阶段起重要作用。GAD90-98特异性CD8+淋巴细胞在体外能有效地裂解胰岛细胞，并将糖尿病转移到NODSCID小鼠体内(100%)。3周龄NOD雌性小鼠腹腔注射糖尿病后，糖尿病明显加速。通过GAD90-98，加强GAD特异性CTL在糖尿病发病机制中的作用。
During the past decade, glutamic acid decarboxylase (GAD) has been considered a crucial β-cell autoantigen involved in type 1 diabetes in the NOD mouse and human. Recently, the etiological role of GAD has remained controversy. In the NOD mouse, some previous studies argued in favor of a regulatory role for GAD-specific CD4+T cells, and no diabetogenic CD8+T cells specific for GAD have been identified so far, discrediting the importance of GAD in β-cell injury. Here, we identified, in the NOD model, a relevant GAD CD8+T cell epitope (GAD90–98) using immunization with a plasmid encoding GAD, a protocol relying on in vivo processing of peptides from the autoantigenic protein. In pancreatic lymph nodes of naïve female NOD mice, CD8+T lymphocytes recognizing GAD90–98peptide were detected during the initial phase of invasive insulitis (between 4 and 8 weeks of age), suggesting an important role for these cells in the first stage of the disease. GAD90–98specific CD8+lymphocytes lysed efficiently islet cells in vitro and transferred diabetes into NODSCIDmice (100%). Finally, diabetes was accelerated greatly in 3-week-old female NOD mice injected i.p. with GAD90–98, strengthening the role of GAD-specific CTLs in diabetes pathogenesis.