Transgenically induced GAD tolerance curtails the development of early beta-cell autoreactivities but causes the subsequent development of supernormal autoreactivities to other beta-cell antigens.
Transgenically induced GAD tolerance curtails the development of early beta-cell autoreactivities but causes the subsequent development of supernormal autoreactivities to other beta-cell antigens.
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DOI：
10.2337/db08-0851
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发表时间：
2009-12
期刊：
影响因子：
7.7
通讯作者：
Kaufman DL
中科院分区：
文献类型：
--
作者：
Tian J;Dang H;von Boehmer H;Jaeckel E;Kaufman DL
目的研究GAD 65转基因（GAD-tg）NOD小鼠对GAD 65的耐受性如何影响对其他β细胞自身抗原（β-CAAs）的自身免疫。我们使用ELISPOT来表征不同年龄GAD-tg小鼠及其NOD小鼠同窝仔中T细胞对GAD 65和其他β-CAA应答的频率和功能表型。在年轻的GAD-tg小鼠中，Th 1对GAD 65的主导决定簇的反应是年轻NOD小鼠的13 - 18%。这与Th 1对其他β-CAA的反应大幅降低相一致。显然，GAD 65反应性T细胞对于激活和/或扩大NOD小鼠的早期自身反应性非常重要。随着GAD-tg小鼠年龄的增长，它们对GAD 65的T细胞反应仍然很低，但它们对其他β-CAA产生了超常的脾和胰腺淋巴结T细胞自身免疫。显然，许多GAD 65反应性T细胞的消除/损伤允许其他β-CAA反应性T细胞最终在更大程度上扩增，这可能是通过减少对抗原呈递细胞的竞争或靶组织中的稳态增殖，这可以解释GAD-tg小鼠的常见疾病发病率。转基因诱导的GAD 65自身反应性降低减少了对其他β-CAA的早期T细胞应答的发展。然而，在以后的生活中，β-CAA反应性T细胞扩展到超常水平。这些数据表明，早期β细胞自身反应性相互依赖于支持以激活和扩增，而在疾病过程的后期，自身抗原特异性T细胞库可以自主扩增。这些发现对于理解1型糖尿病的免疫发病机制和设计基于抗原的免疫治疗药物具有重要意义。
To study how tolerance to GAD65 affects the development of autoimmunity to other β-cell autoantigens (β-CAAs) in GAD65-transgenic (GAD-tg) NOD mice. We used ELISPOT to characterize the frequency and functional phenotype of T-cell responses to GAD65 and other β-CAAs at different ages in GAD-tg mice and their NOD mouse littermates. In young GAD-tg mice, Th1 responses to GAD65's dominant determinants were 13−18% of those in young NOD mice. This coincided with a great reduction in Th1 responses to other β-CAAs. Evidently, GAD65-reactive T-cells are important for activating and/or expanding early autoreactivities in NOD mice. As GAD-tg mice aged, their T-cell responses to GAD65 remained low, but they developed supernormal splenic and pancreatic lymph node T-cell autoimmunity to other β-CAAs. Apparently, the elimination/impairment of many GAD65-reactive T-cells allowed other β-CAA–reactive T-cells to eventually expand to a greater extent, perhaps by reducing competition for antigen-presenting cells, or homeostatic proliferation in the target tissue, which may explain the GAD-tg mouse's usual disease incidence. Transgenically induced reduction of GAD65 autoreactivity curtailed the development of early T-cell responses to other β-CAAs. However, later in life, β-CAA–reactive T-cells expanded to supernormal levels. These data suggest that early β-cell autoreactivities are mutually dependent for support to activate and expand, while later in the disease process, autoantigen-specific T-cell pools can expand autonomously. These findings have implications for understanding type 1 diabetes immunopathogenesis and for designing antigen-based immunotherapeutics.
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通过在胰腺淋巴结中发育调节的胰岛细胞抗原的发育表现来启动自身免疫性糖尿病。
DOI：
10.1084/jem.189.2.331
发表时间：
1999-01-18
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Höglund P;Mintern J;Waltzinger C;Heath W;Benoist C;Mathis D
通讯作者：
Mathis D
影响因子：
3.2
作者：
Chao, CC;McDevitt, HO
通讯作者：
McDevitt, HO
DOI：
10.1073/pnas.95.17.10055
发表时间：
1998-08-18
影响因子：
11.1
作者：
Geng, LP;Solimena, M;Hayday, AC
通讯作者：
Hayday, AC
影响因子：
15.9
作者：
MUIR, A;PECK, A;MACLAREN, N
通讯作者：
MACLAREN, N
影响因子：
64.8
作者：
Nakayama, M;Abiru, N;Eisenbarth, GS
通讯作者：
Eisenbarth, GS