Long-term remission of diabetes in NOD mice is induced by nondepleting anti-CD4 and anti-CD8 antibodies.
Long-term remission of diabetes in NOD mice is induced by nondepleting anti-CD4 and anti-CD8 antibodies.
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作者：
Yi Z;Diz R;Martin AJ;Morillon YM;Kline DE;Li L;Wang B;Tisch R
在1型糖尿病临床发作时发现的残留β细胞如果从持续的自身免疫破坏中拯救出来，足以控制高血糖症。然而，挑战在于开发一种免疫疗法，不仅选择性抑制糖尿病反应并有效逆转糖尿病，而且还建立长期β细胞特异性耐受以维持缓解。在目前的研究中，我们表明，短期的非消耗性抗体（抗体）的CD 4和CD 8辅助受体的特异性迅速逆转临床疾病在最近发病的糖尿病NOD小鼠。一旦建立，缓解无限期维持，对外来抗原的免疫力未受损。缓解的诱导包括胰腺和引流胰腺淋巴结的选择性T细胞净化以及胰腺驻留抗原呈递细胞对转化生长因子（TGF）-β1的上调。TGF-β的中和阻断了缓解的诱导。相反，缓解的维持与组织特异性免疫调节T细胞相关。这些发现表明，使用CD 4和CD 8特异性非消耗性Ab是在临床糖尿病发作时建立长期β细胞特异性T细胞耐受性的稳健方法。
Residual β-cells found at the time of clinical onset of type 1 diabetes are sufficient to control hyperglycemia if rescued from ongoing autoimmune destruction. The challenge, however, is to develop an immunotherapy that not only selectively suppresses the diabetogenic response and efficiently reverses diabetes, but also establishes long-term β-cell–specific tolerance to maintain remission. In the current study, we show that a short course of nondepleting antibodies (Abs) specific for the CD4 and CD8 coreceptors rapidly reversed clinical disease in recent-onset diabetic NOD mice. Once established, remission was maintained indefinitely and immunity to foreign antigens unimpaired. Induction of remission involved selective T-cell purging of the pancreas and draining pancreatic lymph nodes and upregulation of transforming growth factor (TGF)-β1 by pancreas-resident antigen-presenting cells. Neutralization of TGF-β blocked the induction of remission. In contrast, maintenance of remission was associated with tissue-specific immunoregulatory T cells. These findings demonstrate that the use of nondepleting Ab specific for CD4 and CD8 is a robust approach to establish long-term β-cell–specific T-cell tolerance at the onset of clinical diabetes.
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DOI：
10.1084/jem.20110767
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kendal AR;Chen Y;Regateiro FS;Ma J;Adams E;Cobbold SP;Hori S;Waldmann H
通讯作者：
Waldmann H
影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
10.9
作者：
Brown, Melissa L.;Schneyer, Alan L.
通讯作者：
Schneyer, Alan L.
影响因子：
15.3
作者：
Herman, AE;Freeman, GJ;Benoist, C
通讯作者：
Benoist, C
影响因子：
5.4
作者：
Green, Daniel S.;Center, David M.;Cruikshank, William W.
通讯作者：
Cruikshank, William W.