Combination treatment with anti-CD20 and oral anti-CD3 prevents and reverses autoimmune diabetes.
Combination treatment with anti-CD20 and oral anti-CD3 prevents and reverses autoimmune diabetes.
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作者：
Hu C;Ding H;Zhang X;Wong FS;Wen L
1 型糖尿病 (T1D) 是一种 T 细胞介导的自身免疫性疾病，尽管 B 细胞在 T1D 的发展中也发挥着重要作用。 T 细胞和 B 细胞定向免疫疗法均已显示出预防和逆转 T1D 的功效。然而，针对T细胞和B细胞的联合策略是否可以进一步提高治疗效果仍有待探索。我们发现，静脉注射抗人 CD20 (hCD20) 和口服抗 CD3 联合治疗可显着延缓糖尿病前期 hCD20 转基因 NOD 小鼠的糖尿病发展。更重要的是，联合治疗可以逆转 60% 以上新诊断患有糖尿病的小鼠的糖尿病。进一步的机制研究表明，在 B 细胞清除疗法中添加口服抗 CD3 可以协同增强调节性 T 细胞的抑制功能。值得注意的是，口服抗 CD3 治疗通过产生 IL-10 和 IL-27 的树突细胞诱导小肠中产生一小部分白细胞介素 (IL)-10 的 CD4 T 细胞。因此，研究结果表明，联合抗CD20和口服抗CD3在恢复糖尿病NOD小鼠血糖正常方面优于抗CD20单一疗法，为优化B细胞导向的T1D治疗提供了重要的临床前证据。
Type 1 diabetes (T1D) is a T cell–mediated autoimmune disease, although B cells also play an important role in T1D development. Both T cell– and B cell–directed immunotherapies have shown efficacy in the prevention and reversal of T1D. However, whether the combined strategy of targeting both T and B cells could further improve therapeutic efficacy remains to be explored. We show that combined treatment with intravenous antihuman CD20 (hCD20) and oral anti-CD3 significantly delays diabetes development in prediabetic hCD20 transgenic NOD mice. More importantly, the combined treatment reverses diabetes in >60% of mice newly diagnosed with diabetes. Further mechanistic studies demonstrated that the addition of oral anti-CD3 to the B-cell depletion therapy synergistically enhances the suppressive function of regulatory T cells. Of note, the oral anti-CD3 treatment induced a fraction of interleukin (IL)-10–producing CD4 T cells in the small intestine through IL-10– and IL-27–producing dendritic cells. Thus, the findings demonstrate that combining anti-CD20 and oral anti-CD3 is superior to anti-CD20 monotherapy for restoring normoglycemia in diabetic NOD mice, providing important preclinical evidence for the optimization of B cell–directed therapy for T1D.
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DOI：
10.4049/jimmunol.1101590
发表时间：
2012-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Hu C;Du W;Zhang X;Wong FS;Wen L
通讯作者：
Wen L
影响因子：
168.9
作者：
Sherry, Nicole;Hagopian, William;Ludvigsson, Johnny;Jain, Sunil M.;Wahlen, Jack;Ferry, Robert J., Jr.;Bode, Bruce;Aronoff, Stephen;Holland, Christopher;Carlin, David;King, Karen L.;Wilder, Ronald L.;Pillemer, Stanley;Bonvini, Ezio;Johnson, Syd;Stein, Kathryn E.;Koenig, Scott;Herold, Kevan C.;Daifotis, Anastasia G.
通讯作者：
Daifotis, Anastasia G.
影响因子：
82.9
作者：
Ochi, Hirofumi;Abraham, Michal;Weiner, Howard L.
通讯作者：
Weiner, Howard L.
影响因子：
20.3
作者：
Keymeulen, Bart;Candon, Sophie;Chatenoud, Lucienne
通讯作者：
Chatenoud, Lucienne
影响因子：
15.9
作者：
Hu, Chang-Yun;Rodriguez-Pinto, Daniel;Wen, Li
通讯作者：
Wen, Li