Fiorina Paolo, Vergani Andrea, Dada Shirine, Jurewicz Mollie, Wong Masie, Law Kenneth, Wu Erxi, Tian Ze, Abdi Reza, Guleria Indira, Rodig Scott, Dunussi-Joannopoulos Kyri, Bluestone Jeffrey, Sayegh Mohamed H
Transplantation Research Center, Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Diabetes. 2008 Nov;57(11):3013-24. doi: 10.2337/db08-0420. Epub 2008 Aug 8.
To investigate a B-cell-depleting strategy to reverse diabetes in naïve NOD mice.
We targeted the CD22 receptor on B-cells of naïve NOD mice to deplete and reprogram B-cells to effectively reverse autoimmune diabetes.
Anti-CD22/cal monoclonal antibody (mAb) therapy resulted in early and prolonged B-cell depletion and delayed disease in pre-diabetic mice. Importantly, when new-onset hyperglycemic mice were treated with the anti-CD22/cal mAb, 100% of B-cell-depleted mice became normoglycemic by 2 days, and 70% of them maintained a state of long-term normoglycemia. Early therapy after onset of hyperglycemia and complete B-cell depletion are essential for optimal efficacy. Treated mice showed an increase in percentage of regulatory T-cells in islets and pancreatic lymph nodes and a diminished immune response to islet peptides in vitro. Transcriptome analysis of reemerging B-cells showed significant changes of a set of proinflammatory genes. Functionally, reemerging B-cells failed to present autoantigen and prevented diabetes when cotransferred with autoreactive CD4(+) T-cells into NOD.SCID hosts.
Targeting CD22 depletes and reprograms B-cells and reverses autoimmune diabetes, thereby providing a blueprint for development of novel therapies to cure autoimmune diabetes.
研究一种B细胞清除策略，以逆转初发非肥胖糖尿病（NOD）小鼠的糖尿病状态。
我们靶向初发NOD小鼠B细胞上的CD22受体，以清除并重新编程B细胞，从而有效逆转自身免疫性糖尿病。
抗CD22/钙单克隆抗体（mAb）治疗导致糖尿病前期小鼠早期且持久的B细胞清除，并延缓疾病进展。重要的是，当新发高血糖小鼠接受抗CD22/钙mAb治疗时，100%的B细胞清除小鼠在2天内血糖恢复正常，其中70%维持长期血糖正常状态。高血糖发作后早期治疗及完全清除B细胞对于获得最佳疗效至关重要。治疗后的小鼠胰岛和胰腺淋巴结中调节性T细胞百分比增加，体外对胰岛肽的免疫反应减弱。对重新出现的B细胞进行转录组分析显示一组促炎基因有显著变化。在功能上，重新出现的B细胞无法呈递自身抗原，当与自身反应性CD4(+)T细胞共移植到NOD.SCID宿主中时可预防糖尿病。
靶向CD22可清除并重新编程B细胞，逆转自身免疫性糖尿病，从而为开发治愈自身免疫性糖尿病的新疗法提供了蓝图。
