Parker Matthew J, Xue Song, Alexander John J, Wasserfall Clive H, Campbell-Thompson Martha L, Battaglia Manuela, Gregori Silvia, Mathews Clayton E, Song Sihong, Troutt Misty, Eisenbeis Scott, Williams John, Schatz Desmond A, Haller Michael J, Atkinson Mark A
Department of Pathology, University of Florida, Gainesville, Florida, USA.
Diabetes. 2009 Oct;58(10):2277-84. doi: 10.2337/db09-0557. Epub 2009 Jul 23.
The autoimmune destruction of beta-cells in type 1 diabetes results in a loss of insulin production and glucose homeostasis. As such, an immense interest exists for the development of therapies capable of attenuating this destructive process through restoration of proper immune recognition. Therefore, we investigated the ability of the immune-depleting agent antithymocyte globulin (ATG), as well as the mobilization agent granulocyte colony-stimulating factor (GCSF), to reverse overt hyperglycemia in the nonobese diabetic (NOD) mouse model of type 1 diabetes.
Effects of each therapy were tested in pre-diabetic and diabetic female NOD mice using measurements of glycemia, regulatory T-cell (CD4+CD25+Foxp3+) frequency, insulitis, and/or beta-cell area.
Here, we show that combination therapy of murine ATG and GCSF was remarkably effective at reversing new-onset diabetes in NOD mice and more efficacious than either agent alone. This combination also afforded durable reversal from disease (>180 days postonset) in animals having pronounced hyperglycemia (i.e., up to 500 mg/dl). Additionally, glucose control improved over time in mice subject to remission from type 1 diabetes. Mechanistically, this combination therapy resulted in both immunological (increases in CD4-to-CD8 ratios and splenic regulatory T-cell frequencies) and physiological (increase in the pancreatic beta-cell area, attenuation of pancreatic inflammation) benefits.
In addition to lending further credence to the notion that combination therapies can enhance efficacy in addressing autoimmune disease, these studies also support the concept for utilizing agents designed for other clinical applications as a means to expedite efforts involving therapeutic translation.
1型糖尿病中β细胞的自身免疫性破坏导致胰岛素生成和葡萄糖稳态丧失。因此，人们对开发能够通过恢复适当的免疫识别来减轻这种破坏过程的疗法有着极大的兴趣。为此，我们研究了免疫耗竭剂抗胸腺细胞球蛋白（ATG）以及动员剂粒细胞集落刺激因子（GCSF）逆转1型糖尿病非肥胖糖尿病（NOD）小鼠模型中明显高血糖的能力。
在糖尿病前期和糖尿病雌性NOD小鼠中测试每种疗法的效果，测量血糖、调节性T细胞（CD4 + CD25 + Foxp3 +）频率、胰岛炎和/或β细胞面积。
在此，我们表明鼠源ATG和GCSF联合治疗在逆转NOD小鼠新发糖尿病方面非常有效，且比单独使用任何一种药物更有效。这种联合治疗还使高血糖明显（即高达500 mg/dl）的动物实现了疾病的持久逆转（发病后>180天）。此外，1型糖尿病缓解小鼠的血糖控制随着时间的推移有所改善。从机制上讲，这种联合治疗带来了免疫（CD4与CD8比率增加和脾脏调节性T细胞频率增加）和生理（胰腺β细胞面积增加、胰腺炎症减轻）两方面的益处。
这些研究除了进一步证明联合疗法可提高治疗自身免疫性疾病的疗效外，还支持利用为其他临床应用设计的药物来加快治疗转化研究的理念。
