Translational Immunology Program, Benaroya Research Institute, Seattle, Washington, USA.
Diabetes. 2012 Sep;61(9):2340-8. doi: 10.2337/db12-0049. Epub 2012 Jun 20.
Rapamycin/interleukin-2 (IL-2) combination treatment of NOD mice effectively treats autoimmune diabetes. We performed a phase 1 clinical trial to test the safety and immunologic effects of rapamycin/IL-2 combination therapy in type 1 diabetic (T1D) patients. Nine T1D subjects were treated with 2-4 mg/day rapamycin orally for 3 months and 4.5 × 10(6) IU IL-2 s.c. three times per week for 1 month. β-Cell function was monitored by measuring C-peptide. Immunologic changes were monitored using flow cytometry and serum analyses. Regulatory T cells (Tregs) increased within the first month of therapy, yet clinical and metabolic data demonstrated a transient worsening in all subjects. The increase in Tregs was transient, paralleling IL-2 treatment, whereas the response of Tregs to IL-2, as measured by STAT5 phosphorylation, increased and persisted after treatment. No differences were observed in effector T-cell subset frequencies, but an increase in natural killer cells and eosinophils occurred with IL-2 therapy. Rapamycin/IL-2 therapy, as given in this phase 1 study, resulted in transient β-cell dysfunction despite an increase in Tregs. Such results highlight the difficulties in translating therapies to the clinic and emphasize the importance of broadly interrogating the immune system to evaluate the effects of therapy.
雷帕霉素/白细胞介素-2（IL-2）联合治疗 NOD 小鼠可有效治疗自身免疫性糖尿病。我们进行了一项 1 期临床试验，以测试雷帕霉素/IL-2 联合疗法在 1 型糖尿病（T1D）患者中的安全性和免疫效果。9 名 T1D 患者接受了为期 3 个月的 2-4 mg/天雷帕霉素口服治疗和为期 1 个月的每周 3 次皮下注射 4.5×10(6)IU IL-2。通过测量 C 肽监测β细胞功能。使用流式细胞术和血清分析监测免疫变化。治疗的第一个月内 Treg 增加，但临床和代谢数据表明所有患者的病情都暂时恶化。Treg 的增加是短暂的，与 IL-2 治疗平行，而 Treg 对 IL-2 的反应，如 STAT5 磷酸化所示，在治疗后增加并持续存在。效应 T 细胞亚群的频率没有差异，但在接受 IL-2 治疗时，自然杀伤细胞和嗜酸性粒细胞增加。尽管 Treg 增加，但本 1 期研究中给予的雷帕霉素/IL-2 治疗导致短暂的β细胞功能障碍。这些结果突出了将治疗转化为临床的困难，并强调了广泛研究免疫系统以评估治疗效果的重要性。
