La Jolla Institute for Allergy and Immunology, Diabetes Center, La Jolla, CA, USA.
PLoS One. 2013;8(2):e54712. doi: 10.1371/journal.pone.0054712. Epub 2013 Feb 6.
A recent type 1 diabetes (T1D) clinical trial of rituximab (a B cell-depleting anti-CD20 antibody) achieved some therapeutic benefit in preserving C-peptide for a period of approximately nine months in patients with recently diagnosed diabetes. Our previous data in the NOD mouse demonstrated that co-administration of antigen (insulin) with anti-CD3 antibody (a T cell-directed immunomodulator) offers better protection than either entity alone, indicating that novel combination therapies that include a T1D-related autoantigen are possible. To accelerate the identification and development of novel combination therapies that can be advanced into the clinic, we have evaluated the combination of a mouse anti-CD20 antibody with either oral insulin or a proinsulin-expressing DNA vaccine. Anti-CD20 alone, given once or on 4 consecutive days, produced transient B cell depletion but did not prevent or reverse T1D in the NOD mouse. Oral insulin alone (twice weekly for 6 weeks) was also ineffective, while proinsulin DNA (weekly for up to 12 weeks) showed a trend toward modest efficacy. Combination of anti-CD20 with oral insulin was ineffective in reversing diabetes in NOD mice whose glycemia was controlled with SC insulin pellets; these experiments were performed in three independent labs. Combination of anti-CD20 with proinsulin DNA was also ineffective in diabetes reversal, but did show modest efficacy in diabetes prevention (p = 0.04). In the prevention studies, anti-CD20 plus proinsulin resulted in modest increases in Tregs in pancreatic lymph nodes and elevated levels of proinsulin-specific CD4+ T-cells that produced IL-4. Thus, combination therapy with anti-CD20 and either oral insulin or proinsulin does not protect hyperglycemic NOD mice, but the combination with proinsulin offers limited efficacy in T1D prevention, potentially by augmentation of proinsulin-specific IL-4 production.
最近一项关于利妥昔单抗（一种耗竭 B 细胞的抗 CD20 抗体）的 1 型糖尿病（T1D）临床试验在近期诊断为糖尿病的患者中实现了一定的治疗益处，可在大约九个月的时间内保留 C 肽。我们之前在 NOD 小鼠中的数据表明，与抗 CD3 抗体（一种 T 细胞导向的免疫调节剂）共同给予抗原（胰岛素）比单独使用任何一种药物提供更好的保护，这表明包含 T1D 相关自身抗原的新型联合疗法是可能的。为了加速鉴定和开发可进入临床的新型联合疗法，我们评估了抗 CD20 单克隆抗体与口服胰岛素或表达胰岛素原的 DNA 疫苗的联合应用。抗 CD20 单药治疗，单次或连续 4 天给药，可产生短暂的 B 细胞耗竭，但不能预防或逆转 NOD 小鼠的 T1D。单独给予口服胰岛素（每周 2 次，持续 6 周）也无效，而胰岛素原 DNA（每周 1 次，最多 12 周）则显示出适度疗效的趋势。在血糖用 SC 胰岛素丸控制的 NOD 小鼠中，联合抗 CD20 和口服胰岛素治疗在逆转糖尿病方面无效；这些实验在三个独立的实验室进行。抗 CD20 与胰岛素原 DNA 的联合治疗在逆转糖尿病方面也无效，但在预防糖尿病方面显示出适度疗效（p = 0.04）。在预防研究中，抗 CD20 加胰岛素原导致胰腺淋巴结中 Tregs 适度增加，并升高产生 IL-4 的胰岛素原特异性 CD4+ T 细胞的水平。因此，抗 CD20 与口服胰岛素或胰岛素原的联合治疗不能保护高血糖的 NOD 小鼠，但与胰岛素原联合治疗在 T1D 预防方面具有一定的疗效，可能是通过增强胰岛素原特异性 IL-4 的产生。
