Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
Institute of Experimental Diabetes Research, Hannover Medical School, 30625, Hannover, Germany.
J Mol Med (Berl). 2020 Aug;98(8):1125-1137. doi: 10.1007/s00109-020-01941-8. Epub 2020 Jun 30.
Proinflammatory cytokines released from the pancreatic islet immune cell infiltrate in type 1 diabetes (T1D) cause insulinopenia as a result of severe beta cell loss due to apoptosis. Diabetes prevention strategies targeting different cytokines with antibodies in combination with a T cell antibody, anti-TCR, have been assessed for therapy success in the LEW.1AR1-iddm (IDDM) rat, an animal model of human T1D. Immediately after diabetes manifestation, antibody combination therapies were initiated over 5 days with anti-TNF-α (tumour necrosis factor), anti-IL-1β (interleukin), or anti-IFN-γ (interferon) together with anti-TCR for the reversal of the diabetic metabolic state in the IDDM rat. Anti-TCR alone showed only a very limited therapy success with respect to a reduction of immune cell infiltration and beta cell mass regeneration. Anti-TCR combinations with anti-IL-1β or anti-IFN-γ were also not able to abolish the increased beta cell apoptosis rate and the activated immune cell infiltrate leading to a permanent beta cell loss. In contrast, all anti-TCR combinations with anti-TNF-α provided sustained therapy success over 60 to 360 days. The triple combination of anti-TCR with anti-TNF-α plus anti-IL-1β was most effective in regaining sustained normoglycaemia with an intact islet structure in a completely infiltration-free pancreas and with a normal beta cell mass. Besides the triple combination, the double antibody combination of anti-TCR with anti-TNF-α proved to be the most suited therapy for reversal of the T1D metabolic state due to effective beta cell regeneration in an infiltration free pancreas. KEY MESSAGES: Anti-TCR is a cornerstone in combination therapy for autoimmune diabetes reversal. The combination of anti-TCR with anti-TNF-α was most effective in reversing islet immune cell infiltration. Anti-TCR combined with anti-IL-1β was not effective in this respect. The combination of anti-TCR with anti-TNF-α showed a sustained effect over 1 year.
促炎细胞因子从胰岛免疫细胞浸润中释放出来，导致 1 型糖尿病 (T1D) 中胰岛素分泌不足，这是由于细胞凋亡导致严重的β细胞丢失。针对不同细胞因子的抗体与 T 细胞抗体，即抗 TCR，已被用于 LEW.1AR1-iddm (IDDM) 大鼠（人类 T1D 的动物模型）的治疗成功评估。在糖尿病表现后立即，用抗 TNF-α（肿瘤坏死因子）、抗 IL-1β（白细胞介素）或抗 IFN-γ（干扰素）联合抗 TCR 进行为期 5 天的抗体联合治疗，以逆转 IDDM 大鼠的糖尿病代谢状态。单独使用抗 TCR 仅在减少免疫细胞浸润和β细胞质量再生方面显示出非常有限的治疗成功。抗 TCR 与抗 IL-1β或抗 IFN-γ的组合也不能消除增加的β细胞凋亡率和激活的免疫细胞浸润，导致永久性β细胞丢失。相比之下，所有与抗 TNF-α联合的抗 TCR 均在 60 至 360 天内提供持续的治疗成功。抗 TCR 与抗 TNF-α加抗 IL-1β的三联组合在恢复持续的正常血糖水平方面最为有效，其特征为完全无浸润的胰腺中胰岛结构完整、β细胞质量正常。除三联组合外，抗 TCR 与抗 TNF-α的双重抗体组合在恢复 T1D 代谢状态方面也被证明是最适合的治疗方法，因为在无浸润的胰腺中β细胞得到了有效再生。
抗 TCR 是自身免疫性糖尿病逆转联合治疗的基石。
抗 TCR 与抗 TNF-α的组合在逆转胰岛免疫细胞浸润方面最为有效。
抗 TCR 联合抗 IL-1β在这方面没有效果。
抗 TCR 与抗 TNF-α的组合显示出持续超过 1 年的效果。
