Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
Institute of Experimental Diabetes Research, Hannover Medical School, 30623, Hannover, Germany.
BMC Med. 2020 Feb 28;18(1):33. doi: 10.1186/s12916-020-1503-6.
The cytokine IL-17 is a key player in autoimmune processes, while the cytokine IL-6 is responsible for the chronification of inflammation. However, their roles in type 1 diabetes development are still unknown.
Therefore, therapies for 5 days with anti-IL-17A or anti-IL-6 in combination with a T cell-specific antibody, anti-TCR, or in a triple combination were initiated immediately after disease manifestation to reverse the diabetic metabolic state in the LEW.1AR1-iddm (IDDM) rat, a model of human type 1 diabetes.
Monotherapies with anti-IL-6 or anti-IL-17 showed no sustained anti-diabetic effects. Only the combination therapy of anti-TCR with anti-IL-6 or anti-IL-17 at starting blood glucose concentrations up to 12 mmol/l restored normoglycaemia. The triple antibody combination therapy was effective even up to very high initial blood glucose concentrations (17 mmol/l). The β cell mass was raised to values of around 6 mg corresponding to those of normoglycaemic controls. In parallel, the apoptosis rate of β cells was reduced and the proliferation rate increased as well as the islet immune cell infiltrate was strongly reduced in double and abolished in triple combination therapies.
The anti-TCR combination therapy with anti-IL-17 preferentially raised the β cell mass as a result of β cell proliferation while anti-IL-6 strongly reduced β cell apoptosis and the islet immune cell infiltrate with a modest increase of the β cell mass only. The triple combination therapy achieved both goals in a complimentary anti-autoimmune and anti-inflammatory action resulting in sustained normoglycaemia with normalized serum C-peptide concentrations.
细胞因子 IL-17 是自身免疫过程中的关键因素，而细胞因子 IL-6 则负责炎症的慢性化。然而，它们在 1 型糖尿病发展中的作用尚不清楚。
因此，在疾病表现后立即开始用抗 IL-17A 或抗 IL-6 与 T 细胞特异性抗体、抗 TCR 或三联组合进行 5 天的治疗，以逆转 LEW.1AR1-iddm（IDDM）大鼠的糖尿病代谢状态，这是一种人类 1 型糖尿病的模型。
抗 IL-6 或抗 IL-17 的单药治疗没有持续的抗糖尿病作用。只有在起始血糖浓度高达 12mmol/l 时，抗 TCR 与抗 IL-6 或抗 IL-17 的联合治疗才能恢复正常血糖。即使在初始血糖浓度非常高（17mmol/l）时，三联抗体联合治疗也是有效的。β 细胞质量增加到约 6mg，相当于正常血糖对照值。平行地，β 细胞的凋亡率降低，增殖率增加，胰岛免疫细胞浸润也在双抗体和三抗体联合治疗中被强烈减少。
抗 TCR 联合抗 IL-17 的治疗优先通过β 细胞增殖来提高β 细胞质量，而抗 IL-6 则通过强烈减少β 细胞凋亡和胰岛免疫细胞浸润以及适度增加β 细胞质量来实现。三联组合治疗通过互补的抗自身免疫和抗炎作用实现了这两个目标，从而导致持续的正常血糖和正常的血清 C 肽浓度。
