Remission of autoimmune diabetes by anti-TCR combination therapies with anti-IL-17A or/and anti-IL-6 in the IDDM rat model of type 1 diabetes
Remission of autoimmune diabetes by anti-TCR combination therapies with anti-IL-17A or/and anti-IL-6 in the IDDM rat model of type 1 diabetes
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DOI：
10.1186/s12916-020-1503-6
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发表时间：
2020-02-28
期刊：
影响因子：
9.3
通讯作者：
Lenzen, Sigurd
中科院分区：
文献类型：
--
作者：
Joerns, Anne;Ishikawa, Daichi;Lenzen, Sigurd
研究背景细胞因子IL-17在自身免疫过程中起重要作用，而细胞因子IL-6在炎症慢性化过程中起重要作用。因此，在疾病表现后立即开始用抗IL-17 A或抗IL-6与T细胞特异性抗体、抗TCR或三重组合治疗5天，以逆转LEW.1AR1-iddm（IDDM）大鼠的糖尿病代谢状态，人1型糖尿病模型。结果抗IL-6或抗IL-17的单药治疗没有表现出持续的抗糖尿病作用。只有在起始血糖浓度高达12 mmol/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。三抗联合治疗即使在非常高的初始血糖浓度（17 mmol/l）下也有效。β细胞质量升高至约6 mg，与正常血细胞对照组相对应。与此同时，β细胞的凋亡率降低，增殖率增加，胰岛免疫细胞浸润在双重治疗中强烈减少，在三重联合治疗中消除。6强烈降低了β细胞凋亡和胰岛免疫细胞浸润，仅适度增加了β细胞质量。三联疗法在互补的抗自身免疫和抗炎作用中实现了这两个目标，导致持续的正常血糖和正常的血清C肽浓度。
BackgroundThe 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.MethodsTherefore, therapies for 5days 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.ResultsMonotherapies 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 12mmol/l restored normoglycaemia. The triple antibody combination therapy was effective even up to very high initial blood glucose concentrations (17mmol/l). The beta cell mass was raised to values of around 6mg corresponding to those of normoglycaemic controls. In parallel, the apoptosis rate of beta 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.ConclusionsThe anti-TCR combination therapy with anti-IL-17 preferentially raised the beta cell mass as a result of beta cell proliferation while anti-IL-6 strongly reduced beta cell apoptosis and the islet immune cell infiltrate with a modest increase of the beta 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.