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

• Published in: BMC medicine Vol. 18; no. 1; p. 33
• Main Authors: Jörns, Anne, Ishikawa, Daichi, Teraoku, Hiroki, Yoshimoto, Toshiaki, Wedekind, Dirk, Lenzen, Sigurd
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 28.02.2020; BioMed Central; BMC
• Subjects: Animals; Antibodies; Antibody combination therapy; Apoptosis; Autoimmune diseases; Blood; Blood glucose; Cell cycle; Cloning; Combination drug therapy; Combination therapy; Cytokines; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - drug therapy; Diabetes therapy; Disease; Disease Models, Animal; Diseases; Drug therapy; Fashion models; Female; Gene expression; Glucose; Health aspects; Humans; Hyperglycemia; IL-17; IL-6; Immune system; Immunoglobulins; Inflammation; Interleukin 6; Interleukin-17 - antagonists & inhibitors; Interleukin-6 - antagonists & inhibitors; Laboratory animals; LEW.1AR1-iddm rat; Lymphocytes; Male; Metabolism; Pancreas; Pancreatic beta cells; Peptides; Rats; Rats, Inbred Lew; Recurrence (Disease); Remission; Remission (Medicine); Remission Induction - methods; Reversal of hyperglycaemia; Rheumatoid arthritis; T cell receptors; T cells; Therapy; Tumor necrosis factor-TNF; Type 1 diabetes; Germany; Pancreatic beta cells; Reversal of hyperglycaemia; Type 1 diabetes; IL-17; LEW.1AR1-iddm rat; Antibody combination therapy; IL-6
• ISSN: 1741-7015; 1741-7015
• 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.