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

BACKGROUND: 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. METHODS: 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. RESULTS: 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 beta cell mass was raised to values of around 6 mg 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. CONCLUSIONS: The 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.