Anti-IL-21 monoclonal antibody combined with liraglutide effectively reverses established hyperglycemia in mouse models of type 1 diabetes.

Immunotherapy for type 1 diabetes (T1D) has previously focused on suppressing the autoimmune response against pancreatic beta cells to preserve endogenous insulin production and regulate glucose levels. With increased attention toward combination therapy strategies, studies indicate the multifunctional cytokine interleukin-21 (IL-21) may be a suitable target as an immuno-modulatory arm, while glucagon-like peptide-1 receptor (GLP-1R) agonists may be appropriate as a beta cell protective arm in combination therapy for T1D. We report here that treatment with anti-IL-21 monoclonal antibody delays diabetes onset in the spontaneous non-obese diabetic (NOD) and NOD.scid adoptive transfer models, while its effect in reversing recent-onset hyperglycemia is limited. However, the combination of anti-IL-21 plus the GLP-1R agonist liraglutide is effective in reversing established disease compared to either monotherapy in both the NOD and rat insulin promotor-lymphocytic choriomeningitis virus glycoprotein (RIP-LCMV-GP) models of autoimmune diabetes. Enhanced efficacy is particularly evident in severely hyperglycemic mice, with return to normoglycemia remaining stable for the majority of mice even after therapy is withdrawn. Importantly, increased beta cell proliferation does not appear to be the predominant mechanism. In conclusion, combination therapy with anti-IL-21 and liraglutide is able to consistently reverse disease in mouse models of T1D. The observed effects rival the most effective experimental disease-modifying treatments tested in preclinical studies.

Oral insulin (human, murine, or porcine) does not prevent diabetes in the non-obese diabetic mouse.

Studies have shown oral insulin prevents type 1 diabetes (T1D) in mouse models, however human trials were inconclusive. We tested the ability of different insulins to prevent T1D in non-obese diabetic mice. Mice received oral insulin or PBS twice weekly and disease was monitored. Contrary to previous studies, no insulin tested showed significant ability to prevent T1D, nor did testing of linked suppression in a delayed type hypersensitivity model have reproducible effect. To investigate delivery of antigen within the GI tract, blue dye was fed to mice. Dye traveled 5-8 cm from stomach to small intestine within 10s, suggesting orally administered antigen may not get digested in the stomach in mice. Insulin incubated with jejunum extracts was instantly digested. Thus, in humans large doses of insulin may be required to achieve tolerance as antigen may be more vulnerable to digestion in the stomach even before reaching the small intestine.

Non-antigenic and antigenic interventions in type 1 diabetes.

Type 1 diabetes (T1D) results from autoimmune destruction of the pancreatic ß-cells. Current T1D therapies are exclusively focused on regulating glycemia rather than the underlying immune response. A handful of trials have sought to alter the clinical course of T1D using various broad immune-suppressors, e.g., cyclosporine A and azathioprine.(1-3) The effect on ß-cell preservation was significant, however, these therapies were associated with unacceptable side-effects. In contrast, more recent immunomodulators, such as anti-CD3 and antigenic therapies such as DiaPep277, provide a more targeted immunomodulation and have been generally well-tolerated and safe; however, as a monotherapy there appear to be limitations in terms of therapeutic benefit. Therefore, we argue that this new generation of immune-modifying agents will likely work best as part of a combination therapy. This review will summarize current immune-modulating therapies under investigation and discuss how to move the field of immunotherapy in T1D forward.