Combination of proton-pump inhibitor and anti-CD3 F(ab')2 for islet neogenesis and immune modulation in type 1 diabetes.

Abstract

Introduction: Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of pancreatic β cells. Current insulin therapy does not address autoimmune pathology or restore endogenous β-cell function, highlighting the need for disease-modifying strategies.

Methods: We developed a combination therapy integrating a proton pump inhibitor (PPI; omeprazole) with a non-Fc-binding anti-CD3 F(ab')₂ antibody fragment (anti-CD3 F(ab')₂) to concurrently promote β-cell neogenesis and modulate autoimmune T-cell responses. T1D was induced in nonobese diabetic (NOD) mice using a cyclophosphamide-accelerated protocol (CY-NOD). Following hyperglycemia onset, mice received combination treatment and were evaluated by blood glucose monitoring, flow cytometric analysis of T-cell populations, and assessment of pancreatic β-cell function. Therapeutic efficacy was further examined in spontaneous-onset NOD mice.

Results: Combination therapy restored normoglycemia without exogenous insulin, reduced lymphocytic infiltration in pancreatic islets, and preserved endogenous insulin secretion. Treatment decreased pathogenic CD4⁺ and CD8⁺ T cells, increased regulatory T cells, and enhanced transforming growth factor-β expression. Comparable and durable glycemic control was observed in spontaneous-onset NOD mice.

Conclusions: Concurrent modulation of β-cell function and autoimmune immunity achieved sustained glycemic control in T1D models. The use of clinically approved agents supports the translational potential of this non-insulin-dependent therapeutic strategy.