TNF-alpha Antibody Therapy in Combination With the T-Cell-Specific Antibody Anti-TCR Reverses the Diabetic Metabolic State in the LEW.1AR1-iddm Rat

Anti-tumor necrosis factor-alpha (TNF-alpha) therapy (5 mg/kg body weight), alone or combined with the T-cell-specific antibody anti-T-cell receptor (TCR) (0.5 mg/kg body weight), was performed over 5 days immediately after disease manifestation to reverse the diabetic metabolic state in the LEW.1AR1-iddm rat, an animal model of human type 1 diabetes. Only combination therapy starting at blood glucose concentrations below 15 mmol/L restored normoglycemia and normalized C-peptide. Increased beta-cell proliferation and reduced apoptosis led to a restoration of beta-cell mass along with an immune cell infiltration-free pancreas 60 days after the end of therapy. This combination of two antibodies, anti-TCR/CD3, as a cornerstone compound in anti-T-cell therapy, and anti-TNF-alpha, as the most prominent and effective therapeutic antibody in suppressing TNF-alpha action in many autoimmune diseases, was able to reverse the diabetic metabolic state. With increasing blood glucose concentrations during the disease progression, however, the proapoptotic pressure on the residual beta-cell mass increased, ultimately reaching a point where the reservoir of the surviving beta-cells was insufficient to allow a restoration of normal beta-cell mass through regeneration. The present results may open a therapeutic window for reversal of diabetic hyperglycemia in patients, worthwhile of being tested in clinical trials.