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

ABSTRACT

Anti-tumor necrosis factor-α (TNF-α) 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 ß-cell proliferation and reduced apoptosis led to a restoration of ß-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-α, as the most prominent and effective therapeutic antibody in suppressing TNF-α 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 ß-cell mass increased, ultimately reaching a point where the reservoir of the surviving ß-cells was insufficient to allow a restoration of normal ß-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.