Anne Jörns, Ümüs Gül Ertekin, Tanja Arndt, Taivankhuu Terbish, Dirk Wedekind, Sigurd Lenzen

Anti-TNF-α therapy (5 mg/kg b.wt.) alone or in combination with the T-cell specific antibody anti-TCR (0.5 mg/kg b.wt.) 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 β-cell proliferation and reduced apoptosis led to a restoration of β-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 pro-apoptotic pressure on the residual β-cell mass increased, ultimately reaching a point where the reservoir of the surviving β-cells was insufficient to allow a restoration of normal β-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.