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- Title
Anti-TCR therapy combined with fingolimod for reversal of diabetic hyperglycemia by β cell regeneration in the LEW.1AR1- iddm rat model of type 1 diabetes.
- Authors
Jörns, Anne; Akin, Muharrem; Arndt, Tanja; Terbish, Taivankhuu; Vilsendorf, Andreas; Wedekind, Dirk; Hedrich, Hans-Jürgen; Lenzen, Sigurd
- Abstract
The therapeutic capacity of an antibody directed against the T cell receptor (anti-TCR) of the TCR/CD3 complex alone or in combination with fingolimod (FTY720) to reverse the diabetic metabolic state through suppression of autoimmunity and stimulation of β cell regeneration was analyzed in the LEW.1AR1- iddm (IDDM) rat, an animal model of human type 1 diabetes. Animals were treated with anti-TCR (0.5 mg/kg body weight for 5 days) monotherapy or in combination with fingolimod (1 mg/kg body weight for 40 days). Metabolic changes and β cell morphology were analyzed before, immediately after, and 60 days after end of therapy. Both therapies were started early after disease manifestation and led to normoglycemia in parallel with an increase of the C-peptide concentration. Combination therapy increased the β cell mass reaching a range of normoglycemic controls, decreased the apoptosis rate fivefold, and increased the proliferation rate threefold. Additionally, at 60 days after therapy, islets were virtually free of T cells, macrophages, and cytokine expression. In contrast, after anti-TCR monotherapy, β cell mass remained low with an activated immune cell infiltrate. A concomitant fivefold increased β cell apoptosis rate resulted in a complete loss of β cells. Only combination therapy yielded sustained normoglycemia with full reversal of islet infiltration and restoration of pancreatic β cell mass. Key Message:
- Publication
Journal of Molecular Medicine, 2014, Vol 92, Issue 7, p743
- ISSN
0946-2716
- Publication type
Academic Journal
- DOI
10.1007/s00109-014-1137-2