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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

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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

  • Combination therapy of anti-TCR and fingolimod was effective in the reversal of T1D.

  • Combination therapy increased the pancreatic β cell mass to normoglycemic control levels.

  • Combination therapy leads to a full reversal of pancreatic islet infiltration.

  • Anti-TCR monotherapy did not abolish islet infiltration.

  • Combination therapy was successful only immediately after diabetes manifestation.

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Acknowledgements

This work was supported by grants from the Deutsche Forschungsgemeinschaft (JO 395/2-1) and the European Union (Collaborative Project NAIMIT in the 7th Framework Programme, Contract No. 241447). We thank D. Lischke and U. Sommerfeld for skillful technical assistance.

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There is no conflict of interest.

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Authors and Affiliations

  1. Institute of Clinical Biochemistry, Hannover Medical School, 30623, Hannover, Germany

    Anne Jörns, Muharrem Akin, Tanja Arndt, Taivankhuu Terbish & Sigurd Lenzen

  2. Centre of Anatomy, Hannover Medical School, Hannover, Germany

    Anne Jörns

  3. Department of General, Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany

    Andreas Meyer zu Vilsendorf

  4. Institute of Laboratory Animal Science, Hannover Medical School, Hannover, Germany

    Dirk Wedekind & Hans-Jürgen Hedrich

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  1. Anne Jörns
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  2. Muharrem Akin
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Correspondence to Sigurd Lenzen.

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A. J. and M. A. contributed equally to this work.

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Jörns, A., Akin, M., Arndt, T. et al. 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. J Mol Med 92, 743–755 (2014). https://doi.org/10.1007/s00109-014-1137-2

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