Journal of Molecular Medicine

, Volume 92, Issue 7, pp 743–755

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

  • Anne Jörns
  • Muharrem Akin
  • Tanja Arndt
  • Taivankhuu Terbish
  • Andreas Meyer zu Vilsendorf
  • Dirk Wedekind
  • Hans-Jürgen Hedrich
  • Sigurd Lenzen
Original Article

DOI: 10.1007/s00109-014-1137-2

Cite this article as:
Jörns, A., Akin, M., Arndt, T. et al. J Mol Med (2014) 92: 743. doi:10.1007/s00109-014-1137-2

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.

Keywords

Type 1 diabetes Animal model Prevention Beta cells Regeneration 

Supplementary material

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Anne Jörns
    • 1
    • 2
  • Muharrem Akin
    • 1
  • Tanja Arndt
    • 1
  • Taivankhuu Terbish
    • 1
  • Andreas Meyer zu Vilsendorf
    • 3
  • Dirk Wedekind
    • 4
  • Hans-Jürgen Hedrich
    • 4
  • Sigurd Lenzen
    • 1
  1. 1.Institute of Clinical BiochemistryHannover Medical SchoolHannoverGermany
  2. 2.Centre of AnatomyHannover Medical SchoolHannoverGermany
  3. 3.Department of General, Visceral and Transplantation SurgeryHannover Medical SchoolHannoverGermany
  4. 4.Institute of Laboratory Animal ScienceHannover Medical SchoolHannoverGermany

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