Translation of curative therapy concepts with T cell and cytokine antibody combinations for type 1 diabetes reversal in the IDDM rat

Abstract

Proinflammatory cytokines released from the pancreatic islet immune cell infiltrate in type 1 diabetes (T1D) cause insulinopenia as a result of severe beta cell loss due to apoptosis. Diabetes prevention strategies targeting different cytokines with antibodies in combination with a T cell antibody, anti-TCR, have been assessed for therapy success in the LEW.1AR1-iddm (IDDM) rat, an animal model of human T1D. Immediately after diabetes manifestation, antibody combination therapies were initiated over 5 days with anti-TNF-α (tumour necrosis factor), anti-IL-1β (interleukin), or anti-IFN-γ (interferon) together with anti-TCR for the reversal of the diabetic metabolic state in the IDDM rat. Anti-TCR alone showed only a very limited therapy success with respect to a reduction of immune cell infiltration and beta cell mass regeneration. Anti-TCR combinations with anti-IL-1β or anti-IFN-γ were also not able to abolish the increased beta cell apoptosis rate and the activated immune cell infiltrate leading to a permanent beta cell loss. In contrast, all anti-TCR combinations with anti-TNF-α provided sustained therapy success over 60 to 360 days. The triple combination of anti-TCR with anti-TNF-α plus anti-IL-1β was most effective in regaining sustained normoglycaemia with an intact islet structure in a completely infiltration-free pancreas and with a normal beta cell mass. Besides the triple combination, the double antibody combination of anti-TCR with anti-TNF-α proved to be the most suited therapy for reversal of the T1D metabolic state due to effective beta cell regeneration in an infiltration free pancreas.

Key messages

  • Anti-TCR is a cornerstone in combination therapy for autoimmune diabetes reversal.

  • The combination of anti-TCR with anti-TNF-α was most effective in reversing islet immune cell infiltration.

  • Anti-TCR combined with anti-IL-1β was not effective in this respect.

  • The combination of anti-TCR with anti-TNF-α showed a sustained effect over 1 year.

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Data availability

The datasets generated during and/or analysed during the current study are available from the author A.J. upon reasonable questions.

Abbreviations

anti-TCR antibody:

Anti–T cell receptor antibody

Casp3 (Cpp32):

Caspase 3

IDDM rat :

LEW.1AR1-iddm rat

IFN-γ:

Interferon-gamma

IL-1β:

Interleukin-1beta

TCR/CD3 complex:

T cell receptor/cluster of differentiation complex

T1D:

Type 1 diabetes

TNF-α:

Tumour necrosis factor-alpha

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Acknowledgements

S.Y., D.I., and T.Y. were on leave from the Department of Digestive Surgery and Transplantation, University of Tokushima, Tokushima, Japan. We thank D. Lischke and R. Chucholl, both Institute of Clinical Biochemistry, Hannover Medical School, Germany, for skillful technical assistance.

Funding

This work has been supported by a grant from the Deutsche Forschungsgemeinschaft (JO 395/2-2).

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Contributions

A.J. designed the study, performed experiments, analysed and interpreted data, and wrote the manuscript. T.A., D.I., S.Y., T.Y., and T.T. performed experiments. D. W. and P.H.M. provided materials and reviewed the manuscript. S.L. designed the study, analysed and interpreted data, and wrote the manuscript.

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Correspondence to Sigurd Lenzen.

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Jörns, A., Arndt, T., Yamada, S. et al. Translation of curative therapy concepts with T cell and cytokine antibody combinations for type 1 diabetes reversal in the IDDM rat. J Mol Med (2020). https://doi.org/10.1007/s00109-020-01941-8

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Keywords

  • Antibody combination therapy
  • Cytokines
  • LEW.1AR1-iddm rat
  • Pancreatic beta cells
  • Reversal
  • Type 1 diabetes mellitus