Diabetologia

, Volume 61, Issue 2, pp 389–398 | Cite as

Oral histone deacetylase inhibitor synergises with T cell targeted immunotherapy to preserve beta cell metabolic function and induce stable remission of new-onset autoimmune diabetes in NOD mice

  • Alix Besançon
  • Tania Goncalves
  • Fabrice Valette
  • Mattias S. Dahllöf
  • Thomas Mandrup-Poulsen
  • Lucienne Chatenoud
  • Sylvaine You
Article

Abstract

Aim/hypothesis

Combination therapy targeting the major actors involved in the immune-mediated destruction of pancreatic beta cells appears to be an indispensable approach to treat type 1 diabetes effectively. We hypothesised that the combination of an orally active pan-histone deacetylase inhibitor (HDACi: givinostat) with subtherapeutic doses of CD3 antibodies may provide ideal synergy to treat ongoing autoimmunity.

Methods

NOD mice transgenic for the human CD3ε (also known as CD3E) chain (NOD-huCD3ε) were treated for recent-onset diabetes with oral givinostat, subtherapeutic doses of humanised CD3 antibodies (otelixizumab, 50 μg/day, 5 days, i.v.) or a combination of both drugs. Disease remission, metabolic profiles and autoreactive T cell responses were analysed in treated mice.

Results

We demonstrated that givinostat synergised with otelixizumab to induce durable remission of diabetes in 80% of recently diabetic NOD-huCD3ε mice. Remission was obtained in only 47% of mice treated with otelixizumab alone. Oral givinostat monotherapy did not reverse established diabetes but reduced the in situ production of inflammatory cytokines (IL-1β, IL-6, TNF-α). Importantly, the otelixizumab + givinostat combination strongly improved the metabolic status of NOD-huCD3ε mice; the mice recovered the capacity to appropriately produce insulin, control hyperglycaemia and sustain glucose tolerance. Finally, diabetes remission induced by the combination therapy was associated with a significant reduction of insulitis and autoantigen-specific CD8+ T cell responses.

Conclusions/interpretation

HDACi and low-dose CD3 antibodies synergised to abrogate in situ inflammation and thereby improved pancreatic beta cell survival and metabolic function leading to long-lasting diabetes remission. These results support the therapeutic potential of protocols combining these two drugs, both in clinical development, to restore self-tolerance and insulin independence in type 1 diabetes.

Keywords

Beta cells Glucose tolerance HDACi Human CD3 antibodies Humanised NOD mice Insulin secretion Type 1 diabetes 

Abbreviations

APC

Allophycocyanin

HDAC

Histone deacetylase

FOXP3

Forkhead box P3

HDACi

Histone deacetylase inhibitor

IGRP

Islet-specific glucose-6-phosphatase catalytic subunit related protein

LAG-3

Lymphocyte-activation gene 3

PI

Proinsulin

pLN

Pancreatic lymph node

SFU

Spot-forming unit

Tr1

Regulatory type 1 cell

Treg

Regulatory T cell

Notes

Acknowledgements

The authors thank M. Bellanger (INSERM U1151, Paris, France) for taking care of the NOD-huCD3ε mouse colony and for providing technical assistance for the experimental mouse work. We are also grateful to E. Panafieu, S. Fonlebeck and Y. Loudin (INSERM U1151, Department of Immunology, Paris, France) for mouse production and maintenance.

Data availability

The data generated during the current study are available from the corresponding author on reasonable request.

Funding

This work was supported by grants from the JDRF (#1-2011-654), institutional funding from INSERM and University Paris Descartes and also with the support of Fondation Day Solvay and Fondation Centaure. AB was supported by a doctoral fellowship from INSERM and by a grant from the Société Française d’Endocrinologie et Diabétologie Pédiatrique (grant from Novo Nordisk). The funders had no role in study design, data collection, interpretation or decision to submit the work for publication.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

AB designed experiments, acquired and analysed data, and wrote the manuscript. TG and FV designed and performed experiments, and analysed data. MSD provided research material and contributed to the design of the experiments. LC provided critical advice and help in writing the manuscript. TM-P initiated the study with LC and contributed to planning the protocol and reviewed the manuscript. All authors revised the manuscript and approved the final version to be published. SY designed and directed the study, analysed the data and wrote the manuscript. SY is the guarantor of this work.

Supplementary material

125_2017_4459_MOESM1_ESM.pdf (291 kb)
ESM Figures (PDF 290 kb)

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Alix Besançon
    • 1
    • 2
    • 3
  • Tania Goncalves
    • 1
    • 2
    • 3
  • Fabrice Valette
    • 1
    • 2
    • 3
  • Mattias S. Dahllöf
    • 4
  • Thomas Mandrup-Poulsen
    • 4
  • Lucienne Chatenoud
    • 1
    • 2
    • 3
  • Sylvaine You
    • 1
    • 2
    • 3
  1. 1.University Paris Descartes, Sorbonne Paris CitéParisFrance
  2. 2.INSERM U1151, Institut Necker-Enfants Malades, Hôpital NeckerParisFrance
  3. 3.CNRS UMR 8253, Institut Necker-Enfants MaladesParisFrance
  4. 4.Laboratory for Immuno-Endocrinology, Department of Biomedical SciencesUniversity of CopenhagenCopenhagenDenmark

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