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Diabetologia

, Volume 61, Issue 8, pp 1811–1816 | Cite as

A selective CD28 antagonist and rapamycin synergise to protect against spontaneous autoimmune diabetes in NOD mice

  • Alix Besançon
  • Tania Goncalves
  • Fabrice Valette
  • Caroline Mary
  • Bernard Vanhove
  • Lucienne Chatenoud
  • Sylvaine You
Short Communication

Abstract

Aims/hypothesis

The CD28/B7 interaction is critical for both effector T cell activation and forkhead box P3 (FOXP3)+ regulatory T cell (Treg) generation and homeostasis, which complicates the therapeutic use of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)–immunoglobulin fusion protein (CTLA-4Ig) in autoimmunity. Here, we evaluated the impact of a simultaneous and selective blockade of the CD28 and mammalian target of rapamycin (mTOR) pathways in the NOD mouse model of type 1 diabetes.

Methods

NOD mice were treated with PEGylated anti-CD28 Fab′ antibody fragments (PV1-polyethylene glycol [PEG], 10 mg/kg i.p., twice weekly), rapamycin (1 mg/kg i.p., twice weekly) or a combination of both drugs. Diabetes incidence, pancreatic islet infiltration and autoreactive T cell responses were analysed.

Results

We report that 4 week administration of PV1-PEG combined with rapamycin effectively controlled the progression of autoimmune diabetes in NOD mice at 10 weeks of age by reducing T cell activation and migration into the pancreas. Treatment with rapamycin alone was without effect, as was PV1-PEG monotherapy initiated at 4, 6 or 10 weeks of age. Prolonged PV1-PEG administration (for 10 weeks) accelerated diabetes development associated with impaired peripheral Treg homeostasis. This effect was not observed with the combined treatment.

Conclusions/interpretation

CD28 antagonist and rapamycin treatment act in a complementary manner to limit T cell activation and infiltration of pancreatic islets and diabetes development. These data provide new perspectives for the treatment of autoimmune diabetes and support the therapeutic potential of protocols combining antagonists of CD28 (presently in clinical development) and the mTOR pathway.

Keywords

CD28 antagonist Combination therapy NOD mice Rapamycin Type 1 diabetes 

Abbreviations

APC

Antigen-presenting cell

CIA

Collagen-induced arthritis

CTLA-4

Cytotoxic T lymphocyte-associated antigen 4

CTLA-4Ig

Cytotoxic T lymphocyte-associated antigen 4–immunoglobulin fusion protein

EAE

Experimental autoimmune encephalomyelitis

EAU

Experimental autoimmune uveitis

ELISpot

Enzyme-linked immunospot

FOXP3

Forkhead box P3

IGRP

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

mTOR

Mammalian target of rapamycin

PEG

Polyethylene glycol

PI

Proinsulin

PI3K

Phosphoinositide 3-kinase

PV1-PEG

PEGylated CD28-specific Fab′ fragments

SFU

Spot-forming units

TCR

T cell receptor

Teff

Effector T cell

Treg

Regulatory T cell

VPD

Violet Proliferation Dye

Notes

Acknowledgements

The authors thank M. Bellanger, E. Panafieu and S. Fonlebeck (Inserm U1151, Paris, France) for mouse production and housing.

Contribution statement

AB and TG designed experiments, acquired and analysed data and wrote part of the manuscript. FV and CM designed and performed experiments and analysed data. BV contributed to the conception and design of the study, provided PV1-PEG and reviewed the manuscript. LC contributed to the design of the study and interpretation of data, and helped write the manuscript. SY designed and directed the study, analysed the data and wrote the manuscript. All authors revised the manuscript and approved the final version to be published. SY is the guarantor of this work.

Funding

This work was supported by grants from the European Commission (FP7, TRIAD project: Tolerance restoration in autoimmune diseases by selective manipulation of the CD28 costimulatory pathway), by institutional funding from Inserm and University Paris Descartes and by Fondation Day Solvay. AB was supported by a doctoral fellowship from Inserm and a grant from the Société Française d’Endocrinologie et Diabétologie Pédiatrique (grant from Novo Nordisk).

Duality of interest

BV and CM are current employees of OSE Immunotherapeutics (formerly Effimune SAS). The pegylated anti-CD28 Fab′ antibody fragment (PV1-PEG) is the property of OSE Immunotherapeutics, Nantes, France. AB, FV, TG, LC and SY declare no commercial or financial conflict of interest. The study sponsor was not involved in: the design of the study; the collection, analysis or interpretation of data; writing the report; or the decision to submit the report for publication.

Supplementary material

125_2018_4638_MOESM1_ESM.pdf (226 kb)
ESM Fig. 1 (PDF 226 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Alix Besançon
    • 1
    • 2
    • 3
  • Tania Goncalves
    • 1
    • 2
    • 3
  • Fabrice Valette
    • 1
    • 2
    • 3
  • Caroline Mary
    • 4
  • Bernard Vanhove
    • 4
    • 5
  • Lucienne Chatenoud
    • 1
    • 2
    • 3
  • Sylvaine You
    • 1
    • 2
    • 3
    • 6
  1. 1.Université Paris Descartes, Sorbonne Paris CitéParisFrance
  2. 2.INSERM U1151, Institut Necker-Enfants Malades, Hôpital NeckerParisFrance
  3. 3.CNRS UMR 8253, Institut Necker-Enfants Malades, Hôpital NeckerParisFrance
  4. 4.OSE ImmunotherapeuticsNantesFrance
  5. 5.Inserm UMR-1064, Institut de Transplantation Urologie Néphrologie (ITUN)NantesFrance
  6. 6.Inserm U1016, Institut Cochin, Bâtiment CassiniParisFrance

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