A selective CD28 antagonist and rapamycin synergise to protect
against spontaneous autoimmune diabetes in NOD mice
Received: 29 January 2018 /Accepted: 19 April 2018
Springer-Verlag GmbH Germany, part of Springer Nature 2018
Aims/hypothesis The CD28/B7 interaction is critical for both effector T cell activation and forkhead box P3 (FOXP3)
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 autoim-
mune diabetes and support the therapeutic potential of protocols combining antagonists of CD28 (presently in clinical develop-
ment) and the mTOR pathway.
Keywords CD28 antagonist
Type 1 diabetes
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-
mTOR Mammalian target of rapamycin
PEG Polyethylene glycol
PI3K Phosphoinositide 3-kinase
PV1-PEG PEGylated CD28-specific Fab′ fragments
Alix Besançon and Tania Goncalves contributed equally to this work.
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00125-018-4638-7) contains peer-reviewed but
unedited supplementary material, which is available to authorised users.
* Sylvaine You
Université Paris Descartes, Sorbonne Paris Cité, Paris, France
INSERM U1151, Institut Necker-Enfants Malades, Hôpital Necker,
CNRS UMR 8253, Institut Necker-Enfants Malades, Hôpital Necker,
OSE Immunotherapeutics, Nantes, France
Inserm UMR-1064, Institut de Transplantation Urologie Néphrologie
(ITUN), Nantes, France
Present address: Inserm U1016, Institut Cochin, Bâtiment Cassini,
123 Bd de Port Royal, 75014 Paris, France