Alix Besançon1,2,3, Tania Goncalves1,2,3, Fabrice Valette1,2,3, Caroline Mary4, Bernard Vanhove4,5, Lucienne Chatenoud1,2,3, Sylvaine You1,2,3,6. 1. Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 2. INSERM U1151, Institut Necker-Enfants Malades, Hôpital Necker, Paris, France. 3. CNRS UMR 8253, Institut Necker-Enfants Malades, Hôpital Necker, Paris, France. 4. OSE Immunotherapeutics, Nantes, France. 5. Inserm UMR-1064, Institut de Transplantation Urologie Néphrologie (ITUN), Nantes, France. 6. Inserm U1016, Institut Cochin, Bâtiment Cassini, 123 Bd de Port Royal, 75014, Paris, France. sylvaine.you@inserm.fr.
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.
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 NODmouse model of type 1 diabetes. METHODS:NODmice 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 NODmice 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.
Authors: D J Lenschow; K C Herold; L Rhee; B Patel; A Koons; H Y Qin; E Fuchs; B Singh; C B Thompson; J A Bluestone Journal: Immunity Date: 1996-09 Impact factor: 31.745
Authors: N Poirier; N Dilek; C Mary; S Ville; F Coulon; J Branchereau; X Tillou; V Charpy; S Pengam; V Nerriere-Daguin; J Hervouet; D Minault; S Le Bas-Bernardet; K Renaudin; B Vanhove; G Blancho Journal: Am J Transplant Date: 2014-12-08 Impact factor: 8.086
Authors: Vanessa P Houde; Sophie Brûlé; William T Festuccia; Pierre-Gilles Blanchard; Kerstin Bellmann; Yves Deshaies; André Marette Journal: Diabetes Date: 2010-03-18 Impact factor: 9.461
Authors: M P M Vierboom; E Breedveld; Y S Kap; C Mary; N Poirier; B A 't Hart; B Vanhove Journal: Clin Exp Immunol Date: 2015-12-16 Impact factor: 4.330
Authors: Andrew N Macintyre; David Finlay; Gavin Preston; Linda V Sinclair; Caryll M Waugh; Peter Tamas; Carmen Feijoo; Klaus Okkenhaug; Doreen A Cantrell Journal: Immunity Date: 2011-02-03 Impact factor: 31.745
Authors: David K Finlay; Ella Rosenzweig; Linda V Sinclair; Carmen Feijoo-Carnero; Jens L Hukelmann; Julia Rolf; Andrey A Panteleyev; Klaus Okkenhaug; Doreen A Cantrell Journal: J Exp Med Date: 2012-11-26 Impact factor: 14.307