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A selective CD28 antagonist and rapamycin synergise to protect against spontaneous autoimmune diabetes in NOD mice.
Besançon, Alix; Goncalves, Tania; Valette, Fabrice; Mary, Caroline; Vanhove, Bernard; Chatenoud, Lucienne; You, Sylvaine.
Afiliação
  • Besançon A; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
  • Goncalves T; INSERM U1151, Institut Necker-Enfants Malades, Hôpital Necker, Paris, France.
  • Valette F; CNRS UMR 8253, Institut Necker-Enfants Malades, Hôpital Necker, Paris, France.
  • Mary C; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
  • Vanhove B; INSERM U1151, Institut Necker-Enfants Malades, Hôpital Necker, Paris, France.
  • Chatenoud L; CNRS UMR 8253, Institut Necker-Enfants Malades, Hôpital Necker, Paris, France.
  • You S; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Diabetologia ; 61(8): 1811-1816, 2018 08.
Article em En | MEDLINE | ID: mdl-29845333
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.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Fragmentos Fab das Imunoglobulinas / Antígenos CD28 / Sirolimo / Diabetes Mellitus Tipo 1 Tipo de estudo: Guideline Limite: Animals Idioma: En Revista: Diabetologia Ano de publicação: 2018 Tipo de documento: Article País de afiliação: França

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Fragmentos Fab das Imunoglobulinas / Antígenos CD28 / Sirolimo / Diabetes Mellitus Tipo 1 Tipo de estudo: Guideline Limite: Animals Idioma: En Revista: Diabetologia Ano de publicação: 2018 Tipo de documento: Article País de afiliação: França