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

被引:7
作者
Besancon, Alix [1 ,2 ,3 ]
Goncalves, Tania [1 ,2 ,3 ]
Valette, Fabrice [1 ,2 ,3 ]
Mary, Caroline [4 ]
Vanhove, Bernard [4 ,5 ]
Chatenoud, Lucienne [1 ,2 ,3 ]
You, Sylvaine [1 ,2 ,3 ,6 ]
机构
[1] Univ Paris 05, Sorbonne Paris Cite, Paris, France
[2] Hop Necker Enfants Malad, Inst Necker Enfants Malad, INSERM U1151, Paris, France
[3] Hop Necker Enfants Malad, Inst Necker Enfants Malad, CNRS UMR 8253, Paris, France
[4] OSE Immunotherapeut, Nantes, France
[5] ITUN, Inserm UMR 1064, Nantes, France
[6] Inst Cochin, Inserm U1016, Batiment Cassini,123 Bd Port Royal, F-75014 Paris, France
关键词
CD28; antagonist; Combination therapy; NOD mice; Rapamycin; Type; 1; diabetes; CO-STIMULATION; COSTIMULATION; HOMEOSTASIS; BLOCKADE;
D O I
10.1007/s00125-018-4638-7
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:1811 / 1816
页数:6
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