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

A selective CD28 antagonist and rapamycin synergise to protect against spontaneous autoimmune... 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 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diabetologia Springer Journals

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

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Publisher
Springer Journals
Copyright
Copyright © 2018 by Springer-Verlag GmbH Germany, part of Springer Nature
Subject
Medicine & Public Health; Internal Medicine; Metabolic Diseases; Human Physiology
ISSN
0012-186X
eISSN
1432-0428
D.O.I.
10.1007/s00125-018-4638-7
Publisher site
See Article on Publisher Site

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

Journal

DiabetologiaSpringer Journals

Published: May 29, 2018

References

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