Limitations of IL-2 and rapamycin in immunotherapy of type 1 diabetes
- Audrey Baeyens1,2,3,*,
- Louis Pérol1,2,3,#,*,
- Gwladys Fourcade1,2,3,
- Nicolas Cagnard4,
- Wassila Carpentier5,
- Janine Woytschak6,
- Onur Boyman6,7,
- Agnès Hartemann8,9 and
- Eliane Piaggio1,2,3,#,**
- 1Université Pierre et Marie Curie Univ Paris 06
- 2Centre National de la Recherche Scientifique, UMR 7211
- 3Institut National de la Santé et de la Recherche Médicale (INSERM), U 959, Immunology-Immunopathology-Immunotherapy (I3), 75013 Paris, France
- 4INSERM U580
- 5Bioinformatics Platform, Faculty of Medicine Paris Descartes, Hôpital Necker-Enfants Malades, 75015 Paris, France
- 5Plate-forme Post-Génomique P3S, UPMC Univ Paris 6, Faculty of Medicine, 75013 Paris, France.
- 6Laboratory of Applied Immunobiology, University of Zurich, CH-8006 Zurich, Switzerland.
- 7Allergy Unit, Department of Dermatology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
- 8Department of Endocrinology, Nutrition and Diabetes, Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière-Charles Foix Hospital, Paris, France.
- 9Department of Medicine Faculty, Université Pierre et Marie Curie - Paris 6, Paris, France.
- **Corresponding author:
* These authors contributed equally to this work
Administration of low-dose IL-2 alone or combined with rapamycin (RAPA) prevents hyperglycemia in NOD mice. Also, low-dose IL-2 cures recent onset type 1 diabetes (T1D) in NOD mice, partially by boosting pancreatic regulatory T cells (Treg cells). These approaches are currently being evaluated in humans. Our objective was to study the effect of higher IL-2 doses (250,000-500,000 IU, daily) as well as low-dose IL-2 (25,000 IU, daily) and RAPA (1mg/kg, daily) (RAPA/IL-2) combination. We show that despite further boosting Treg cells, high doses of IL-2 rapidly precipitated T1D in pre-diabetic female and male mice and increased myeloid cells in the pancreas. Also, we observed that RAPA counteracted IL-2 effects on Treg cells, failed to control IL-2-boosted NK cells and broke IL-2-induced tolerance in a reversible way. Notably, RAPA/IL-2 combination failure to cure T1D was associated to an unexpected deleterious effect on glucose homeostasis at multiple levels, including β-cell division, glucose tolerance and liver glucose metabolism. Our data help understand the therapeutic limitations of IL-2 alone or RAPA/IL-2 combination and could lead to the design of improved therapies for T1D.
- Received February 8, 2013.
- Accepted May 7, 2013.
- © 2013 by the American Diabetes Association.
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