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 Cagnard4,5,
- Wassila Carpentier1,6,
- Janine Woytschak7,
- Onur Boyman7,8,
- Agnès Hartemann9,10 and
- Eliane Piaggio1,2,3⇑
- 1Université Pierre et Marie Curie, Paris, France
- 2Centre National de la Recherche Scientifique, UMR 7211, Paris, France
- 3Department of Immunology-Immunopathology-Immunotherapy, INSERM U959, Paris, France
- 4INSERM U580, Paris, France
- 5Bioinformatics Platform, Faculty of Medicine Paris Descartes, Hôpital Necker-Enfants Malades, Paris, France
- 6Plateforme Post-Génomique P3S, Université Pierre et Marie Curie, Faculty of Medicine, Paris, France
- 7Laboratory of Applied Immunobiology, University of Zurich, Zurich, Switzerland
- 8Allergy Unit, Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
- 9Department of Endocrinology, Nutrition and Diabetes, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière-Charles Foix Hospital, Paris, France
- 10Department of Medicine Faculty, Université Pierre et Marie Curie, Paris, France
- Corresponding author: Eliane Piaggio, .
A.B. and L.P. contributed equally to this study.
Administration of low-dose interleukin-2 (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 (1 mg/kg daily) (RAPA/IL-2) combination. We show that, despite further boosting of Treg cells, high doses of IL-2 rapidly precipitated T1D in prediabetic 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, the RAPA/IL-2 combination failure to cure T1D was associated with an unexpected deleterious effect on glucose homeostasis at multiple levels, including β-cell division, glucose tolerance, and liver glucose metabolism. Our data help to understand the therapeutic limitations of IL-2 alone or RAPA/IL-2 combination and could lead to the design of improved therapies for T1D.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0214/-/DC1.
- Received February 8, 2013.
- Accepted May 8, 2013.
- © 2013 by the American Diabetes Association.
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