Limitations of IL-2 and rapamycin in immunotherapy of type 1 diabetes

  1. Eliane Piaggio1,2,3,#,**
  1. 1Université Pierre et Marie Curie Univ Paris 06
  2. 2Centre National de la Recherche Scientifique, UMR 7211
  3. 3Institut National de la Santé et de la Recherche Médicale (INSERM), U 959, Immunology-Immunopathology-Immunotherapy (I3), 75013 Paris, France
  4. 4INSERM U580
  5. 5Bioinformatics Platform, Faculty of Medicine Paris Descartes, Hôpital Necker-Enfants Malades, 75015 Paris, France
  6. 5Plate-forme Post-Génomique P3S, UPMC Univ Paris 6, Faculty of Medicine, 75013 Paris, France.
  7. 6Laboratory of Applied Immunobiology, University of Zurich, CH-8006 Zurich, Switzerland.
  8. 7Allergy Unit, Department of Dermatology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
  9. 8Department of Endocrinology, Nutrition and Diabetes, Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière-Charles Foix Hospital, Paris, France.
  10. 9Department of Medicine Faculty, Université Pierre et Marie Curie - Paris 6, Paris, France.
  1. **Corresponding author: eliane.piaggio{at}yahoo.com
  1. * These authors contributed equally to this work

  • # Current address: Institut National de la Santé et de la Recherche Médicale Unité 932, 75005 Paris, France; and Centre de Recherche, Laboratoire d’Immunologie Clinique, Institut Curie, 75005 Paris, France.

Abstract

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.

Footnotes

    • Received February 8, 2013.
    • Accepted May 7, 2013.

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