Limitations of IL-2 and Rapamycin in Immunotherapy of Type 1 Diabetes

  1. Eliane Piaggio1,2,3
  1. 1Université Pierre et Marie Curie, Paris, France
  2. 2Centre National de la Recherche Scientifique, UMR 7211, Paris, France
  3. 3Department of Immunology-Immunopathology-Immunotherapy, INSERM U959, Paris, France
  4. 4INSERM U580, Paris, France
  5. 5Bioinformatics Platform, Faculty of Medicine Paris Descartes, Hôpital Necker-Enfants Malades, Paris, France
  6. 6Plateforme Post-Génomique P3S, Université Pierre et Marie Curie, Faculty of Medicine, Paris, France
  7. 7Laboratory of Applied Immunobiology, University of Zurich, Zurich, Switzerland
  8. 8Allergy Unit, Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
  9. 9Department of Endocrinology, Nutrition and Diabetes, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière-Charles Foix Hospital, Paris, France
  10. 10Department of Medicine Faculty, Université Pierre et Marie Curie, Paris, France
  1. Corresponding author: Eliane Piaggio, elianepiaggio{at}yahoo.com.
  1. A.B. and L.P. contributed equally to this study.

  • E.P. and L.P. are currently affiliated with INSERM 932, Paris, France, and Centre de Recherche, Laboratoire d’Immunologie Clinique, Institut Curie, Paris, France.

Abstract

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.

Footnotes

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

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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  1. Diabetes vol. 62 no. 9 3120-3131
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