title: Limitations of IL-2 and rapamycin in immunotherapy of type 1 diabetes.
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.
authors.affiliation: Université Pierre et Marie Curie, Paris, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Baeyens
authors.forename: Louis
authors.initials: L
authors.lastname: Pérol
authors.forename: Gwladys
authors.initials: G
authors.lastname: Fourcade
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cagnard
authors.forename: Wassila
authors.initials: W
authors.lastname: Carpentier
authors.forename: Janine
authors.initials: J
authors.lastname: Woytschak
authors.forename: Onur
authors.initials: O
authors.lastname: Boyman
authors.forename: Agnès
authors.initials: A
authors.lastname: Hartemann
authors.forename: Eliane
authors.initials: E
authors.lastname: Piaggio
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000628:therapy*; D004338:Drug Combinations; D005434:Flow Cytometry; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D020123:Sirolimus / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism
chemical_list: D004338:Drug Combinations; D007376:Interleukin-2; D020123:Sirolimus