E-MEXP-3789 - Transcription profiling by array of NOD mouse livers treated with interleukin-2, rapamycin, a combination of both, or no compounds to evaluate the compounds' efficacy in type 1 diabetes therapies
Last updated on 14 December 2012, released on 10 December 2013
Administration of low-dose IL-2 prevents and cures type 1 diabetes (T1D) in NOD mice by boosting pancreatic regulatory T cells (Tregs) and is currently being evaluated in humans. Here, to improve treatment efficacy we tested higher IL-2 doses that, despite further boosting Tregs, rapidly precipitated T1D in pre-diabetic mice due to generalized immune activation. Although the combination of rapamycin (RAPA) plus IL-2 prevents NOD T1D development, a recent clinical trial translating this strategy into patients was halted due to C-peptide decline. Here, we show that RAPA/IL-2 combination was also ineffective to cure new onset T1D in mice and, surprisingly, RAPA broke IL-2-induced tolerance in a reversible way. RAPA partially counteracted IL-2 effects on Tregs and the combined treatment unexpectedly, impaired glucose homeostasis at multiple levels, possibly explaining the clinical outcome. Our data help understand IL-2 alone or RAPA/IL-2 combination limitations and could lead to the design of improved T1D therapies.
transcription profiling by array, co-expression, in vivo, stimulated type