IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells.
Regulatory T cells (T reg cells) play a major role in controlling the pathogenic autoimmune process in type 1 diabetes (T1D). Interleukin 2 (IL-2), a cytokine which promotes T reg cell survival and function, may thus have therapeutic efficacy in T1D. We show that 5 d of low-dose IL-2 administration starting at the time of T1D onset can reverse established disease in NOD (nonobese diabetic) mice, with long-lasting effects. Low-dose IL-2 increases the number of T reg cells in the pancreas and induces expression of T reg cell-associated proteins including Foxp3, CD25, CTLA-4, ICOS (inducible T cell costimulator), and GITR (glucocorticoid-induced TNF receptor) in these cells. Treatment also suppresses interferon gamma production by pancreas-infiltrating T cells. Transcriptome analyses show that low-dose IL-2 exerts much greater influence on gene expression of T reg cells than effector T cells (T eff cells), suggesting that nonspecific activation of pathogenic T eff cells is less likely. We provide the first preclinical data showing that low-dose IL-2 can reverse established T1D, suggesting that this treatment merits evaluation in patients with T1D.
Grinberg-Bleyer
Yenkel
Y
Université Pierre et Marie Curie Univ Paris 06, Centre National de la Recherche Scientifique, UMR 7211, Paris, France.
Baeyens
Audrey
A
You
Sylvaine
S
Elhage
Rima
R
Fourcade
Gwladys
G
Gregoire
Sylvie
S
Cagnard
Nicolas
N
Carpentier
Wassila
W
Tang
Qizhi
Q
Bluestone
Jeffrey
J
Chatenoud
Lucienne
L
Klatzmann
David
D
Salomon
Benoît L
BL
Piaggio
Eliane
E
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D006410:Hematopoiesis / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology* / Q000627:therapeutic use; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
D007376:Interleukin-2; D007371:Interferon-gamma