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J Autoimmun. 2015 Apr;58:48-58. doi: 10.1016/j.jaut.2015.01.001. Epub 2015 Jan 26.

Low-dose interleukin-2 fosters a dose-dependent regulatory T cell tuned milieu in T1D patients.

Author information

1
AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), F-75651, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France; Inserm, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France.
2
Inserm, U1016, Institut Cochin, Immunology of Diabetes Team, DeAR Lab, F-75014, Paris, France; CNRS, UMR8104, F-75014, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, F-75014, Paris, France; AP-HP, Hôpital Cochin-Port Royal, Diabetology Department, F-75014, Paris, France.
3
Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
4
ILTOO Pharma, iPEPS ICM, Hôpital Pitié Salpêtrière, 75013, Paris, France.
5
AP-HP, Hôpital Pitié-Salpêtrière, Diabetology, F-75651, Paris, France.
6
The Diabetes Research Institute, University of Miami, Miami, FL, USA; Department of Microbiology and Immunology, University of Miami, Miami, FL, USA.
7
The Diabetes Research Institute, University of Miami, Miami, FL, USA; Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Microbiology and Immunology, University of Miami, Miami, FL, USA.
8
AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), F-75651, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France; Inserm, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France. Electronic address: david.klatzmann@upmc.fr.

Abstract

Most autoimmune diseases (AID) are linked to an imbalance between autoreactive effector T cells (Teffs) and regulatory T cells (Tregs). While blocking Teffs with immunosuppression has long been the only therapeutic option, activating/expanding Tregs may achieve the same objective without the toxicity of immunosuppression. We showed that low-dose interleukin-2 (ld-IL-2) safely expands/activates Tregs in patients with AID, such HCV-induced vasculitis and Type 1 Diabetes (T1D). Here we analyzed the kinetics and dose-relationship of IL-2 effects on immune responses in T1D patients. Ld-IL-2 therapy induced a dose-dependent increase in CD4(+)Foxp3(+) and CD8(+)Foxp3(+) Treg numbers and proportions, the duration of which was markedly dose-dependent. Tregs expressed enhanced levels of activation markers, including CD25, GITR, CTLA-4 and basal pSTAT5, and retained a 20-fold higher sensitivity to IL-2 than Teff and NK cells. Plasma levels of regulatory cytokines were increased in a dose-dependent manner, while cytokines linked to Teff and Th17 inflammatory cells were mostly unchanged. Global transcriptome analyses showed a dose-dependent decrease in immune response signatures. At the highest dose, Teff responses against beta-cell antigens were suppressed in all 4 patients tested. These results inform of broader changes induced by ld-IL-2 beyond direct effects on Tregs, and relevant for further development of ld-IL-2 for therapy and prevention of T1D, and other autoimmune and inflammatory diseases.

KEYWORDS:

Immunopathology; Immunotherapy; Inflammation; Pharmacokinetics; Tolerance

PMID:
25634360
DOI:
10.1016/j.jaut.2015.01.001
[Indexed for MEDLINE]
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