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

Michelle Rosenzwajg, Guillaume Churlaud, Roberto Mallone, Adrien Six, Nicolas Dérian, Wahiba Chaara, Roberta Lorenzon, S. Alice Long, Jane H. Buckner, Georgia Afonso, Hang Phuong Pham, Agnès Hartemann, Aixin Yu, Alberto Pugliese, Thomas R. Malek, David Klatzmann

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)48-58
Number of pages11
JournalJournal of Autoimmunity
Volume58
DOIs
StatePublished - Apr 1 2015

Keywords

  • Immunopathology
  • Immunotherapy
  • Inflammation
  • Pharmacokinetics
  • Tolerance

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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