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

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

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • CD8 Antigens / metabolism
  • Cells, Cultured
  • Cytokines / metabolism
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / therapy*
  • Dose-Response Relationship, Drug
  • Drug Dosage Calculations
  • Female
  • Forkhead Transcription Factors / metabolism
  • Glucocorticoid-Induced TNFR-Related Protein / metabolism
  • Humans
  • Immunosuppression
  • Immunotherapy / methods*
  • Insulin-Secreting Cells / immunology
  • Interleukin-2 / administration & dosage*
  • Interleukin-2 / adverse effects
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Lymphocyte Activation
  • Male
  • Middle Aged
  • STAT5 Transcription Factor / metabolism
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocytes, Regulatory / immunology*
  • Transcriptome
  • Young Adult

Substances

  • CD8 Antigens
  • Cytokines
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Glucocorticoid-Induced TNFR-Related Protein
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • STAT5 Transcription Factor
  • TNFRSF18 protein, human