Ultra-low dose interleukin-2 promotes immune-modulating function of regulatory t cells and natural killer cells in healthy volunteers

Sawa Ito, Catherine M. Bollard, Mattias Carlsten, Jan Joseph Melenhorst, Angélique Biancotto, Ena Wang, Jinguo Chen, Yuri Kotliarov, Foo Cheung, Zhi Xie, Francesco Marincola, Kazushi Tanimoto, Minoo Battiwalla, Matthew J. Olnes, Shira Perl, Paula Schum, Thomas E. Hughes, Keyvan Keyvanfar, Nancy Hensel, Pawel MuranskiNeal S. Young, A. John Barrett

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Abstract

Low-dose interleukin-2 (IL-2) expands regulatory T cells (T regs) and natural killer (NK) cells after stem cell transplantation (SCT) and may reduce graft-versus-host disease (GVHD). We hypothesized that ultra-low dose (ULD) IL-2 could serve as an immune-modulating agent for stem cell donors to prevent GVHD following SCT. However, the safety, dose level, and immune signatures of ULD IL-2 in immune-competent healthy subjects remain unknown. Here, we have characterized the phenotype and function of T regs and NK cells as well as the gene expression and cytokine profiles of 21 healthy volunteers receiving 50,000 to 200,000 units/m 2 /day IL-2 for 5 days. ULD IL-2 was well tolerated and induced a significant increase in the frequency of T regs with increased suppressive function. There was a marked expansion of CD56 bright NK cells with enhanced interferon-γ (IFN-γ) production. Serum cytokine profiling demonstrated increase of IFN-γ induced protein 10 (IP-10). Gene expression analysis revealed significant changes in a highly restricted set of genes, including FOXP3, IL-2RA, and CISH. This is the first study to evaluate global immune-modulating function of ULD IL-2 in healthy subjects and to support the future studies administrating ULD IL-2 to stem cell donors.

Original languageEnglish
Pages (from-to)1388-1395
Number of pages8
JournalMolecular Therapy
Volume22
Issue number7
DOIs
Publication statusPublished - Jul 2014

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ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Ito, S., Bollard, C. M., Carlsten, M., Melenhorst, J. J., Biancotto, A., Wang, E., Chen, J., Kotliarov, Y., Cheung, F., Xie, Z., Marincola, F., Tanimoto, K., Battiwalla, M., Olnes, M. J., Perl, S., Schum, P., Hughes, T. E., Keyvanfar, K., Hensel, N., ... Barrett, A. J. (2014). Ultra-low dose interleukin-2 promotes immune-modulating function of regulatory t cells and natural killer cells in healthy volunteers. Molecular Therapy, 22(7), 1388-1395. https://doi.org/10.1038/mt.2014.50