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 Muranski & 2 others Neal S. Young, A. John Barrett

Research output: Contribution to journalArticle

51 Citations (Scopus)

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 - 2014

Fingerprint

Natural Killer Cells
Interleukin-2
Healthy Volunteers
Natural Killer T-Cells
Stem Cell Transplantation
Graft vs Host Disease
Interferons
Stem Cells
Tissue Donors
Cytokines
Interleukin-5
Regulatory T-Lymphocytes
Transcriptome
Phenotype
Safety
Gene Expression
Serum
Genes
Proteins

ASJC Scopus subject areas

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

Cite this

Ultra-low dose interleukin-2 promotes immune-modulating function of regulatory t cells and natural killer cells in healthy volunteers. / Ito, Sawa; Bollard, Catherine M.; Carlsten, Mattias; Melenhorst, Jan Joseph; Biancotto, Angélique; Wang, Ena; Chen, Jinguo; Kotliarov, Yuri; Cheung, Foo; Xie, Zhi; Marincola, Francesco; Tanimoto, Kazushi; Battiwalla, Minoo; Olnes, Matthew J.; Perl, Shira; Schum, Paula; Hughes, Thomas E.; Keyvanfar, Keyvan; Hensel, Nancy; Muranski, Pawel; Young, Neal S.; Barrett, A. John.

In: Molecular Therapy, Vol. 22, No. 7, 2014, p. 1388-1395.

Research output: Contribution to journalArticle

Ito, S, Bollard, CM, Carlsten, M, Melenhorst, JJ, Biancotto, A, Wang, E, Chen, J, Kotliarov, Y, Cheung, F, Xie, Z, Marincola, F, Tanimoto, K, Battiwalla, M, Olnes, MJ, Perl, S, Schum, P, Hughes, TE, Keyvanfar, K, Hensel, N, Muranski, P, Young, NS & Barrett, AJ 2014, 'Ultra-low dose interleukin-2 promotes immune-modulating function of regulatory t cells and natural killer cells in healthy volunteers', Molecular Therapy, vol. 22, no. 7, pp. 1388-1395. https://doi.org/10.1038/mt.2014.50
Ito, Sawa ; Bollard, Catherine M. ; Carlsten, Mattias ; Melenhorst, Jan Joseph ; Biancotto, Angélique ; Wang, Ena ; Chen, Jinguo ; Kotliarov, Yuri ; Cheung, Foo ; Xie, Zhi ; Marincola, Francesco ; Tanimoto, Kazushi ; Battiwalla, Minoo ; Olnes, Matthew J. ; Perl, Shira ; Schum, Paula ; Hughes, Thomas E. ; Keyvanfar, Keyvan ; Hensel, Nancy ; Muranski, Pawel ; Young, Neal S. ; Barrett, A. John. / Ultra-low dose interleukin-2 promotes immune-modulating function of regulatory t cells and natural killer cells in healthy volunteers. In: Molecular Therapy. 2014 ; Vol. 22, No. 7. pp. 1388-1395.
@article{ee627e77e05342e9a8fbdba787909244,
title = "Ultra-low dose interleukin-2 promotes immune-modulating function of regulatory t cells and natural killer cells in healthy volunteers",
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.",
author = "Sawa Ito and Bollard, {Catherine M.} and Mattias Carlsten and Melenhorst, {Jan Joseph} and Ang{\'e}lique Biancotto and Ena Wang and Jinguo Chen and Yuri Kotliarov and Foo Cheung and Zhi Xie and Francesco Marincola and Kazushi Tanimoto and Minoo Battiwalla and Olnes, {Matthew J.} and Shira Perl and Paula Schum and Hughes, {Thomas E.} and Keyvan Keyvanfar and Nancy Hensel and Pawel Muranski and Young, {Neal S.} and Barrett, {A. John}",
year = "2014",
doi = "10.1038/mt.2014.50",
language = "English",
volume = "22",
pages = "1388--1395",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "7",

}

TY - JOUR

T1 - Ultra-low dose interleukin-2 promotes immune-modulating function of regulatory t cells and natural killer cells in healthy volunteers

AU - Ito, Sawa

AU - Bollard, Catherine M.

AU - Carlsten, Mattias

AU - Melenhorst, Jan Joseph

AU - Biancotto, Angélique

AU - Wang, Ena

AU - Chen, Jinguo

AU - Kotliarov, Yuri

AU - Cheung, Foo

AU - Xie, Zhi

AU - Marincola, Francesco

AU - Tanimoto, Kazushi

AU - Battiwalla, Minoo

AU - Olnes, Matthew J.

AU - Perl, Shira

AU - Schum, Paula

AU - Hughes, Thomas E.

AU - Keyvanfar, Keyvan

AU - Hensel, Nancy

AU - Muranski, Pawel

AU - Young, Neal S.

AU - Barrett, A. John

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84903777370&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84903777370&partnerID=8YFLogxK

U2 - 10.1038/mt.2014.50

DO - 10.1038/mt.2014.50

M3 - Article

VL - 22

SP - 1388

EP - 1395

JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

IS - 7

ER -