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 (Tregs) 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 Tregs 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 Tregs 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.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA. Electronic address: S.I.itos2@mail.nih.gov.
authors.forename: Sawa
authors.initials: S
authors.lastname: Ito
authors.affiliation: Children's National Health System and The George Washington University, Washington, District of Columbia, USA.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Bollard
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Mattias
authors.initials: M
authors.lastname: Carlsten
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA; Current address: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Jan Joseph
authors.initials: JJ
authors.lastname: Melenhorst
authors.affiliation: Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Angélique
authors.initials: A
authors.lastname: Biancotto
authors.affiliation: Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, National Institutes of Health, Bethesda, Maryland, USA; Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA; Current address: Research Branch, Sidra Medical and Research Centre, Doha, Qatar.
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.affiliation: Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jinguo
authors.initials: J
authors.lastname: Chen
authors.affiliation: Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kotliarov
authors.affiliation: Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Foo
authors.initials: F
authors.lastname: Cheung
authors.affiliation: Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, National Institutes of Health, Bethesda, Maryland, USA; Current address: Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, National Institutes of Health, Bethesda, Maryland, USA; Current address: Research Branch, Sidra Medical and Research Centre, Doha, Qatar.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marincola
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA; Current address: Department of Hematology, Clinical Immunology and Infectious Disease, Ehime University, Ehime, Japan.
authors.forename: Kazushi
authors.initials: K
authors.lastname: Tanimoto
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Minoo
authors.initials: M
authors.lastname: Battiwalla
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA; Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, National Institutes of Health, Bethesda, Maryland, USA; Current address: Alaska Native Tribal Health Consortium, Anchorage, Alaska, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Olnes
authors.affiliation: Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Shira
authors.initials: S
authors.lastname: Perl
authors.affiliation: Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Schum
authors.affiliation: Pharmacy Department, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hughes
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Keyvan
authors.initials: K
authors.lastname: Keyvanfar
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Hensel
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Pawel
authors.initials: P
authors.lastname: Muranski
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA; Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Neal S
authors.initials: NS
authors.lastname: Young
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: A John
authors.initials: AJ
authors.lastname: Barrett
mesh_terms: D000328:Adult; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*; D055815:Young Adult
chemical_list: D007376:Interleukin-2; D018664:Interleukin-12; D007371:Interferon-gamma