title: Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease.
abstract: CD4(+)Foxp3(+) regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation. We recently reported that daily administration of low-dose interleukin-2 (IL-2) induces selective expansion of functional Tregs and clinical improvement of chronic graft-versus-host disease (GVHD). To define the mechanisms of action of IL-2 therapy, we examined the immunologic effects of this treatment on homeostasis of CD4(+) T cell subsets after transplant. We first demonstrated that chronic GVHD is characterized by constitutive phosphorylation of signal transducer and activator of transcription 5 (Stat5) in conventional CD4(+) T cells (Tcons) associated with elevated amounts of IL-7 and IL-15 and relative functional deficiency of IL-2. IL-2 therapy resulted in the selective increase of Stat5 phosphorylation in Tregs and a decrease of phosphorylated Stat5 in Tcons. Over an 8-week period, IL-2 therapy induced a series of changes in Treg homeostasis, including increased proliferation, increased thymic export, and enhanced resistance to apoptosis. Low-dose IL-2 had minimal effects on Tcons. These findings define the mechanisms whereby low-dose IL-2 therapy restores the homeostasis of CD4(+) T cell subsets and promotes the reestablishment of immune tolerance.
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Matsuoka
authors.forename: John
authors.initials: J
authors.lastname: Koreth
authors.forename: Haesook T
authors.initials: HT
authors.lastname: Kim
authors.forename: Gregory
authors.initials: G
authors.lastname: Bascug
authors.forename: Sean
authors.initials: S
authors.lastname: McDonough
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawano
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Murase
authors.forename: Corey
authors.initials: C
authors.lastname: Cutler
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Ho
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Alyea
authors.forename: Philippe
authors.initials: P
authors.lastname: Armand
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology*; D006706:Homeostasis / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000627:therapeutic use*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D055815:Young Adult
chemical_list: D007376:Interleukin-2; D050799:STAT5 Transcription Factor
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