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: Ken-ichi Matsuoka, John Koreth, Haesook T Kim, Gregory Bascug, Sean McDonough, Yutaka Kawano, Kazuyuki Murase, Corey Cutler, Vincent T Ho, Edwin P Alyea, Philippe Armand, Bruce R Blazar, Joseph H Antin, Robert J Soiffer, Jerome Ritz
• Journal: Science translational medicine (Sci Transl Med) Vol. 5 Issue 179 Pg. 179ra43 (Apr 03 2013) ISSN: 1946-6242 [Electronic] United States
• PMID: 23552371 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-2
• STAT5 Transcription Factor

Topics

• Adult
• Apoptosis (drug effects, immunology)
• Cell Proliferation (drug effects)
• Chronic Disease
• Dose-Response Relationship, Drug
• Female
• Graft vs Host Disease (drug therapy, immunology)
• Homeostasis (drug effects, immunology)
• Humans
• Immunophenotyping
• Interleukin-2 (administration & dosage, therapeutic use)
• Lymphocyte Activation (drug effects, immunology)
• Male
• Middle Aged
• STAT5 Transcription Factor (metabolism)
• Signal Transduction (drug effects, immunology)
• T-Lymphocytes, Regulatory (drug effects, immunology)
• Young Adult