Functional analysis of clinical response to low-dose IL-2 in patients with refractory chronic graft-versus-host disease.

Abstract

Patients with chronic graft-versus-host disease (cGVHD) have a paucity of regulatory CD4 T cells (CD4Tregs) that mediate peripheral tolerance. In clinical trials, daily low-dose interleukin-2 (IL-2) has been administered safely for prolonged periods in patients with steroid-refractory cGVHD. Peripheral CD4Tregs expand dramatically in all patients during IL-2 therapy but clinical improvement was observed in ∼50% of patients. Here, we examined the impact of low-dose IL-2 therapy on functional T-cell markers and the T-cell repertoire within CD4Tregs, conventional CD4 T cells (CD4Tcons), and CD8+ T cells. IL-2 had profound effects on CD4Tregs homeostasis in both response groups including selective expansion of the naive subset, improved thymic output, and increased expression of Ki67, FOXP3, and B-cell lymphoma 2 within CD4Tregs. Similar changes were not seen in CD4Tcons or CD8 T cells. Functionally, low-dose IL-2 enhanced, in vitro, CD4Treg-suppressive activity in both response groups, and all patient CD4Tcons were similarly suppressed by healthy donor CD4Tregs. High-throughput sequencing of the T-cell receptor β (TCRβ) locus demonstrated that low-dose IL-2 therapy increased TCR repertoire diversity and decreased evenness within CD4Tregs without affecting CD4Tcons or CD8 T cells. Using clone-tracking analysis, we observed rapid turnover of highly prevalent clones in CD4Tregs as well as the conversion of CD4Tcons to CD4Tregs. After 12 weeks of daily IL-2, clinical responders had a greater influx of novel clones within the CD4Treg compartment compared with nonresponders. Further studies to define the function and specificity of these novel CD4Treg clones may help establish the mechanisms whereby low-dose IL-2 therapy promotes immune tolerance.

• Authors: Jennifer S Whangbo, Haesook T Kim, Sarah Nikiforow, John Koreth, Ana C Alho, Bryn Falahee, Soomin Kim, Katharine Dusenbury, Marie J Fields, Carol G Reynolds, Edwin P Alyea 3rd, Philippe Armand, Corey S Cutler, Vincent T Ho, Joseph H Antin, Robert J Soiffer, Jerome Ritz
• Journal: Blood advances (Blood Adv) Vol. 3 Issue 7 Pg. 984-994 (04 09 2019) ISSN: 2473-9537 [Electronic] United States
• PMID: 30936059 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 by The American Society of Hematology.

Chemical References

• Interleukin-2
• Receptors, Antigen, T-Cell
• Steroids

Topics

• CD4-Positive T-Lymphocytes
• CD8-Positive T-Lymphocytes
• Cell Proliferation
• Chronic Disease
• Drug Resistance
• Female
• Genetic Variation
• Graft vs Host Disease (drug therapy, immunology)
• Humans
• Immune Tolerance (drug effects)
• Interleukin-2 (administration & dosage, pharmacology)
• Lymphocyte Count
• Male
• Middle Aged
• Receptors, Antigen, T-Cell (genetics)
• Steroids (pharmacology)
• T-Lymphocytes, Regulatory (cytology, drug effects)