IL-35 mitigates murine acute graft-versus-host disease with retention of graft-versus-leukemia effects

Leukemia. 2015 Apr;29(4):939-46. doi: 10.1038/leu.2014.310. Epub 2014 Nov 3.

Abstract

IL-35 is a newly discovered inhibitory cytokine secreted by regulatory T cells (Tregs) and may have therapeutic potential in several inflammatory disorders. Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation and caused by donor T cells and inflammatory cytokines. The role of IL-35 in aGVHD is still unknown. Here we demonstrate that IL-35 overexpression suppresses CD4(+) effector T-cell activation, leading to a reduction in alloreactive T-cell responses and aGVHD severity. It also leads to the expansion of CD4(+)Foxp3(+) Tregs in the aGVHD target organs. Furthermore, IL-35 overexpression results in a selective decrease in the frequency of Th1 cells and an increase of IL-10-producing CD4(+) T cells in aGVHD target tissues. Serum levels of TNF-α, IFN-γ, IL-6, IL-22 and IL-23 decrease and IL-10 increases in response to IL-35. Most importantly, IL-35 preserves graft-versus-leukemia effect. Finally, aGVHD grade 2-4 patients have decreased serum IL-35 levels comparing with time-matched patients with aGVHD grade 0-1. Our findings indicate that IL-35 has an important role in reducing aGVHD through promoting the expansion of Tregs and repressing Th1 responses, and should be investigated as the therapeutic strategy for aGVHD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Cell Proliferation
  • Female
  • Gene Expression Regulation, Leukemic*
  • Graft vs Host Disease / genetics*
  • Graft vs Host Disease / immunology
  • Graft vs Host Disease / pathology
  • Graft vs Leukemia Effect / immunology*
  • Hematopoietic Stem Cell Transplantation*
  • Humans
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Interleukin-10 / genetics
  • Interleukin-10 / immunology
  • Interleukin-23 / genetics
  • Interleukin-23 / immunology
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology
  • Interleukins / genetics
  • Interleukins / immunology*
  • Leukemia / genetics*
  • Leukemia / immunology
  • Leukemia / pathology
  • Lymphocyte Activation
  • Male
  • Mice
  • Signal Transduction
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology
  • Th1 Cells / immunology
  • Th1 Cells / pathology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • IL10 protein, mouse
  • Interleukin-23
  • Interleukin-6
  • Interleukins
  • Tumor Necrosis Factor-alpha
  • interleukin-35, mouse
  • Interleukin-10
  • Interferon-gamma
  • interleukin-22