Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD

Blood. 2015 Jan 15;125(3):570-80. doi: 10.1182/blood-2014-06-581793. Epub 2014 Oct 28.

Abstract

The common γ chain (CD132) is a subunit of the interleukin (IL) receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Because levels of several of these cytokines were shown to be increased in the serum of patients developing acute and chronic graft-versus-host disease (GVHD), we reasoned that inhibition of CD132 could have a profound effect on GVHD. We observed that anti-CD132 monoclonal antibody (mAb) reduced acute GVHD potently with respect to survival, production of tumor necrosis factor, interferon-γ, and IL-6, and GVHD histopathology. Anti-CD132 mAb afforded protection from GVHD partly via inhibition of granzyme B production in CD8 T cells, whereas exposure of CD8 T cells to IL-2, IL-7, IL-15, and IL-21 increased granzyme B production. Also, T cells exposed to anti-CD132 mAb displayed a more naive phenotype in microarray-based analyses and showed reduced Janus kinase 3 (JAK3) phosphorylation upon activation. Consistent with a role of JAK3 in GVHD, Jak3(-/-) T cells caused less severe GVHD. Additionally, anti-CD132 mAb treatment of established chronic GVHD reversed liver and lung fibrosis, and pulmonary dysfunction characteristic of bronchiolitis obliterans. We conclude that acute GVHD and chronic GVHD, caused by T cells activated by common γ-chain cytokines, each represent therapeutic targets for anti-CD132 mAb immunomodulation.

Publication types

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

MeSH terms

  • Acute Disease
  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Blotting, Western
  • Bone Marrow Transplantation / adverse effects*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • Cells, Cultured
  • Chronic Disease
  • Cytokines / metabolism*
  • Female
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Graft vs Host Disease / etiology
  • Graft vs Host Disease / mortality
  • Graft vs Host Disease / prevention & control*
  • Humans
  • Interleukin Receptor Common gamma Subunit / antagonists & inhibitors*
  • Janus Kinase 3 / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL

Substances

  • Antibodies, Monoclonal
  • Cytokines
  • Interleukin Receptor Common gamma Subunit
  • Jak3 protein, mouse
  • Janus Kinase 3