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

Anne Kathrin Hechinger, Benjamin A H Smith, Ryan Flynn, Kathrin Hanke, Cameron McDonald-Hyman, Patricia A. Taylor, Dietmar Pfeifer, Björn Hackanson, Franziska Leonhardt, Gabriele Prinz, Heide Dierbach, Annette Schmitt-Graeff, Jiri Kovarik, Bruce R. Blazar, Robert Zeiser

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)570-580
Number of pages11
JournalBlood
Volume125
Issue number3
DOIs
StatePublished - Jan 15 2015

Fingerprint Dive into the research topics of 'Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD'. Together they form a unique fingerprint.

Cite this