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

نویسندگان

  • 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
چکیده

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.

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منابع مشابه

Therapeutic activity of multiple common gamma chain cytokine inhibition in acute and chronic GvHD Running title: CD132 INHIBITION REDUCES GVHD

• Monoclonal antibody blockade of the common gamma chain attenuates acute and chronic GvHD. • Common gamma chain cytokines increase granzyme B levels in CD8 T cells, which is reduced upon CD132 blockade in vivo. Abstract The common gamma 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 sh...

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

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عنوان ژورنال:
  • Blood

دوره 125 3  شماره 

صفحات  -

تاریخ انتشار 2015