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

Hechinger, Anne-Kathrin and Smith, Benjamin and Flynn, Ryan and Hanke, Kathrin and McDonald-Hyman, Cameron and Taylor, Patricia A and Pfeifer, Dietmar and Hackanson, Björn and Leonhardt, Franziska and Prinz, Gabriele and Dierbach, Heide and Schmmitt-Gräff, Annette and Kovarik, Jiri and Blazar, Bruce and Zeiser, Robert (2015) Therapeutic activity of multiple common g-chain cytokine inhibition in acute and chronic GVHD. Blood, 125 (3). pp. 570-580.

Abstract

The common g 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-g, and
IL-6, and GVHD histopathology. Anti-CD132 mAb afforded protection from GVHD partly
via inhibition of granzymeBproduction inCD8 T cells, whereas exposure of CD8 T cells to
IL-2, IL-7, IL-15, and IL-21 increased granzymeBproduction. Also, T cells exposed to anti-
CD132mAbdisplayed 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, Jak32/2 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 g-chain cytokines, each
represent therapeutic targets for anti-CD132 mAb immunomodulation.

Item Type: Article
Additional Information: The anti-CD132 monoclonal antibody used in this study is a mouse specific tool or surrogate antibody that was generated at NIBR. It is not crossreactive to human CD132 and thus not a development candidate and not at all related to the current CSP candidate NVP-CSJ095. CD132 is a known target and mouse CD132 specific antibodies were reported to modulate allograft rejection. This study describes for the first time an activity of an anti-mouse CD132 mAb in the murine GvHD model.
Keywords: acute and chronic GvHD, CD132, common gamma chain, allogeneic bone marrow transplantation, CD8 T cells, Granzyme B
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/22353

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