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 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 TNF, IFN-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, while 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 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 gamma chain cytokines, each represent therapeutic targets for anti-CD132 mAb immunomodulation.