| First Author | Hechinger AK | Year | 2015 |
| Journal | Blood | Volume | 125 |
| Issue | 3 | Pages | 570-80 |
| PubMed ID | 25352130 | Mgi Jnum | J:221211 |
| Mgi Id | MGI:5638497 | Doi | 10.1182/blood-2014-06-581793 |
| Citation | Hechinger AK, et al. (2015) Therapeutic activity of multiple common gamma-chain cytokine inhibition in acute and chronic GVHD. Blood 125(3):570-80 |
| abstractText | 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 tumor necrosis factor, interferon-gamma, 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 gamma-chain cytokines, each represent therapeutic targets for anti-CD132 mAb immunomodulation. |
