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.
journal_name
Bloodjournal_title
Bloodauthors
Hechinger AK,Smith BA,Flynn R,Hanke K,McDonald-Hyman C,Taylor PA,Pfeifer D,Hackanson B,Leonhardt F,Prinz G,Dierbach H,Schmitt-Graeff A,Kovarik J,Blazar BR,Zeiser Rdoi
10.1182/blood-2014-06-581793subject
Has Abstractpub_date
2015-01-15 00:00:00pages
570-80issue
3eissn
0006-4971issn
1528-0020pii
blood-2014-06-581793journal_volume
125pub_type
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