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

Abstract

Key Points• Monoclonal antibody blockade of the common g chain attenuates acute and chronic GVHD.• Common g-chain cytokines increase granzyme B levels in CD8 T cells, which are reduced upon CD132 blockade in vivo.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 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 2/2 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. (Blood. 2015;125(3):570-580)

Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism

“…There is mounting evidence that these 3 cytokines have important roles in cGVHD, transplantation, and autoimmunity. 7,[37][38][39] We also showed that KD025 treatment decreases the presence of TFH cells in cGVHD patient samples ( Figure 5D). This is supported by a decrease in Bcl6 expression in treated cells (Figure 5E,H).…”

Short-Term Variation of Lung Function and Airway Inflammation in Children and Adolescents with Bronchiolitis Obliterans

“…Promising new anti-inflammatory drugs such as p38 mitogen-activated protein (MAP) kinase inhibitors [33], anti-CD132 (mAb) [34] and resolvins [35] have not been studied in BO. However, it is important to note that for future proof of concept studies down regulation of neutrophilic inflammation, i.e.…”

Chronic graft-versus-host disease: biological insights from preclinical and clinical studies

“…114,115 Consistent with a link between antibody secretion and fibrosis, mice incapable of producing B cells or that produce B cells incapable of immunoglobulin isotype switching, 26 or that receive agents that either preclude GC formation 29,73,116 or deplete B cells 29,117-119 are unable to induce fibrosis or cGVHD. Thus, although unproven at this point, the interaction of allo-(and/or auto) antibody with tissue macrophages would appear an attractive unifying mechanism driving the aberrant macrophage differentiation and function that culminates in tissue fibrosis during cGVHD.…”