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SOCS3 regulates graft-versus-host disease


Hill, GR; Kuns, RD; Raffelt, NC; Don, ALJ; Olver, SD; Markey, KA; Wilson, YA; Tocker, J; Alexander, WS; Clouston, AD; Roberts, AW; MacDonald, KPA
2010-07-15
BLOOD
Journal Article
116
2
287-296
Suppressor of cytokine signaling-3 (SOCS3) is the main intracellular regulator of signaling by granulocyte colony-stimulating factor, an immune-modulatory cytokine used to mobilize stem cells for transplantation. We have therefore studied the contribution of SOCS3 to the spectrum of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Grafts from SOCS3(-/Delta vav) donor mice in which SOCS3 deficiency is restricted to the hematopoietic compartment had an augmented capacity to induce acute GVHD. With the use of SOCS3(-/Delta LysM) and SOCS3(-/Delta lck) donors in which SOCS3 deficiency was restricted to the myeloid or T-cell lineage, respectively, we confirmed SOCS3 deficiency promoted acute GVHD mortality and histopathology within the gastrointestinal tract by effects solely within the donor T cell. SOCS3(-/Delta lck) donor T cells underwent enhanced alloantigen-dependent proliferation and generation of interleukin-10 (IL-10), IL-17, and interferon-gamma (IFN gamma) after SCT. The enhanced capacity of the SOCS3(-/Delta lck) donor T cell to induce acute GVHD was dependent on IFN gamma but independent of IL-10 or IL-17. Surprisingly, SOCS3(-/Delta lck) donor T cells also induced severe, transforming growth factor beta- and IFN gamma-dependent, sclerodermatous GVHD. Thus, the delivery of small molecule SOCS3 mimetics may prove to be useful for the inhibition of both acute and chronic GVHD. (Blood. 2010; 116(2): 287-296)
AMER SOC HEMATOLOGY
IDIOPATHIC PNEUMONIA SYNDROME; BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; COLONY-STIMULATING FACTOR; ANTIGEN-PRESENTING CELLS; T-CELLS; DENDRITIC CELLS; IFN-GAMMA; TGF-BETA; CYTOKINE SIGNALING-3
10.1182/blood-2009-12-259598
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