Blockade of Syk ameliorates the development of murine sclerodermatous chronic graft-versus-host disease

Background: Murine sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) is a model for human Scl-cGVHD and systemic sclerosis (SSc). Syk is expressed in most of hematopoietic cells, fibroblasts, and endothelial cells. Syk is a protein tyrosine kinase that has an important role in transmitting signals from a variety of cell surface receptors. Objective: This study aims to investigate the effect of R788 (fostamatinib sodium), an oral prodrug that is rapidly converted to a potent inhibitor of Syk, R406, on Scl-cGVHD. Methods: R788 was orally administered twice a day to allogeneic recipients from day 14 to day 42 after bone marrow transplantation (BMT). In vitro, proliferation of GVHD-derived CD4(+) T cells and CD11b(+) cells was analyzed by R406. Results: Allogeneic BMT increased Syk phosphorylation in T, B, and CD11b(+) cells. The administration of R788 attenuated severity and fibrosis of Scl-cGVHD. The elevated expressions of CXCR4 on T cells, B cells, and CD11b(+) cells were significantly down-regulated by R788 treatment. R788 reduced memory CD4(+) T cells (CD44(hi)CD62L-CD4(+)). R406 inhibited proliferation of GVHD CD4(+)T cells and CD11b(+) cells in vitro. In addition, R788 treatment, inhibited proliferation of CD11b(+) cells in Scl-cGVHD mice. R788 treatment also reduced skin mRNA expressions of MCP-1, MIP-1 alpha, IFN-gamma, IL-13, IL-17A, and TGF-beta 1 but not influenced RANTES, CXCL12, and TFN-alpha. Conclusion: Blockade of Syk suppressed migration factor of immune cells and antigen-specific memory CD4(+) T cells and proliferation and activation of GVHD CD4(+)T cells and CD11b(+) cells. The current studies suggested that Syk inhibitor is a potential candidate for use in treating patients with Scl-cGVHD and SSc. (C) 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.