Attenuation of murine sclerodermatous models by the selective S1P1 receptor modulator cenerimod.

Sphingosine-1-phosphate (S1P), a lipid mediator, regulates lymphocyte migration between lymphoid tissue and blood. Furthermore, S1P participates in several physiological phenomena including angiogenesis, inflammation, immune regulation, and neurotransmitter release. Moreover, S1P/S1P receptor signaling involves in systemic sclerosis (SSc) pathogenesis. This study aimed to investigate whether the selective S1P1 receptor modulator cenerimod attenuates murine sclerodermatous models. Cenerimod was orally administered to murine sclerodermatous chronic graft versus host disease (Scl-cGVHD) mice, either from day 0 to 42 or day 22 to 42 after bone marrow transplantation. Bleomycin-induced SSc model mice were administered cenerimod from day 0 to 28. Early cenerimod administration inhibited, and delayed cenerimod administration attenuated skin and lung fibrosis in Scl-cGVHD mice. Cenerimod suppressed the infiltration of CD4+ T cells, CD8+ T cells, and CD11b+ cells into the inflamed skin of Scl-cGVHD mice as opposed to control mice. In contrast, cenerimod increased the frequency of regulatory T cells in the spleen and skin of Scl-cGVHD mice. Additionally, cenerimod attenuated the mRNA expression of extracellular matrix and fibrogenic cytokines in the skin. Furthermore, cenerimod attenuated bleomycin-induced fibrosis in the skin and lung. Hence, the selective S1P1 receptor modulator cenerimod is a promising candidate for treating patients with SSc and Scl-cGVHD.

Blockade of p38 Mitogen-Activated Protein Kinase Inhibits Murine Sclerodermatous Chronic Graft-versus-Host Disease.

Bone marrow transplantation (BMT) of B10.D2 mice into sublethally irradiated BALB/c mice across minor histocompatibility loci is a well-established animal model for human sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) and systemic sclerosis (SSc). The p38 mitogen-activated protein kinase (MAPK) pathway is a key regulator of inflammation and cytokine production. Furthermore, the activation of p38 MAPK plays an important role in collagen production in SSc. We investigated the effects of p38 MAPK inhibitor, VX-702, on Scl-cGVHD mice. VX-702 was orally administered to Scl-cGVHD mice from day 7 to 35 after BMT. We compared skin fibrosis of Scl-cGVHD mice between the VX-702-treated group and control group. Allogeneic BMT increased the phosphorylation of p38 MAPK in the skin. The administration of VX-702 attenuated the skin fibrosis of Scl-cGVHD compared to the control mice. Immunohistochemical staining showed that VX-702 suppressed the infiltration of CD4+ T cells, CD8+ T cells, and CD11b+ cells into the dermis of Scl-cGVHD mice compared to the control mice. VX-702 attenuated the mRNA expression of extracellular matrix and fibrogenic cytokines, such as IL-6 and IL-13, in the skin of Scl-cGVHD mice. In addition, VX-702 directly inhibited collagen production from fibroblasts in vitro. VX-702 was shown to be a promising candidate for use in treating patients with Scl-cGVHD and SSc.

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-1α, IFN-γ, IL-13, IL-17A, and TGF-ß1, but not influenced RANTES, CXCL12, and TFN-α. 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.