FTY720 ameliorates GvHD by blocking T lymphocyte migration to target organs and by skin fibrosis inhibition

Abstract

Background: Fibrosis is the formation of excess connective tissue in an organ or tissue during a reparative or reactive process. Graft-versus-host disease (GvHD) is a medical complication of allogeneic tissue transplantation with transplanted donor T cell-mediated inflammatory response; it is characterized by a severe immune response with fibrosis in the final stage of the inflammatory process. T helper 17 cells play a critical role in the pathogenesis of GvHD. Fingolimod (FTY720), an analogue of sphingosine-1-phosphate (S1P), is an effective immunosuppressive agent in experimental transplantation models. Methods: In this study, we evaluated the effects of FTY720 as a treatment for an animal GvHD model with inflammation and fibrosis. The splenocytes, lymph nodes, blood, tissues from Syngeneic mice and GvHD-induced mice treated vehicle or FTY720 were compared using flow cytometry, hematological analyses, histologic analyses. Results: FTY720 reduced clinical scores based on the following five clinical parameters: weight loss, posture, activity, fur texture, and skin integrity. FACS data showed that T lymphocyte numbers increased in mesenteric lymph nodes and decreased in splenocytes of FTY720-treated mice. Tissue analysis showed that FTY720 reduced skin, intestinal inflammation, and fibrotic markers. FTY720 dramatically decreased α-smooth muscle actin, connective tissue growth factor, and fibronectin protein levels in keloid skin fibroblasts. Conclusions: Thus, FTY720 suppressed migration of pathogenic T cells to target organs, reducing inflammation. FTY720 also inhibited fibrogenesis marker expression in vitro and in vivo. Together, these results suggest that FTY720 prevents GvHD progression via immunosuppression of TH17 and simultaneously acts an anti-fibrotic agent.

Current Preventions and Treatments of aGVHD: From Pharmacological Prophylaxis to Innovative Therapies

“…This is in accordance with the more recently defined fourth criteria of GVHD development (20). A variety of molecules have been testing for this effect, notably maraviroc that blocks CCR5 ( Figure 2) (81, 82), fingolimod (FTY720) that mostly interferes with T cells' infiltration into skin (83)(84)(85), and natalizumab that has been shown to mediates homing of lymphocytes to the gastrointestinal tract (86), with promising results.…”

Sphingolipid metabolism in T cell responses after allogeneic hematopoietic cell transplantation

“…Consistent with the results in acute GVHD, treatment with FTY720 early after allo-HCT restores PTEN expression and normalization of Smad3 phosphorylation and diminishes immune cell infiltration into skin, improving sclerodermatous during chronic GVHD ( 58 ). Another study also supports these findings, demonstrating that FTY720 treatment impairs CD4 + T cells differentiation into Th1, Th2, and Th17 and further ameliorates skin fibrosis ( 59 ). Moreover, FTY720 treatment increases IL-10 production in a subset of B cells via S1PR1 ( 57 ) and decreases splenic dendritic cells (CD11c + ) by 50%, contributing to chronic GVHD control ( 58 ).…”

Intranasal Vaccination with rePcrV Protects against Pseudomonas aeruginosa and Generates Lung Tissue-Resident Memory T Cells

“…To exclude the contribution of circulating memory cells to the recall responses, we administered FTY720 [ 37 , 38 ] (a S1P inhibitor that blocks the egress of T cells from repositioning from secondary lymphoid organs to the tissue). We found that FTY720 treatment followed by a P. aeruginosa XN-1 challenge induced higher survival in immunized mice ( P < 0.0001) but not in unimmunized mice ( Figure 4(a) ).…”