Insights into the mechanism of FTY720 and compatibility with regulatory T cells for the inhibition of graft-versus-host disease (GVHD)

Abstract

The immunomodulator FTY720 (FTY) has been shown to be beneficial in experimental models of organ transplantation and autoimmunity. We show that FTY significantly inhibited but did not prevent graftversus-host disease (GVHD) in lethally irradiated or nonirradiated allogeneic recipients. Although most studies implicate prevention of lymphocyte egress from lymphoid organs as the primary mechanism of action, our data indicate that FTY effects on the host are more likely to be responsible for GVHD inhibition. IntroductionDespite advances in the field, graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality in patients undergoing bone marrow transplantation (BMT). In this study, we examine the effect of FTY720 (FTY), a potent immunomodulator, in a murine model of GVHD.FTY, derived from a metabolite of the fungus Isaria sinclairii, is a high-affinity agonist for 4 of the 5 known sphingosine 1-phosphate receptors (S1PRs). S1P 1 is expressed on all cell types, while S1P 3 is found in endothelial cells, S1P 4 is found primarily on lymphoid cells, and S1P 5 is expressed on the white matter of the central nervous system. [1][2][3][4] These receptors are critically involved in cell survival, cytoskeletal rearrangements, cell motility, and cell migration. [1][2][3][4] FTY induces internalization of the receptor, rendering the cells unresponsive to serum lipid S1P that is produced by platelets. 1,5,6 It is generally accepted that FTY exerts its immunomodulatory effects primarily by sequestering lymphocytes within secondary lymphoid organs, thereby denying them the ability to recirculate to peripheral sites of inflammation. FTY is also thought to act on endothelial cells by enhancing the adherens junction assembly, thereby strengthening the endothelial barrier. 7 More recent data indicate that in addition to exhibiting profound effects on lymphocyte migration and endothelial barrier integrity, FTY also modulates dendritic cell (DC) trafficking and function. [8][9][10][11] Accumulating data in animal studies indicate that FTY is a promising immunosuppressive agent for the treatment of various autoimmunities, promotion of engraftment in several models of solid organ transplantation (reviewed in Brinkmann, 1 Brinkmann and Lynch, 2 Chiba, 3 Yopp et al, 4 and Brinkmann et al 12 ), and inhibition of GVHD. [13][14][15] Although the complete mechanism of FTY is not completely understood, most studies implicate an important role for lymph node (LN) trapping as a mechanism of action. It is generally accepted that sequestration of effector T cells in secondary lymphoid organs is associated with a decrease in T-cell migration and infiltration to sites of inflammation, solid organ grafts, or GVHD target organs, thereby ameliorating autoimmunity, solid organ graft rejection, or GVHD.Our studies indicate that FTY inhibits but does not prevent GVHD. In contrast to other studies, we did not find that FTY sequestered effector T cells to secondary lymphoid organs, thereby reducing their migration to GVHD target or...

Tissue Requirements for Establishing Long-Term CD4+ T Cell–Mediated Immunity following Leishmania donovani Infection

“…If FTY720 was simply preventing lymphocyte egress from SLTs, then one might predict an accumulation of lymphocytes in these tissue sites. Previous work (36) in a model of graft-versus-host disease reported similar findings, which may be related to the effects of FTY720 on DCs' ability to move in the spleen and position themselves for efficient CD4 + T cell activation (35). Our results indicate a similar effect; however, because the drug did not interfere with Ag-specific CD4 + T cell proliferation in the first 3 d of infection (Fig.…”

“…Data are representative of two independent experiments (n = 4 mice/group). *p , 0.05, **p , 0.01. responder T cells in a model of graft-versus-host disease (36). Therefore, a more detailed analysis of the kinetics of CD4 + T cell responses in the liver and spleen of L. donovani-infected mice treated for 28 d with FTY720 was undertaken (Fig.…”

The S1P1 receptor-selective agonist CYM-5442 reduces the severity of acute GVHD by inhibiting macrophage recruitment

“…Although it has been suggested that FTY720 may modulate lymphocyte trafficking, especially donor-derived T-cell infiltration into target organs, to inhibit aGVHD, 20,39,40 another recent study demonstrated that FTY720 did not inhibit donor effector T-cell trafficking into the aGVHD target organs. 41 The same report also showed FTY720 reduced the number of DCs in the target organs, which has been suggested to be the mechanism underlying aGVHD inhibition. We did not observe any changes in DCs in the GVHD target organs with CYM treatment.…”

IL-21 blockade reduces graft-versus-host disease mortality by supporting inducible T regulatory cell generation

“…23 Lethally irradiated Balb/c recipients undergoing BMT received A20 luc (10 5 ). Groups received 2 ϫ 10 6 CD25 Ϫ Teffs from wild type (wt), IL-21 Ϫ/Ϫ , IL-21R Ϫ/Ϫ , or perforin Ϫ/Ϫ mice in the presence or absence of anti-IL-21 mAb, as indicated, for a period of 6 weeks.…”