Graft-versus-host disease can be separated from graft-versus-lymphoma effects by control of lymphocyte trafficking with FTY720

Kim, Yong-Mi; Sachs, Teviah E.; Asavaroengchai, Wannee; Bronson, Roderick T.; Sykes, Megan

doi:10.1172/jci200316950

Cited by 124 publications

(59 citation statements)

References 60 publications

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“…We did not observe any effect of CYM on the infiltration of donor T cells to the aGVHD organs at an early stage of the disease. 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.…”

Section: Discussionmentioning

confidence: 99%

“…9,12,13 FTY720 has been shown to be a promising immunosuppressive agent for the treatment of autoimmune disease, promotion of solid organ engraftment and inhibition of aGVHD. 8,[14][15][16][17][18][19][20][21] However, the mechanism underlying the action of FTY720 is not completely known. Clinically, FTY720 mediates both lymphopenia and transient dose-dependent bradycardia on initial dosing in humans.…”

Section: Introductionmentioning

confidence: 99%

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

Cheng

Lin

et al. 2014

Cell Mol Immunol

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FTY720, an agonist for four of the five known sphingosine-1-phosphate (S1P) receptors, has been reported to inhibit acute graft-versus-host disease (aGVHD). Because FTY720 functions through multiple S1P receptors, the mechanism of action through one or more of these receptors may account for its side effects. Thus, more selective S1P receptor modulators are needed to evaluate the roles of different S1P receptors and their therapeutic efficacies. In this study, we investigated the effect of an S1P 1 -selective agonist, CYM-5442, on the progression of aGVHD. We showed that CYM-5442 significantly inhibited but did not prevent aGVHD. CYM-5442 did not affect the infiltration of the donor T cells into the target organs, while the number of macrophages in GVHD organs was significantly reduced by CYM-5442 treatment. In vivo proliferation assays showed that the proliferation of macrophages was not suppressed by CYM-5442. Further studies using human endothelial cells demonstrated that CYM-5442 treatment downregulated CCL2 and CCL7 expression in endothelial cells, therefore reducing the migration of monocytes, from which tissue macrophages originate. Our data demonstrate the therapeutic efficacy of an S1P 1 -selective agonist in aGVHD and its possible mechanism of action. The results suggest that further investigations are needed regarding CYM-5442 as a potential therapeutic regimen for aGVHD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Cheng

Lin

et al. 2014

Cell Mol Immunol

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“…32 On the basis of the published clinical GVHD scores, each parameter was scored as follows: 0 ¼ normal, 1 ¼ mild, 2 ¼ moderate and 3 ¼ severe. 33 The maximal score was 12. For histological confirmation of GVHD, liver, colon and spleen were obtained from moribund animals or from necropsies.…”

Section: Assessment Of Gvhdmentioning

confidence: 97%

CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease

et al. 2007

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We studied the effect of CTLA-4 blockade on graft-versusleukemia and graft-versus-host responses in a mouse model of minor histocompatibility-mismatched bone marrow transplantation. Early CTLA-4 blockade induced acute graft-versus-host disease. Delayed CTLA-4 blockade resulted in a lethal condition with lymphosplenomegaly, but with stable mixed T-cell chimerism, unchanged alloreactive T-cell frequencies and absent anti-host reactivity in vitro. In contrast, multiorgan lymphoproliferative disease with autoimmune hepatitis and circulating anti-DNA auto-antibodies were documented. Splenic lymphocytes exhibited ex vivo spontaneous proliferation and a marked proliferative response against host-type dendritic cells pulsed with syngeneic (host-type) tissue-peptides. Both phenomena were exclusively mediated by host and not donor T cells, supporting an autoimmune pathogenesis. Selectively hostderived T-cell immune reactivity was equally documented against leukemia-peptide-pulsed dendritic cells, and this was paralleled by a strong in vivo antileukemic effect in anti-CTLA-4-treated and subsequently leukemia-challenged chimeras. In conclusion, delayed CTLA-4 blockade induced a host-derived antileukemic effect, occurring in the context of an autoimmune syndrome and strictly separated from graft-versus-host disease. Both antileukemic and autoimmune responses depended on the allogeneic component, as neither effect was seen after syngeneic bone marrow transplantation. Our findings reveal the potential of using CTLA-4 blockade to establish antileukemic effects after allogeneic hematopoietic stem cell transplantation, provided autoimmunity can be controlled.

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“…It has been shown to control some autoimmunities and allergic diseases as well as to suppress transplant rejection and graft vs. host disease (3). The drug has shown efficacy in advanced clinical trials for the treatment of multiple sclerosis (4).…”

Section: Introductionmentioning

confidence: 99%

The sphingosine-1-phosphate receptor agonist FTY720 and its phosphorylated form affect the function of CD4+CD25+ T cells in vitro

Liu

Jiang

Xiao³

et al. 2012

Int J Mol Med

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Abstract. The sphingosine-1-phosphate receptor agonist FTY720 and FTY720-P have a wide variety of fundamental functions. Many studies have demonstrated that CD4 + CD25 + regulatory T (Treg) cells engage in the maintenance of immunological self-tolerance by actively suppressing self-reactive lymphocytes. Although FTY720 has also recently shown to possess an additional effect that increases the functional activity of Treg cells, the mechanism leading to the enhanced Treg activity after FTY720 treatment is still not clear. We isolated Treg cells, which were co-cultured with FTY720 or FTY720-P. The proliferation of co-cultured Treg cells was detected by the cell counting kit-8. The changes of the phenotype CD25 + and forkhead box P3 (Foxp3) + of co-cultured Treg cells were measured by flow cytometry. The levels of IL-10 and TGF-β1 in the supernatants were detected by ELISA. Cytokine mRNA expressions in co-cultured Treg cells were analyzed by real-time quantitative PCR. Mixed lymphocyte reaction assay examined the suppressive function. We found that neither FTY720 nor FTY720-P affected the proliferation of co-cultured Treg cells. The percentages of CD25 + and Foxp3 + were enhanced in the high-dose FTY720-P group. The levels of TGF-β1 in the supernatants were enhanced in the high-dose FTY720 group. Medium and high-dose FTY720-P also enhanced the levels of TGF-β1. TGF-β1 and Foxp3 mRNA expression were upregulated in the high-dose FTY720-P group. The proliferation of effector T (Teff) cells was suppressed significantly in the medium and high-dose FTY720-P group at a Treg/Teff cell ratio of 1:1. At a ratio of 1:1, the proliferation of Teff cells was also suppressed in the high-dose FTY720 group. It can be concluded that high-dose FTY720-P can enhance the immune function of co-cultured Treg cells, and that medium-dose FTY720-P and high-dose FTY720 could partly enhance the function. The reason may be attributed to enhanced levels of TGF-β1 and Foxp3. IntroductionAs a synthetic structural analog of myriocin, the sphingosine-1-phosphate (S1P) receptor agonist FTY720 can regulate a wide variety of fundamental functions including cell survival, cytoskeletal rearrangements, and cell motility (1,2). It has been shown to control some autoimmunities and allergic diseases as well as to suppress transplant rejection and graft vs. host disease (3). The drug has shown efficacy in advanced clinical trials for the treatment of multiple sclerosis (4). Once FTY720 is phosphorylated in vivo by sphingosine kinase 2 (SphK2), the phosphorylated compound (FTY720-P) acts as an agonist on 4 of the 5 known S1P receptors (S1P1, S1P3, S1P4 and S1P5) (5). In contrast to classical immunosuppressants, such as cyclosporine A or FK506, FTY720 does not impair antigen-driven T-cell activation and does not interfere with T-cell proliferation at therapeutically relevant concentrations, but induces a severe deprivation in lymphocytes in the blood due to modification of S1P signaling (6-8).Regulatory T (Treg) cells have been demonstrated to engage in the main...

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Graft-versus-host disease can be separated from graft-versus-lymphoma effects by control of lymphocyte trafficking with FTY720

Cited by 124 publications

References 60 publications

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

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

CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease

The sphingosine-1-phosphate receptor agonist FTY720 and its phosphorylated form affect the function of CD4+CD25+ T cells in vitro

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