Combined Fty720/Cyclosporine Treatment Promotes Graft Survival and Lowers the Peripheral Lymphocyte Count in a Murine Cardiac Allotransplantation Model

Nikolova, Zariana; Hof, Akiko; Baumlin, Yves; Hof, Robert P.

doi:10.1097/00007890-200107150-00033

Cited by 23 publications

(16 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the peak effect appears to be achieved at a dose of 3 mg/kg/d, with no further protection seen at a higher dose of 6 mg/kg/d. While clinical use of FTY to prevent graft rejection usually has been in combination with other immunosuppressive agents and has involved lower FTY doses than those used in our mice (62,63), doses of 3 mg/kg/d have been used in nonhuman primate studies as a monotherapy with no apparent toxicity (64). A higher dose of 5 mg/kg/d (days -5 and -4 pre-BMT) in a canine nonmyeloablative BMT model induced hemorrhagic enteritis in one of five animals (65).…”

Section: Discussionmentioning

confidence: 99%

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

Kim

Sachs²,

Asavaroengchai³

et al. 2003

J. Clin. Invest.

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

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

Kim

Sachs²,

Asavaroengchai³

et al. 2003

J. Clin. Invest.

View full text Add to dashboard Cite

“…twice per week until the end of the experiment. In other groups, recipients were treated daily with FTY720 (Enzo Life Sciences) at 0.3 mg/kg, administered daily by gavage in a volume of 100 μl/10 g body weight (24). In some experiments, naive B/6 mice were treated with 500 μg of anti-CD154 (i.v.…”

Section: Methodsmentioning

confidence: 99%

“…FTY720 causes lymphocyte sequestration into secondary lymphoid organs, thereby preventing antigen-activated T cells' egress to sites of inflammation (21)(22)(23)(24)(25). FTY720 has been shown to be most effective for naive and TCM cells (26) but has also been reported to impact TEM migration in mice (27).…”

Section: Ctla4-ig Fails To Inhibit the Accumulation Of T Cells Into Tmentioning

confidence: 99%

CTLA4-Ig in combination with FTY720 promotes allograft survival in sensitized recipients

Khiew¹,

Yang²,

Young³

et al. 2017

JCI Insight

View full text Add to dashboard Cite

“…We consider this mechanism highly unlikely in view of the low nanomolar levels (C max Ͻ 50 nM) of FTY720 realized in the blood of rats treated with the high dose of 1 mg/kg (29). Nevertheless we determined whether the apoptotic potential of our compounds correlated with activities in vitro or in vivo.…”

Section: Fty720 and Sphingosine 1-phosphate Signalingmentioning

confidence: 99%

The Immune Modulator FTY720 Targets Sphingosine 1-Phosphate Receptors

Brinkmann¹,

Davis²,

Heise³

et al. 2002

Journal of Biological Chemistry

1,403

1,358

View full text Add to dashboard Cite

Immunosuppressant drugs such as cyclosporin have allowed widespread organ transplantation, but their utility remains limited by toxicities, and they are ineffective in chronic management of autoimmune diseases such as multiple sclerosis. In contrast, the immune modulating drug FTY720 is efficacious in a variety of transplant and autoimmune models without inducing a generalized immunosuppressed state and is effective in human kidney transplantation. FTY720 elicits a lymphopenia resulting from a reversible redistribution of lymphocytes from circulation to secondary lymphoid tissues by unknown mechanisms. Using FTY720 and several analogs, we show now that FTY720 is phosphorylated by sphingosine kinase; the phosphorylated compound is a potent agonist at four sphingosine 1-phosphate receptors and represents the therapeutic principle in a rodent model of multiple sclerosis. Our results suggest that FTY720, after phosphorylation, acts through sphingosine 1-phosphate signaling pathways to modulate chemotactic responses and lymphocyte trafficking.FTY720 is derived from ISP-1 (myriocin), a fungal metabolite that is an eternal youth nostrum in traditional Chinese herbal medicine (1). The compound (2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol) is a novel, high potency immune modulating agent that is remarkably effective in a variety of autoimmune and transplant models including islet transplantation (2) and has recently proven to be effective in renal transplantation in man (3). Unlike the currently used immunosuppressive agents (e.g. the calcineurin inhibitors cyclosporin and tacrolimus), FTY720 does not inhibit T cell activation and proliferation and in rodent models does not impair immunity to systemic viral infection (4). If confirmed in man, the latter property provides a striking advantage over current immunosuppressive therapies. FTY720 apparently sequesters lymphocytes from circulation to secondary lymph tissue compartments (5) with concomitant reduction of specific effector T cells recirculating from the lymph nodes to inflamed peripheral tissues (4) and graft sites (6). FTY720 does not act via the lymphocytehoming chemokine receptor CCR-7 because FTY720 is active both in CCR-7-deficient mice and plt (paucity of lymph node T cells) mice, which lack CCR-7 ligands (CCL-19 and CCL-21) (7).FTY720-induced lymphocyte homing is sensitive to suppression by pertussis toxin (6 -8), which suggests that the molecular target of the drug is a G protein-coupled receptor (GPCR) 1 interacting with heterotrimeric G proteins of the ␣ i/o type. The affected GPCR(s) is on the lymphocyte since fluorescently labeled lymphocytes treated with pertussis toxin ex vivo and transferred to mice are not depleted by FTY720 in vivo (8). The structural similarity of FTY720 and sphingosine has prompted speculation that the drug might act via the sphingosine 1-phosphate (S1P) receptor S1P 4 (formerly 2 that is known to be expressed by lymphocytes (9). S1P is a pleiotropic lysophospholipid mediator; the prominent cellular responses to applied S...

show abstract

Combined Fty720/Cyclosporine Treatment Promotes Graft Survival and Lowers the Peripheral Lymphocyte Count in a Murine Cardiac Allotransplantation Model

Abstract: Combined FTY720 and CsA treatment was well tolerated, promoted graft survival, and suppressed the inflammatory allo-response. The PLC lowering correlated well with the antirejection effects in the two-drug regimens, suggesting that the PLC might guide FTY720 therapy at low doses.

Cited by 23 publications

References 7 publications

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

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

CTLA4-Ig in combination with FTY720 promotes allograft survival in sensitized recipients

The Immune Modulator FTY720 Targets Sphingosine 1-Phosphate Receptors

Contact Info

Product

Resources

About