FTY720 (fingolimod) in renal transplantation

Budde, Klemens; Schütz, Manuela; Glander, Petra; Peters, Harm; Waiser, Johannes; Liefeldt, Lutz; Neumayer, Hans‐H.; Böhler, Torsten

doi:10.1111/j.1399-0012.2006.00596.x

Cited by 95 publications

(52 citation statements)

References 54 publications

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“…These effects could also be shown with the phosphorylated S1P receptor agonist AFD-R (22), suggesting that targeting S1P receptors locally in the lung and on DC was sufficient to inhibit proinflammatory cytokine release and virus-specific T cells expansion. Others have reported that systemic delivery of sphingosine analog FTY720 can sequester normal expanding lymphocytes in lymphoid organs in various models (30)(31)(32) including during virus infection (33). However, this was unlikely a mechanism in our studies for the following reasons.…”

Section: Discussioncontrasting

confidence: 42%

A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection

Marsolais

Hahm

Walsh

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

116

141

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Pulmonary tissue damage resulting from influenza virus infection is caused by both the cytolytic activity of the virus and the host immune response. Immune-mediated injury results from T cellmediated destruction of virus-infected cells and by release of cytokines and chemokines that attract polymorphonuclear leukocytes (PML) and macrophages to the infected site. The cytokines/ chemokines potentiate dendritic cell (DC) activation and T cell expansion, which further enhances local damage. Here we report that immune modulation by local administration to the respiratory tract of sphingosine analog AAL-R significantly dampens the release of cytokines and chemokines while maintaining protective neutralizing antibody and cytotoxic T cell responses. As a result there was a marked reduction of infiltrating PML and macrophages into the lung and resultant pulmonary tissue injury. DC maturation was suppressed, which limited proliferation of specific antiviral T cells in the lung and draining lymph nodes. Further, AAL-R was effective in controlling CD8 ؉ T cell accumulation in the lungs even when given 4 days after initiation of influenza virus infection. These data indicate that sphingosine analogs display useful potential for controlling the immunopathology caused by influenza virus.immunopathology ͉ dendritic cells ͉ cytokine storm ͉ T cells T he antiviral host response evolved to limit the spread of infection at the cost of causing tissue injury. There is a balance between the protective and injurious responses that leads either to the purging of infectious virus and host recovery or to severe disease and even death. Thus, strategies to balance the antiviral immune response in favor of host outcome need to be developed.T cell response elicited early in the course of infection recognizes, attacks and lyses virus-infected cells to eliminate potential factories of progeny viruses (1-5). The protective influenza antibody response is elicited later and plays a role in controlling re-infection (6, 7). The innate and adaptive immune systems release wide varieties of cytokines and chemokines that activate and attract inflammatory cells to the site of infection (2,8,9). However, these molecules can also cause the host harm by a phenomenon known as cytokine storm. Cytokine storm has been convincingly documented both in experimental animals infected with the 1918/1919 and H5N1 influenza viruses (2, 10-13) as well as in humans (14-18) succumbing to H5N1 infection. Although antiviral drugs can be used to treat the virus, a strategy to balance the resultant cytokine release and lung injury while maintaining benefits of the antiviral protective immune response is needed (19). Influenza virus replication is most often limited primarily to the respiratory tract but the systemic signs and symptoms of disease, e.g., fever, muscle pain and shakes, intestinal tract involvement, are related to cytokine effects (20, 21).We reported that intratracheal (i.t.) delivery of the sphingosine analog AAL-R or its phosphate ester inhibited virus-specifi...

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Section: Discussioncontrasting

confidence: 42%

A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection

Marsolais

Hahm

Walsh

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

116

141

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“…FTY720 has been proven to prolong allograft survival in both rodents and men (26,27) by acting as a sphingosine-1 phosphate (S1P) agonist inducing a prolonged down-regulation of the cell surface expression of the S1P receptor. The latter enables a blockade of S1P-mediated T cell egress from SLO, which is normally induced by a S1P gradient from blood and lymph fluid to tissue (28).…”

Section: Various Target Cells Such As Cd4mentioning

confidence: 99%

The Sphingosine 1-Phosphate Receptor Agonist FTY720 Potently Inhibits Regulatory T Cell Proliferation In Vitro and In Vivo

Wolf

Eller

Zeiser³

et al. 2009

The Journal of Immunology

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CD4+CD25+ regulatory T cell (Treg) entry into secondary lymphoid organs and local expansion is critical for their immunosuppressive function. Long-term application of the sphingosine-1 phosphate receptor agonist FTY720 exerts pleiotropic anti-inflammatory effects, whereas short-term FTY720 boosts antiviral immunity. In this study, we provide evidence that FTY720 potently inhibits Treg proliferation in vitro and in vivo without affecting their viability, phenotype, or in vitro immunosuppression. In contrast, adoptively transferred Treg exposed ex vivo to FTY720 lost their protective effects in murine models of acute glomerulonephritis and acute graft-vs-host disease. On a cellular level, FTY720 inhibits IL-2-induced STAT-5 phosphorylation, paralleled by a loss of FoxP3 expression during Treg expansion in vitro. Notably, loss of in vivo immunosuppression is not due to impaired migration to or localization within secondary lymphoid organs. We could even show a selective trapping of adoptively transferred Treg in inflammatory lymph nodes by FTY720. Finally, Treg isolated from animals systemically exposed to FTY720 also exhibit a significantly impaired proliferative response upon restimulation when compared with Treg isolated from solvent-treated animals. In summary, our data suggest that sphingosine-1 phosphate receptor-mediated signals induced by FTY720 abrogate their in vivo immunosuppressive potential by blocking IL-2 induced expansion, which is indispensable for their in vivo immunosuppressive activity.

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“…Phase I and phase II studies showed good tolerability and efficacy in preventing acute rejection in de novo transplant recipients (reviewed in reference 55 ). These studies also described the pharmacokinetics, characterized by a prolonged absorption phase, a long half-life (ϳ200 h) and a large volume of distribution, consistent with the lipophilic properties of the drug.…”

Section: Fingolimod (Fty720)mentioning

confidence: 99%

Emerging Therapies for Multiple Sclerosis

Muraro

Bielekova

2007

Neurotherapeutics

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Summary:This review examines the mode of action, safety profile and clinical efficacy of some of the most promising new therapeutic strategies for multiple sclerosis. Autologous hematopoietic stem cell transplantation can regenerate a new and tolerant immune system and is a potentially effective rescue therapy in a subset of patients with aggressive forms of MS refractory to approved immunomodulatory and immunosuppressive agents. High-dose cyclophosphamide without stem cell support is suggested to induce prolonged remissions through similar immunological mechanisms with less toxicity. Fingolimod (FTY720) is a novel oral immunomodulating agent that acts through preventing lymphocyte recirculation from lymphoid organs. Monoclonal antibody therapy has provided scientists and clinicians the opportunity to rationally direct the therapeutic intervention against specific molecules. Targeting molecules of the immune system such as CD52 (alemtuzumab), CD25 (daclizumab), VLA-4 (natalizumab) and CD20 (rituximab) have resulted in potent immunomodulatory effects through sometimes unpredicted mechanisms. The potential of immunoglobulins to induce remyelination in the CNS is being investigated in an attempt to develop therapies promoting tissue repair and functional recovery. The evidence supporting the potential of these emerging immunotherapies suggests that strong progress is being made in the development of effective cures for multiple sclerosis.

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FTY720 (fingolimod) in renal transplantation

Cited by 95 publications

References 54 publications

A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection

A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection

The Sphingosine 1-Phosphate Receptor Agonist FTY720 Potently Inhibits Regulatory T Cell Proliferation In Vitro and In Vivo

Emerging Therapies for Multiple Sclerosis

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