Transient T cell accumulation in lymph nodes and sustained lymphopenia in mice treated with FTY720

Morris, Margaret A.; Gibb, David R.; Picard, Franck; Brinkmann, Volker; Straume, Martin; Ley, Klaus

doi:10.1002/eji.200526218

Cited by 84 publications

(83 citation statements)

References 30 publications

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“…3), these effects appear to impact upon DCs recruited to tissues p.i. In experiments involving FTY720 treatment during established infection, we also observed decreased mononuclear cell numbers in the liver and spleen (data not shown), consistent with previous reports showing that long-term drug treatment results in decreased lymphocyte numbers in the body (53). Thus, we were unable to assess the requirements for tissue migration of CD4 + T cells on the maintenance of antiparasitic immunity in infected organs.…”

Section: Discussionsupporting

confidence: 88%

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

Bunn

Stanley

Rivera

et al. 2014

The Journal of Immunology

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Organ-specific immunity is a feature of many infectious diseases, including visceral leishmaniasis caused by Leishmania donovani. Experimental visceral leishmaniasis in genetically susceptible mice is characterized by an acute, resolving infection in the liver and chronic infection in the spleen. CD4+ T cell responses are critical for the establishment and maintenance of hepatic immunity in this disease model, but their role in chronically infected spleens remains unclear. In this study, we show that dendritic cells are critical for CD4+ T cell activation and expansion in all tissue sites examined. We found that FTY720-mediated blockade of T cell trafficking early in infection prevented Ag-specific CD4+ T cells from appearing in lymph nodes, but not the spleen and liver, suggesting that early CD4+ T cell priming does not occur in liver-draining lymph nodes. Extended treatment with FTY720 over the first month of infection increased parasite burdens, although this associated with blockade of lymphocyte egress from secondary lymphoid tissue, as well as with more generalized splenic lymphopenia. Importantly, we demonstrate that CD4+ T cells are required for the establishment and maintenance of antiparasitic immunity in the liver, as well as for immune surveillance and suppression of parasite outgrowth in chronically infected spleens. Finally, although early CD4+ T cell priming appeared to occur most effectively in the spleen, we unexpectedly revealed that protective CD4+ T cell–mediated hepatic immunity could be generated in the complete absence of all secondary lymphoid tissues.

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Section: Discussionsupporting

confidence: 88%

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

Bunn

Stanley

Rivera

et al. 2014

The Journal of Immunology

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“…FTY720 administration causes transient sequestration of circulating lymphocytes in lymph nodes and a sustained decrease of lymphocytes in the blood and spleen (13,14,(36)(37)(38). Consistent with other studies (38), we observed a marked reduction of lymphocytes in the blood (data not shown).…”

Section: Fty720 Treatment Of Ecm Decreases Central Nervous System Lymsupporting

confidence: 92%

“…During FTY720 and LX2931 treatment, oral rather than intravenous administration was preferred since it has been shown that lower blood lymphocyte counts can be achieved using this route (38). Dosing was based on the preestablished range shown to reduce lymphocyte numbers in the blood (15).…”

Section: Genetic Approaches Using Hs1plmentioning

confidence: 99%

S1P Is Associated with Protection in Human and Experimental Cerebral Malaria

Finney

Hawkes

Kain

et al. 2011

Mol Med

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Cerebral malaria (CM) is associated with excessive inflammatory responses and endothelial activation. Sphingosine 1-phosphate (S1P) is a signaling sphingolipid implicated in regulating vascular integrity, inflammation and T-cell migration. We hypothesized that altered S1P signaling during malaria contributes to endothelial activation and inflammation, and show that plasma S1P levels were decreased in Ugandan children with CM compared with children with uncomplicated malaria. Using the Plasmodium berghei ANKA (PbA) model of experimental CM (ECM), we demonstrate that humanized S1P lyase (hS1PL) -/-mice with reduced S1P lyase activity (resulting in increased bio-available S1P) had improved survival compared with wild-type littermates. Prophylactic and therapeutic treatment of infected mice with compounds that modulate the S1P pathway and are in human trials for other conditions (FTY720 or LX2931) significantly improved survival in ECM. FTY720 treatment improved vascular integrity as indicated by reduced levels of soluble intercellular adhesion molecule (sICAM), increased angiopoietin 1 (Ang1) (regulator of endothelial quiescence) levels, and decreased Evans blue dye leakage into brain parenchyma. Furthermore, treatment with FTY720 decreased IFNγ levels in plasma as well as CD4 + and CD8 + T-cell infiltration into the brain. Finally, when administered during infection in combination with artesunate, FTY720 treatment resulted in increased survival to ECM. These findings implicate dysregulation of the S1P pathway in the pathogenesis of human and murine CM and suggest a novel therapeutic strategy to improve clinical outcome in severe malaria.

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“…Although it is considered that FTY720 is a prodrug that is active only after phosphorylation, it should be noted that plasma concentrations not only of FTY720-P but also of FTY720 reach steadystate levels of 30 nM, both in humans and in experimental animal models. [61][62][63] This is within the range of concentrations that significantly inhibit cPLA 2 . Of importance, the half-life for clearance of FTY720 in humans is nearly 8 days, 61 and we observed that nanomolar concentrations of FTY720 markedly inhibited eicosanoid release from mast cells and macrophages within a very short period of treatment (15 minutes to 2 hours).…”

Section: Discussionmentioning

confidence: 53%

The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors

Payne

Oskeritzian

Griffiths

et al. 2006

Blood

142

101

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FTY720 is a potent immunomodulator drug that inhibits the egress of lymphocytes from secondary lymphoid tissues and thymus. FTY720 is phosphorylated in vivo by sphingosine kinase 2 to FTY720-phosphate, which acts as a potent sphingosine-1-phosphate (S1P) receptor agonist. However, in contrast to S1P, FTY720 has no effect on mast-cell degranulation, yet significantly reduces antigen-induced secretion of PGD 2 and cysteinyl-leukotriene. Unexpectedly, this effect of FTY720 was independent of its phosphorylation and S1P receptor functions. The rate-limiting step in the biosynthesis of all eicosanoids is the phospholipase A 2 (PLA 2 )-mediated release of arachidonic acid from glycerol phospholipids. Although FTY720 also reduced arachidonic acid release in response to antigen, it had no effect on translocation of cPLA 2 or ERK1/2 activation, suggesting that it does not interfere with Fc⑀RI-mediated events leading to cPLA 2 activation. Remarkably, however, FTY720 drastically inhibited recombinant cPLA 2 ␣ activity, whereas FTY720-phosphate, sphingosine, or S1P had no effect. This study has uncovered a unique action of FTY720 as an inhibitor of cPLA 2 ␣ and hence on production of all eicosanoids. Our results have important implications for the potential therapeutic mechanism of action of FTY720 in eicosanoid-driven inflammatory disorders such as asthma and multiple sclerosis. IntroductionFTY720 is a novel immunosuppressive agent that was derived from myriocin, a sphingosine-like fungal metabolite. 1 FTY720 potently inhibits a variety of experimental autoimmune disorders, such as type I diabetes 2 and arthritis, 3 but clinically, its greatest potential for humans appears to be in the prevention of renal graft rejection and treatment of multiple sclerosis (MS) where it is currently in phase 3 clinical trials. 4,5 The immunosuppressive properties of FTY720 stem from its ability to prevent T cells' egress from secondary lymphoid organs and back into circulation, sequestering them away from the transplanted graft, [6][7][8] or preventing their entry into the central nervous system. 9 FTY720 is phosphorylated by sphingosine kinase 2 (SphK2), [10][11][12] and a large body of evidence suggests that the phosphorylated drug (FTY720-P), an analog of sphingosine-1-phosphate (S1P), is the biologically active form. FTY720-P can bind to all of the known S1P receptors, except S1P 2 , 6,13,14 and has been shown to regulate S1P 1 actions that are crucial for lymphocyte migration and trafficking. [15][16][17][18] Nevertheless, the exact mechanism of action of this prodrug is still a matter of debate. [19][20][21] S1P is also an important chemoattractant in the immune system, modulating T-cell responses to chemokines (reviewed in Cyster 13 and Rosen and Goetzl 18 ).FTY720 inhibits airway inflammation, induction of bronchial hyperresponsiveness, and lymphocyte and eosinophil infiltration in an actively Ag-sensitized murine asthma model, 22 suggesting that it might have therapeutic benefits in asthma.Given that S1P and its receptors may pla...

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Transient T cell accumulation in lymph nodes and sustained lymphopenia in mice treated with FTY720

Cited by 84 publications

References 30 publications

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

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

S1P Is Associated with Protection in Human and Experimental Cerebral Malaria

The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors

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