FTY720, a novel immunosuppressant, induces sequestration of circulating lymphocytes by acceleration of lymphocyte homing

Chiba, Kenji; Yanagawa, Yoshiki; Kataoka, Hirotoshi; Kawaguchi, Takafumi; Ohtsuki, M; Hoshino, Yukio

doi:10.1016/s0041-1345(98)01975-7

Cited by 51 publications

(45 citation statements)

References 3 publications

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“…2) suggesting that G-specific memory CD4 ϩ T cells present in the spleen do not contribute significantly to the subsequent recall response in the lungs. Because FTY720 strongly inhibits the egress of cells from the thymus, the peripheral and mesenteric lymph nodes, and Peyer's patches, but inhibits less effectively those from the spleen or bone marrow (29,30), any responding T cells of splenic origin would not be blocked by treatment with the drug either before or during RSV infection. As Fig.…”

Section: Discussionmentioning

confidence: 99%

Proliferative Expansion and Acquisition of Effector Activity by Memory CD4+ T Cells in the Lungs following Pulmonary Virus Infection

Wissinger

Stevens

Varga

et al. 2008

The Journal of Immunology

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The memory CD4+ T cell response to the respiratory syncytial virus (RSV) attachment (G) protein in the lungs of primed BALB/c mice undergoing challenge pulmonary RSV infection is dominated by effector T cells expressing a single Vβ-chain, Vβ14. We have used Vβ14 expression to examine the kinetics of the activation, accumulation, and acquisition of the effector activity of memory CD4+ T cells responding to pulmonary infection. This analysis revealed that proliferative expansion and effector CD4+ T cell differentiation preferentially occur in the respiratory tract following rapid activation within and egress from the lymph nodes draining the respiratory tract. These findings suggest that, in response to natural infection at a peripheral mucosal site such as the lungs, memory CD4+ T cell expansion and differentiation into activated effector T cells may occur predominantly in the peripheral site of infection rather than exclusively in the lymph nodes draining the site of infection.

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Section: Discussionmentioning

confidence: 99%

Proliferative Expansion and Acquisition of Effector Activity by Memory CD4+ T Cells in the Lungs following Pulmonary Virus Infection

Wissinger

Stevens

Varga

et al. 2008

The Journal of Immunology

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“…The immunosuppressive mechanisms of its action are completely different from those of cyclosporin A or tacrolimus; FTY720 does not affect interleukin-2 production from mitogen-stimulated lymphocytes (Suzuki, 1999). The drug was reported to significantly accelerate lymphocyte homing to peripheral lymph nodes, mesenteric lymph nodes, and Peyers' patches in a dose-dependent manner (Chiba et al, 1999).…”

mentioning

confidence: 99%

Distinct Pathways of Apoptosis Triggered by FTY720, Etoposide, and Anti-Fas Antibody in Human T-Lymphoma Cell Line (Jurkat Cells)

Fujino

Li²,

Kitazawa³

et al. 2002

J Pharmacol Exp Ther

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2-Amino-2-[2-(4-octylphenyl)ethyl] propane-1,3-diol hydrochloride (FTY720), a synthetic product derived from a metabolite of Isaria sinclairii, has been demonstrated to have a potent immunosuppressive activity that induces apoptotic cell death in T cells and several other cell lines. In this study, using the human T-lymphoma cell line, Jurkat cells, we investigated the apoptotic signal transduction mediated by FTY720, in particular comparing its role on the cleavage of caspases, with that mediated by etoposide or anti-Fas antibody. All of these agents cleaved caspases, inducing their active form in the affected cells. Pretreatment with a broad caspase inhibitor [benzyloxycarbonyl-Val-Ala-Asp-(Ome) fluoromethyl ketone] markedly decreased the incidence of apoptotic cells induced by FTY720, etoposide, and anti-Fas antibody, through the abrogation of cleavage of Bid, poly(ADP-ribose) polymerase, and caspases 3, 8, and 9. The overexpression of Bcl-2 gene prevented FTY720-and etoposide-mediated apoptosis, but not Fas-mediated apoptosis. In addition, mitochondria were demonstrated to play a critical role in FTY720-triggered cell death, suggesting that this drug has a potent anticancer activity.

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“…Some of the findings from pharmacological studies appear inconsistent with those from genetic analyses, and these issues will be addressed below. Investigations of the mechanisms of clinical immunosuppression by the novel drug FTY720, which is a sphingosine analog phosphorylated by sphingosine kinase 2, first implicated S1P systems in the regulation of lymphoid cell traffic in vivo (33)(34)(35)(36). The phosphate ester of FTY720 (FTY720-P) is a true agonist of nanomolar potency for S1P 1 , S1P 3 , S1P 4 , and S1P 5 , but not S1P 2 (37), and most components of FTY720-mediated immunosuppression can be replicated by nonhydrolysable phosphonate analogs of FTY720 (38).…”

Section: Pharmacological and Genetic Manipulation Of S1p And Its Recementioning

confidence: 99%

“…Alterations of numerous aspects of lymphocyte development, circulation, tissue migration, and function by FTY720 also prevents T cell access to and damage of heart, lungs, intestines, kidneys, and brain in transplantation rejection and diverse autoimmune diseases. S1P 1 GPCR-active agents act synergistically with lower-than-conventional doses of other immunosuppressive agents, such as cyclosporine A, and minimize their toxicities without apparent additional impairment of intrinsic lymphocyte or myeloid defense functions (34). Further studies of effects of S1P 1 GPCR-active agents alone and in combination with other immunosuppressive drugs on host defenses against microbial infections are necessary.…”

Section: S1p Receptors In Animal Models Of Diseasementioning

confidence: 99%

Regulation of immunity by lysosphingolipids and their G protein–coupled receptors

Goetzl¹,

Rosen²

2004

J. Clin. Invest.

116

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T and B lymphocytes, as well as endothelial cells, express distinctive profiles of G protein-coupled receptors for sphingosine 1-phosphate, which is a major regulator of T cell development, B and T cell recirculation, tissue homing patterns, and chemotactic responses to chemokines. The capacity of drugs that act on type 1 sphingosine 1-phosphate receptors to suppress organ graft rejection in humans and autoimmunity in animal models without apparent impairment of host defenses against infections suggests that this system is a promising target for new forms of immunotherapy. Lysosphingolipids in the constellation of immunoregulatory lipidsLysophospholipids (LPLs) with biological mediator activity include lysoglycero-phospholipids, epitomized by lysophosphatidic acid (LPA), and lysosphingophospholipids, such as sphingosine 1-phosphate (S1P). The defining property of each LPL is an absence of 1 fatty acid from 1 of the 2 possible positions of acylation on the glycerol backbone. Both classes of LPLs share 3 important characteristics. First, their structures have a lipid domain and 1 or more polar charged substituents, and they are bound extensively in vivo by albumin and other plasma proteins. Second, they affect numerous functions of many types of cells, from proliferation and survival to migration and secretion. There is solid evidence for involvement of LPLs in processes as diverse as oxidative metabolism, angiogenesis, and carcinogenesis. Third, they all signal cells predominantly through structurally related G protein-coupled receptors (GPCRs). Of the known lipid biomediators, only leukotriene B 4 (LTB4), derived by 5-lipoxygenation of arachidonic acid, and S1P are considered major immune cytokines. As the effects of both S1P and LTB4 are transduced by GPCRs that are prime targets for drug development, normal and pathological contributions of the S1P and LTB4 systems are expected to be highly susceptible to pharmaceutical intervention.All immunoregulatory lipid mediators are produced predominantly by cells of the innate immune system, such as mast cells, macrophages, and granulocytes, and act on T and B cells of the adaptive immune system, as well as phagocytes and endothelial cells, through their respective GPCRs. Arachidonic acid-derived lipid mediators, such as COX-generated prostaglandin E2 and thromboxane A2, affect some aspects of B cell and T cell development and survival, as well as cytokine secretion with low to moderate potency (1). LTB4 is a potent and selective chemotactic factor for subsets of effector T cells, but not for naive T cells, and does not effect other lymphocyte functions (2, 3). The phospholipid platelet-activating factor (PAF) and PAF-like fragments of oxidized phosphatidylcholine are potent inflammatory mediators but have modest or restricted suppressive immune effects on adaptive immunity that have been recognized only in very specialized settings (4). In contrast, profound effects of S1P, LPA, and other LPLs are seen on diverse aspects of differentiation, survival, migration, tissue...

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FTY720, a novel immunosuppressant, induces sequestration of circulating lymphocytes by acceleration of lymphocyte homing

Cited by 51 publications

References 3 publications

Proliferative Expansion and Acquisition of Effector Activity by Memory CD4+ T Cells in the Lungs following Pulmonary Virus Infection

Proliferative Expansion and Acquisition of Effector Activity by Memory CD4+ T Cells in the Lungs following Pulmonary Virus Infection

Distinct Pathways of Apoptosis Triggered by FTY720, Etoposide, and Anti-Fas Antibody in Human T-Lymphoma Cell Line (Jurkat Cells)

Regulation of immunity by lysosphingolipids and their G protein–coupled receptors

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