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FTY720—the first compound of a new promising class of immunosuppressive drugs

FTY720—the first compound of a new promising class of immunosuppressive drugs FTY720, kidney transplantation, immunosuppression Immunosuppressive regimens containing cyclosporin or tacrolimus have reduced acute kidney graft rejections to an incidence as low as 10–30%, but acute rejections remain one of the strongest predictors for long-term kidney graft function [1–3]. Even though an increased dosage of calcineurin inhibitors can easily suppress rejection episodes, the risk of chronic transplant nephropathy, cardiovascular diseases and diabetes mellitus rises concomitantly with such treatments [4–6]. Therefore, standard immunosuppressive regimes combine calcineurin inhibitors with azathioprin, mycophenolate mofetil or rapamycin and corticosteroids, which inhibit an ongoing immune response synergistically. FTY720 is the first compound of a new class of immunosuppressive drugs that exhibit the potency to suppress initiation and continuation of a rejection using a different mechanism in comparison with other known immunosuppressive drugs. Recirculation of lymphocytes is a prerequisite for an immune response The immunosuppressive effect of FTY720 relies on inhibition of lymphocyte recirculation. The initiation as well as the effector phase of an immune response depends on lymphocyte recirculation. Naive T cells can only be activated by antigen-presenting dendritic cells in so-called secondary lymphoid organs, such as lymph nodes, spleen and Peyer's patches [7], and probably also in the bone marrow [8]. After organ transplantation, mature host and donor antigen-loaded dendritic cells migrate from the allotransplant into the T-cell zones of secondary lymphoid organs guided by cytokines and chemokines [9]. There, dendritic cells are able to inform the immune system by activating appropriate T cells for the remaining 2–3 days of their life. Naive and central memory T cells continuously leave the blood and enter lymph nodes through high endothelial venules in a multistep adhesion cascade. This process requires certain homing molecules expressed on T cells and endothelial cells, together with various chemokines, including CCL19 (also termed ELC, EBI ligand chemokine), CCL21 (SLC, secondary lymphoid tissue chemokine) and CXCL13 (BLC, B lymphocyte chemoattractant) which are recognized by the chemokine receptors CCR7 and CXCR5 [10–12]. After entering the paracortex of lymph nodes, naive and central memory T cells encounter numerous dendritic cells in their search for a stimulating antigen. If the T cells find nothing of interest, they leave the lymph node via efferent lymphatics and join the venous blood again via subclavian vein [13]. Twice daily, naive T cells circulate between blood and secondary lymphoid organs in search of appropriate antigens. Long-lived central memory T cells also follow this constitutive homing paradigm [14]. T cells that have been activated by antigen stimulation undergo differentiation into effector cells and clonal expansion, and migrate from the lymph node. Those effector T cells travel from the lymphatics back into the blood. With the ability acquired to leave the blood through post-capillary venules, they migrate into the tissue in order to reject the transplanted organ [15]. The egress of lymphocytes from the thymus into the blood as well as from the tissue of secondary lymphoid organs into the efferent lymphatic vessels is tightly regulated. Sphingosine-1-phosphate and its receptors are substantially involved in this immune regulatory step [16] (Figure 1). Fig. 1. Open in new tabDownload slide FTY720 inhibits lymphocyte traffic: naive thymus-derived T cells and memory T cells circulate between blood and secondary lymphoid organs in a search for appropriate antigens presented by dendritic cells. After antigen-dependent activation, T cells leave secondary lymphoid organs to travel via the blood to the allograft. FTY720 blocks egress of lymphocytes from both thymus and lymph nodes. Fig. 1. Open in new tabDownload slide FTY720 inhibits lymphocyte traffic: naive thymus-derived T cells and memory T cells circulate between blood and secondary lymphoid organs in a search for appropriate antigens presented by dendritic cells. After antigen-dependent activation, T cells leave secondary lymphoid organs to travel via the blood to the allograft. FTY720 blocks egress of lymphocytes from both thymus and lymph nodes. A new target for immunosuppression: sphingosine-regulated lymphocyte traffic Sphingosine-1 is generated during metabolism of sphingomyelin, an abundant component of biological membranes. Sphingosine-1 and FTY720, which share structural homology, are phosphorylated by a sphingosine kinase, expressed in various cells. The efflux of phosphorylated FTY720 (FTY720-P) from the cell is mediated by the multidrug transporter MDR-1 [17] (Figure 2). The phosphorylation of FTY720 is reversible in blood. Therefore, plasma pharmacokinetics of FTY720 show a stable equilibrium between FTY720 and a 2- to 4-fold higher concentration of FTY720-P [18] (Figure 2). FTY720-P but not the parental drug is recognized by four of the five sphingosine-1-phosphate receptors (S1PR1, S1PR3, S1PR4 and S1PR5) in nano- or picomolar concentrations [18]. These G-protein-coupled receptors are expressed on T cells (S1PR4 and S1PR5), endothelial cells (S1PR1 and S1PR3), vascular smooth muscle cells and myocardium (S1PR1 and S1PR2) [16], correlating with immunosuppressive and cardiovascular effects. Interestingly, FTY720 inhibits signalling through the S1PR1, S1PR2 and S1PR5 by inducing S1PR internalization at nanomolar concentrations, without activating or inducing recycling of the receptor [19]. The immunosuppressive effect of FTY720 correlates with the degree of blood lymphopoenia. Intravenous administration of FTY720 induces lymphopoenia in blood with a nadir within 4 h. At the same time, the number of lymphocytes markedly increases in peripheral lymph nodes, mesenteric lymph nodes and Peyer's patches, but not in spleen [20]. Myelo-monocytic cells are not affected [20]. It has been suggested that FTY720 induces lymphopoenia by increased influx of lymphocytes into lymph nodes and Peyer's patches due to an accelerated chemotactic response. Indeed, FTY720-P promotes homing of lymphocytes due to an enhanced leukotriene-dependent chemokine receptor CCR7-mediated chemotaxis [17]. However, experiments in CXCR5 and CCR7 knockout mice demonstrated that FTY720-induced lymphocyte sequestration in lymph nodes appears to involve additional mechanisms [21,22]. A single dose of FTY720 induces trafficking of lymphocytes to the abluminal side of the sinus lymphaticus-lining endothelium and the disappearance of lymphocytes from subcapsular and medullary areas rich in dendritic cells [18]. However, lymphocytes do not overcome the endothial barrier to enter the sinus lymphaticus. Egress of T and B cells into the efferent lymphatics is inhibited by FTY720. In accordance with this, lymphocytes are not detectable in the thoracic duct of FTY720-treated rats [20]. The mechanism of FTY720-regulated inhibition of cell egress remains uncertain at the cellular level. S1PRs are involved in the assembly of vascular endothelial cell–cell junctions [23]. FTY720 inhibits vascular permeability [24]. Therefore, the sinus-lining endothelium might contribute to the inhibition of lymphocyte egress under the influence of FTY720. FTY720 also inhibits the migration of naive T cells from thymus into the blood, resulting in a declining supply of naive T cells to the organism [25]. Fig. 2. Open in new tabDownload slide FTY720 is phosphorylated intracellulary before binding to sphingosine-1-phosphate receptors. Fig. 2. Open in new tabDownload slide FTY720 is phosphorylated intracellulary before binding to sphingosine-1-phosphate receptors. In summary, the immunosuppressive effect of FTY720 reflects the induction of ignorance of peripheral antigens by various mechanisms: naive T cells are directed to the wrong place in the lymph node, which limits their ability to recognize antigens. The interruption of recirculation of naive T cells bearing a specific antigen receptor further reduces the probability of T cells encountering the appropriate antigen-presenting dendritic cell. Moreover, the number of naive T cells is reduced, since the organism is cut off from supply from the thymus. However, the effector phase is also inhibited by FTY720, since already activated CD4+ and CD8+ effector T cells are trapped in the draining lymph nodes and prevented from travelling to the lymph and the blood [26]. These immunosuppressive mechanisms, which are completely different from those alternative immunosuppressive agents, make this drug attractive for immunosuppressive protocols in transplantation and autoimmune disorders. FTY720 effectively suppresses allotransplant rejections and autoimmune disorders in various animal models Treatment of rats, mice, dogs or monkeys with FTY720 alone or in combination with cyclosporin prolonged survival of various allotransplants including skin, heart, liver, kidney and intestine [27]. In such experimental models, FTY720 treatment results in a marked reduction of graft-infiltrating lymphocytes [28]. The effectiveness of FTY720 in suppressing a pathological immune response has also been proven in experimental animal models of autoimmune encephalomyelitis, certain models of systemic lupus erythematosus and autoimmune myocarditis [29]. These promising results justified trials to test the immune-modulatory effect of FTY720 in patients. FTY720 in renal transplantation—human trials Pharmacokinetic data were evaluated in multicentre studies in stable kidney-transplanted patients maintained on cyclosporin and corticosteroids after single or multiple dosages of FTY720 in a range of 0.125–5.0 mg/day [30,31]. FTY720 displayed dose linearity with drug absorption independently of formulation and of interaction with food, and a high oral bioavailability of 37–71%. The maximum concentration (Cmax) is reached after 12–36 h due to a long absorption phase. FTY720 is metabolized extensively in the liver by cytochrome P450 4F2/3 enzymes. None of the identified metabolites exhibited immunosuppressive activity [32]. The metabolites could be detected in urine (40–50%) and in faeces (20–50%). Although FTY720 utilizes the common cytochrome P450 metabolic pathway, no interaction with cyclosporin or rapamycin has been described, since the P450 isoenzymes used are different. FTY720 displays an elimination half-life of 89–157 h. Impaired kidney function after renal transplantation was not associated with accumulation of FTY720. Recently, two phase II trials have analysed the safety and efficacy of FTY720 after kidney transplantation [33,34]. The administration of 5 mg FTY720 in combination with steroids, and a cyclosporin dose adjusted to blood levels at 2 h post-dose (C2) to achieve a difference in exposure from 50% of a full cyclosporin dose, reduced the incidence of acute biopsy-proven kidney graft rejection significantly when compared with a standard immunosuppressive regimen containing 2–3 g/day mycophenolate mofetil in combination with a full dose of cyclosporin and corticosteroids; 12.5 vs 17.9% [34]. FTY720 treatment was associated with a drop in lymphocyte count, with a nadir 4 h after initiation of the therapy. The drug was tolerated very well. The main adverse advent was bradycardia, which was reported in ∼25% of all FTY720-treated patients. Bradycardia was observed most often during the first 2 days after initiation of FTY720 treatment [34,35]. Although bradycardia was usually self-limited and modest, with a mean decrease in pulse rate of 13–15 b.p.m., bradycardia was managed using atropine or β-mimetics in ∼12% of FTY720-treated patients. The surprising negative chronotropic effect of FTY720 may be explained by the fact that it binds to S1PRs (S1PR1 and S1PR2) in the heart. Activation of S1PRs reduces the activity of adenylate cyclase and the intracellular level of cAMP in a β-adrenergic agonist-sensitive manner [36]. It is likely that FTY720-P uses the same pathway. Hypertensive kidney graft recipients pre-treated with β-blockers may therefore be at considerable risk of a further reduction of the heart rate after initiation of FTY720 therapy. However, the incidence of cardiac failure, arrhythmia, myocardial infarction and cardiac arrest in FTY720-treated patients was similar to the incidence reported in >2500 kidney graft recipients treated with cyclosporin, azathioprin and prednisolone [37]. The overall incidence and severity of infections did not differ between FTY720 and mycophenolate mofetil treatments. In patients receiving a single oral dose of FTY270, the peripheral blood lymphocyte counts were reduced by 30–70% and returned to baseline levels within 24 h [35]. Lymphopoenia persisted for >96 h only in patients treated with the highest dose (3.5 mg) of FTY270. In animal experiments, FTY720 impaired a delayed-type hypersensitivity reaction (DTH), the induction of T cell-mediated autoimmune responses and allograft rejections, while an immune response against systemic viral infections remained unaffected [39]. An antibody-mediated immune response against systemic viral infections is generated in secondary lymphoid organs including spleen, and does not require lymphocyte recirculation and migration of B and T cells to the periphery. In contrast, in order to combat a transplanted solid organ, T cells have to migrate from lymph nodes. Since FTY720 inhibits egress of lymphocytes from lymph nodes, the mode of action is in accordance with the results obtained from virus-infected mice. Indeed, the incidence of cytomegalovirus (CMV) infections in kidney graft recipients was lower in the FTY720 groups in comparison with the mycophenolate mofetil group [34]. However, CMV infections after transplantation are affected by several factors including immunosuppressive co-medication, donor and recipient immunity against CMV prior to transplantation, and others. In summary, FTY720 is a potent immunosuppressive agent that is well tolerated in patients. Due to its mode of action, which differs substantially from that of other known immunosuppressive drugs, and due to its different side effect profile, FTY720 is a promising partner in immunosuppressive regimens and will substantially extend the standard immunosuppressive repertoire. Conflict of interest statement. None declared. References 1 Nankivell BJ, Borrows RJ, Fung CLS et al. The natural history of chronic allograft nephropathy. N Engl J Med 2003 ; 349 : 2326 –23334 2 Johnson C, Ahsan N, Gonwa T et al. Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation. Transplantation 2000 ; 69 : 834 –841 3 Gonwa T, Mendez R, Yang HC et al. Randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 6 months. Transplantation 2003 ; 75 : 1213 –1220 4 Almond PS, Matas A, Gillingham K et al. Risk factors for chronic rejection in renal allograft recipients. Transplantation 1993 ; 55 : 752 –756 5 Solez K, Vincenti F, Filo RS. Histopathologic findings from 2-year protocol biopsies from a U.S. multicenter kidney transplant trial comparing tacrolimus versus cyclosporine: a report of the FK506 Kidney Transplant Study Group. Transplantation 1998 ; 66 : 1736 –1740 6 Kramer BK, Zulke C, Kammerl MC et al. Cardiovascular risk factors and estimated risk for CAD in a randomized trial comparing calcineurin inhibitors in renal transplantation. Am J Transplant 2003 ; 3 : 982 –987 7 Lakkis FG, Arakelov A, Konieczny BT et al. Immunologic ‘ignorance’ of vascularized organ transplants in the absence of secondary lymphoid tissue. Nature Med 2000 ; 6 : 686 –688 8 Feuerer M, Beckhove P, Garbi N et al. Bone marrow as a priming site for T-cell responses to blood-borne antigen. Nature Med 2003 ; 9 : 1151 –1157 9 Lanzavecchia A, Sallusto F. The instructive role of dendritic cells on T cell responses: lineages, plasticity and kinetics. Curr Opin Immunol 2001 ; 13 : 291 –298 10 von Andrian UH, Mempel TR. Homing and cellular traffic in lymph nodes. Nature Rev Immunol 2003 ; 3 : 867 –878 11 Förster R, Schubel A, Breitfeld D et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 1999 ; 99 : 23 –33 12 Cyster JG. Lymphoid organ development and cell migration. Immunol Rev 2003 ; 195 : 5 –14 13 Melchers F, Rolink AG, Schaniel C. The role of chemokines in regulating cell migration during humoral immune responses. Cell 1999 ; 99 : 351 –354 14 Weninger W, Crowley MA, Manjunath N et al. Migratory properties of naive, effector, and memory CD8+ T cells. J Exp Med 2001 ; 194 : 953 –966 15 Butcher EC, Williams M, Youngman K et al. Lymphocyte trafficking and regional immunity. Adv Immunol 1999 ; 72 : 209 –253. 16 Rosen H, Sanna G, Alfonso C. Egress: a receptor-regulated step in lymphocyte trafficking. Immunol Rev 2003 ; 195 : 160 –177 17 Honig SM, Fu S, Mao X et al. FTY720 stimulates multidrug transporter- and cysteinyl leukotriene-dependent T cell chemotaxis to lymph nodes. J Clin Invest 2003 ; 111 : 627 –637 18 Mandala S, Hajdu R, Bergstrom J et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 2002 ; 296 : 346 –349 19 Gräler MH, Goetzl EJ. The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G protein-coupled receptors. FASEB J 2004 Mar; (18)3 : 551 –3. 20 Chiba K, Yanagawa Y, Masubuchi Y et al. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J Immunol 1998 ; 160 : 5037 –5044 21 Müller G, Reiterer P, Höpken UE et al. Role of homeostatic chemokine and sphingosine-1-phosphate receptors in the organization of lymphoid tissue. Ann NY Acad Sci 2003 ; 987 : 107 –116 22 Henning G, Ohl L, Junt T et al. CC chemokine receptor 7-dependent and -independent pathways for lymphocyte homing: modulation by FTY720. J Exp Med 2001 ; 194 : 1875 –1881 23 Lee MJ, Thangada S, Claffey KP et al. Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate. Cell 1999 ; 99 : 301 –312 24 Sanchez T, Estrada-Hernandez T, Paik JH et al. Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular permeability. J Biol Chem 2003 ; 278 : 47281 –47290 25 Yagi H, Kamba R, Chiba K et al. Immunosuppressant FTY720 inhibits thymocyte emigration. Eur J Immunol 2000 ; 30 : 1435 –1444 26 Xie JH, Nomura N, Koprak SL et al. Sphingosine-1-phosphate receptor agonism impairs the efficiency of the local immune response by altering trafficking of naive and antigen-activated CD4+ T cells. J Immunol 2003 ; 170 : 3662 –3670 27 Brinkmann V, Pinschewer DD, Feng L et al. FTY720: altered lymphocyte traffic results in allograft protection. Transplantation 2001 ; 72 : 764 –769 28 Kimura T, Hasegawa T, Nakai H et al. FTY720 reduced T-cell recruitment into murine intestinal allograft and prevents activation of graft-infiltrating cells. Transplantation 2003 ; 75 : 1469 –1474 29 Brinkmann V, Lynch KR. FTY720: targeting G-protein-coupled receptors for sphingosine 1-phosphate in transplantation and autoimmunity. Curr Opin Immunol 2002 ; 14 : 569 –575 30 Budde K, Schmouder L, Nashan B et al. Pharmacodynamics of single doses of the novel immunosuppressant FTY720 in stable renal transplant patients. Am J Transplant 2003 ; 3 : 846 –854 31 Kahan BD, Karlix JL, Ferguson RM et al. Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study. Transplantation 2003 ; 76 : 1079 –1084 32 Kahan BD. Update on pharmacokinetic/pharmacodynamic studies with FTY720 and sirolimus. Ther Drug Monit 2002 ; 24 : 47 –52 33 Tedesco H, Hahan B, Mourad G et al. FTY720 combined with Neoral and corticosteroids is effective and safe in prevention of acute rejection in renal allograft recipients. Am J Transplant 2001 ; 1 : S243 34 Ferguson RM, Mulgaonkar S, Oppenheimer F et al. FTY720 with reduced cyclosporine therapy in de novo renal transplantation: 6-month safety and efficacy results from a randomised, multicenter dose-finding study. Am J Transplant 2003 ; 3 : 311 (Abstract 624) 35 Budde K, Schmouder RL, Brunkhorst R et al. First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients. J Am Soc Nephrol 2002 ; 13 : 1073 –1083 36 Okamoto H, Takuwa N, Gonda K et al. EDG1 is a functional sphingosine-1-phosphate receptor that is linked via a Gi/o to multiple signaling pathways, including phospholipase C activation, Ca2+ mobilization, Ras-mitogen-activated protein kinase activation, and adenylate cyclase inhibition. J Biol Chem 1998 ; 273 : 27104 –27110 37 Humar A, Kerr SR, Ramcharan T et al. Peri-operative cardiac morbidity in kidney transplant recipients: incidence and risk factors. Clin Transplant 2001 ; 15 : 154 –158 38 Bohler T, Waiser J, Schutz M et al. Pharmacodynamics of FTY720, the first member of a new class of immune-modulating therapeutics in transplantation medicine. Int J Clin Pharmacol Ther 2003 ; 41 : 482 –487 39 Pinschewer DD, Ochsenbein AF, Odermatt B et al. FTY720 immunosuppression impairs effector T cell peripheral homing without affecting induction, expansion, and memory. J Immunol 2000 ; 164 : 5761 –5770 Author notes 1Division of Nephrology and Hypertension and 2Institute of Immunology, University Hospital of Schleswig-Holstein, Campus Kiel, Germany Nephrol Dial Transplant Vol. 19 No. 7 © ERA-EDTA 2004; all rights reserved http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nephrology Dialysis Transplantation Oxford University Press

FTY720—the first compound of a new promising class of immunosuppressive drugs

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Oxford University Press
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Nephrol Dial Transplant Vol. 19 No. 7 © ERA-EDTA 2004; all rights reserved
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0931-0509
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1460-2385
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Abstract

FTY720, kidney transplantation, immunosuppression Immunosuppressive regimens containing cyclosporin or tacrolimus have reduced acute kidney graft rejections to an incidence as low as 10–30%, but acute rejections remain one of the strongest predictors for long-term kidney graft function [1–3]. Even though an increased dosage of calcineurin inhibitors can easily suppress rejection episodes, the risk of chronic transplant nephropathy, cardiovascular diseases and diabetes mellitus rises concomitantly with such treatments [4–6]. Therefore, standard immunosuppressive regimes combine calcineurin inhibitors with azathioprin, mycophenolate mofetil or rapamycin and corticosteroids, which inhibit an ongoing immune response synergistically. FTY720 is the first compound of a new class of immunosuppressive drugs that exhibit the potency to suppress initiation and continuation of a rejection using a different mechanism in comparison with other known immunosuppressive drugs. Recirculation of lymphocytes is a prerequisite for an immune response The immunosuppressive effect of FTY720 relies on inhibition of lymphocyte recirculation. The initiation as well as the effector phase of an immune response depends on lymphocyte recirculation. Naive T cells can only be activated by antigen-presenting dendritic cells in so-called secondary lymphoid organs, such as lymph nodes, spleen and Peyer's patches [7], and probably also in the bone marrow [8]. After organ transplantation, mature host and donor antigen-loaded dendritic cells migrate from the allotransplant into the T-cell zones of secondary lymphoid organs guided by cytokines and chemokines [9]. There, dendritic cells are able to inform the immune system by activating appropriate T cells for the remaining 2–3 days of their life. Naive and central memory T cells continuously leave the blood and enter lymph nodes through high endothelial venules in a multistep adhesion cascade. This process requires certain homing molecules expressed on T cells and endothelial cells, together with various chemokines, including CCL19 (also termed ELC, EBI ligand chemokine), CCL21 (SLC, secondary lymphoid tissue chemokine) and CXCL13 (BLC, B lymphocyte chemoattractant) which are recognized by the chemokine receptors CCR7 and CXCR5 [10–12]. After entering the paracortex of lymph nodes, naive and central memory T cells encounter numerous dendritic cells in their search for a stimulating antigen. If the T cells find nothing of interest, they leave the lymph node via efferent lymphatics and join the venous blood again via subclavian vein [13]. Twice daily, naive T cells circulate between blood and secondary lymphoid organs in search of appropriate antigens. Long-lived central memory T cells also follow this constitutive homing paradigm [14]. T cells that have been activated by antigen stimulation undergo differentiation into effector cells and clonal expansion, and migrate from the lymph node. Those effector T cells travel from the lymphatics back into the blood. With the ability acquired to leave the blood through post-capillary venules, they migrate into the tissue in order to reject the transplanted organ [15]. The egress of lymphocytes from the thymus into the blood as well as from the tissue of secondary lymphoid organs into the efferent lymphatic vessels is tightly regulated. Sphingosine-1-phosphate and its receptors are substantially involved in this immune regulatory step [16] (Figure 1). Fig. 1. Open in new tabDownload slide FTY720 inhibits lymphocyte traffic: naive thymus-derived T cells and memory T cells circulate between blood and secondary lymphoid organs in a search for appropriate antigens presented by dendritic cells. After antigen-dependent activation, T cells leave secondary lymphoid organs to travel via the blood to the allograft. FTY720 blocks egress of lymphocytes from both thymus and lymph nodes. Fig. 1. Open in new tabDownload slide FTY720 inhibits lymphocyte traffic: naive thymus-derived T cells and memory T cells circulate between blood and secondary lymphoid organs in a search for appropriate antigens presented by dendritic cells. After antigen-dependent activation, T cells leave secondary lymphoid organs to travel via the blood to the allograft. FTY720 blocks egress of lymphocytes from both thymus and lymph nodes. A new target for immunosuppression: sphingosine-regulated lymphocyte traffic Sphingosine-1 is generated during metabolism of sphingomyelin, an abundant component of biological membranes. Sphingosine-1 and FTY720, which share structural homology, are phosphorylated by a sphingosine kinase, expressed in various cells. The efflux of phosphorylated FTY720 (FTY720-P) from the cell is mediated by the multidrug transporter MDR-1 [17] (Figure 2). The phosphorylation of FTY720 is reversible in blood. Therefore, plasma pharmacokinetics of FTY720 show a stable equilibrium between FTY720 and a 2- to 4-fold higher concentration of FTY720-P [18] (Figure 2). FTY720-P but not the parental drug is recognized by four of the five sphingosine-1-phosphate receptors (S1PR1, S1PR3, S1PR4 and S1PR5) in nano- or picomolar concentrations [18]. These G-protein-coupled receptors are expressed on T cells (S1PR4 and S1PR5), endothelial cells (S1PR1 and S1PR3), vascular smooth muscle cells and myocardium (S1PR1 and S1PR2) [16], correlating with immunosuppressive and cardiovascular effects. Interestingly, FTY720 inhibits signalling through the S1PR1, S1PR2 and S1PR5 by inducing S1PR internalization at nanomolar concentrations, without activating or inducing recycling of the receptor [19]. The immunosuppressive effect of FTY720 correlates with the degree of blood lymphopoenia. Intravenous administration of FTY720 induces lymphopoenia in blood with a nadir within 4 h. At the same time, the number of lymphocytes markedly increases in peripheral lymph nodes, mesenteric lymph nodes and Peyer's patches, but not in spleen [20]. Myelo-monocytic cells are not affected [20]. It has been suggested that FTY720 induces lymphopoenia by increased influx of lymphocytes into lymph nodes and Peyer's patches due to an accelerated chemotactic response. Indeed, FTY720-P promotes homing of lymphocytes due to an enhanced leukotriene-dependent chemokine receptor CCR7-mediated chemotaxis [17]. However, experiments in CXCR5 and CCR7 knockout mice demonstrated that FTY720-induced lymphocyte sequestration in lymph nodes appears to involve additional mechanisms [21,22]. A single dose of FTY720 induces trafficking of lymphocytes to the abluminal side of the sinus lymphaticus-lining endothelium and the disappearance of lymphocytes from subcapsular and medullary areas rich in dendritic cells [18]. However, lymphocytes do not overcome the endothial barrier to enter the sinus lymphaticus. Egress of T and B cells into the efferent lymphatics is inhibited by FTY720. In accordance with this, lymphocytes are not detectable in the thoracic duct of FTY720-treated rats [20]. The mechanism of FTY720-regulated inhibition of cell egress remains uncertain at the cellular level. S1PRs are involved in the assembly of vascular endothelial cell–cell junctions [23]. FTY720 inhibits vascular permeability [24]. Therefore, the sinus-lining endothelium might contribute to the inhibition of lymphocyte egress under the influence of FTY720. FTY720 also inhibits the migration of naive T cells from thymus into the blood, resulting in a declining supply of naive T cells to the organism [25]. Fig. 2. Open in new tabDownload slide FTY720 is phosphorylated intracellulary before binding to sphingosine-1-phosphate receptors. Fig. 2. Open in new tabDownload slide FTY720 is phosphorylated intracellulary before binding to sphingosine-1-phosphate receptors. In summary, the immunosuppressive effect of FTY720 reflects the induction of ignorance of peripheral antigens by various mechanisms: naive T cells are directed to the wrong place in the lymph node, which limits their ability to recognize antigens. The interruption of recirculation of naive T cells bearing a specific antigen receptor further reduces the probability of T cells encountering the appropriate antigen-presenting dendritic cell. Moreover, the number of naive T cells is reduced, since the organism is cut off from supply from the thymus. However, the effector phase is also inhibited by FTY720, since already activated CD4+ and CD8+ effector T cells are trapped in the draining lymph nodes and prevented from travelling to the lymph and the blood [26]. These immunosuppressive mechanisms, which are completely different from those alternative immunosuppressive agents, make this drug attractive for immunosuppressive protocols in transplantation and autoimmune disorders. FTY720 effectively suppresses allotransplant rejections and autoimmune disorders in various animal models Treatment of rats, mice, dogs or monkeys with FTY720 alone or in combination with cyclosporin prolonged survival of various allotransplants including skin, heart, liver, kidney and intestine [27]. In such experimental models, FTY720 treatment results in a marked reduction of graft-infiltrating lymphocytes [28]. The effectiveness of FTY720 in suppressing a pathological immune response has also been proven in experimental animal models of autoimmune encephalomyelitis, certain models of systemic lupus erythematosus and autoimmune myocarditis [29]. These promising results justified trials to test the immune-modulatory effect of FTY720 in patients. FTY720 in renal transplantation—human trials Pharmacokinetic data were evaluated in multicentre studies in stable kidney-transplanted patients maintained on cyclosporin and corticosteroids after single or multiple dosages of FTY720 in a range of 0.125–5.0 mg/day [30,31]. FTY720 displayed dose linearity with drug absorption independently of formulation and of interaction with food, and a high oral bioavailability of 37–71%. The maximum concentration (Cmax) is reached after 12–36 h due to a long absorption phase. FTY720 is metabolized extensively in the liver by cytochrome P450 4F2/3 enzymes. None of the identified metabolites exhibited immunosuppressive activity [32]. The metabolites could be detected in urine (40–50%) and in faeces (20–50%). Although FTY720 utilizes the common cytochrome P450 metabolic pathway, no interaction with cyclosporin or rapamycin has been described, since the P450 isoenzymes used are different. FTY720 displays an elimination half-life of 89–157 h. Impaired kidney function after renal transplantation was not associated with accumulation of FTY720. Recently, two phase II trials have analysed the safety and efficacy of FTY720 after kidney transplantation [33,34]. The administration of 5 mg FTY720 in combination with steroids, and a cyclosporin dose adjusted to blood levels at 2 h post-dose (C2) to achieve a difference in exposure from 50% of a full cyclosporin dose, reduced the incidence of acute biopsy-proven kidney graft rejection significantly when compared with a standard immunosuppressive regimen containing 2–3 g/day mycophenolate mofetil in combination with a full dose of cyclosporin and corticosteroids; 12.5 vs 17.9% [34]. FTY720 treatment was associated with a drop in lymphocyte count, with a nadir 4 h after initiation of the therapy. The drug was tolerated very well. The main adverse advent was bradycardia, which was reported in ∼25% of all FTY720-treated patients. Bradycardia was observed most often during the first 2 days after initiation of FTY720 treatment [34,35]. Although bradycardia was usually self-limited and modest, with a mean decrease in pulse rate of 13–15 b.p.m., bradycardia was managed using atropine or β-mimetics in ∼12% of FTY720-treated patients. The surprising negative chronotropic effect of FTY720 may be explained by the fact that it binds to S1PRs (S1PR1 and S1PR2) in the heart. Activation of S1PRs reduces the activity of adenylate cyclase and the intracellular level of cAMP in a β-adrenergic agonist-sensitive manner [36]. It is likely that FTY720-P uses the same pathway. Hypertensive kidney graft recipients pre-treated with β-blockers may therefore be at considerable risk of a further reduction of the heart rate after initiation of FTY720 therapy. However, the incidence of cardiac failure, arrhythmia, myocardial infarction and cardiac arrest in FTY720-treated patients was similar to the incidence reported in >2500 kidney graft recipients treated with cyclosporin, azathioprin and prednisolone [37]. The overall incidence and severity of infections did not differ between FTY720 and mycophenolate mofetil treatments. In patients receiving a single oral dose of FTY270, the peripheral blood lymphocyte counts were reduced by 30–70% and returned to baseline levels within 24 h [35]. Lymphopoenia persisted for >96 h only in patients treated with the highest dose (3.5 mg) of FTY270. In animal experiments, FTY720 impaired a delayed-type hypersensitivity reaction (DTH), the induction of T cell-mediated autoimmune responses and allograft rejections, while an immune response against systemic viral infections remained unaffected [39]. An antibody-mediated immune response against systemic viral infections is generated in secondary lymphoid organs including spleen, and does not require lymphocyte recirculation and migration of B and T cells to the periphery. In contrast, in order to combat a transplanted solid organ, T cells have to migrate from lymph nodes. Since FTY720 inhibits egress of lymphocytes from lymph nodes, the mode of action is in accordance with the results obtained from virus-infected mice. Indeed, the incidence of cytomegalovirus (CMV) infections in kidney graft recipients was lower in the FTY720 groups in comparison with the mycophenolate mofetil group [34]. However, CMV infections after transplantation are affected by several factors including immunosuppressive co-medication, donor and recipient immunity against CMV prior to transplantation, and others. In summary, FTY720 is a potent immunosuppressive agent that is well tolerated in patients. Due to its mode of action, which differs substantially from that of other known immunosuppressive drugs, and due to its different side effect profile, FTY720 is a promising partner in immunosuppressive regimens and will substantially extend the standard immunosuppressive repertoire. Conflict of interest statement. None declared. References 1 Nankivell BJ, Borrows RJ, Fung CLS et al. 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J Immunol 2000 ; 164 : 5761 –5770 Author notes 1Division of Nephrology and Hypertension and 2Institute of Immunology, University Hospital of Schleswig-Holstein, Campus Kiel, Germany Nephrol Dial Transplant Vol. 19 No. 7 © ERA-EDTA 2004; all rights reserved

Journal

Nephrology Dialysis Transplantation – Oxford University Press

Published: Jul 1, 2004

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