FTY720: a novel transplantation drug that modulates lymphocyte traffic rather than activation
2000; Elsevier BV; Volume: 21; Issue: 2 Linguagem: Inglês
10.1016/s0165-6147(99)01419-4
ISSN1873-3735
AutoresVolker Brinkmann, Daniel D. Pinschewer, Kenji Chiba, Lilli Feng,
Tópico(s)Immune Response and Inflammation
ResumoThe novel immunomodulator FTY720 is a synthetic structural analogue of myriocin, a metabolite of the ascomycete Isaria sinclairii1 Adachi K et al. Design, synthesis, and structure–activity relationships of 2-substituted-2-amino-1,3–propanediols: discovery of a novel immunosuppressant, FTY720. Bioorg. Med. Chem. Lett. 1995; 5: 853-856 Crossref Scopus (280) Google Scholar , 2 Fujita T et al. Simple compounds, 2-alkyl-2-amino-1,3-propanediols have potent immunosuppressive activity. Bioorg. Med. Chem. Lett. 1995; 5: 847-852 Crossref Scopus (97) Google Scholar , 3 Fujita T et al. Potent immunosuppressants, 2-alkyl-2-aminopropane-1,3-diols. J. Med. Chem. 1996; 39: 4451-4459 Crossref PubMed Scopus (131) Google Scholar , 4 Fujita T et al. 2-Substituted 2-aminoethanol: minimum essential structure for immunosuppressive activity of ISP-I (myriocin). Bioorg. Med. Chem. Lett. 1995; 5: 1857-1860 Crossref Scopus (25) Google Scholar . FTY720 prolongs, with remarkable potency, the survival of solid organ grafts in animal models including non-human primates 5 Chiba K et al. FTY720, a novel immunosuppressant possessing unique mechanisms. I. Prolongation of skin allograft survival and synergistic effect in combination with CsA in rats. Transplant. Proc. 1996; 28: 1056-1059 PubMed Google Scholar , 6 Yanagawa Y et al. FTY720, a novel immunosuppressant possessing unique mechanisms. II. FTY720 prolongs skin allograft survival by decreasing T cell infiltration into grafts but not cytokine production in vivo. J. Immunol. 1998; 160: 5493-5499 PubMed Google Scholar , 7 Hwang M.-W et al. FTY720, a new immunosuppressant, promotes long term graft survival and inhibits the progression of graft coronary artery disease in a murine model of cardiac transplantation. Circulation. 1999; 100: 1322-1329 Crossref PubMed Scopus (77) Google Scholar , 8 Suzuki S et al. Immunosuppressive effect of a new drug, FTY720, on lymphocyte responses in vitro and cardiac allograft survival in rats. Transplant. Immunol. 1996; 4: 252-255 Crossref PubMed Scopus (46) Google Scholar , 9 Hoshino Y et al. FTY720, a novel immunosuppressant possessing unique mechanisms. II. Long-term graft survival induction in rat heterotopic cardiac allografts and synergistic effect in combination with cyclosporin A. Transplant. Proc. 1996; 28: 1060-1061 PubMed Google Scholar , 10 Suzuki S et al. A novel immunosuppressant, FTY720, with a unique mechanism of action, induces long-term graft acceptance in rat and dog allotransplantation. Transplantation. 1996; 61: 200-205 Crossref PubMed Scopus (281) Google Scholar , 11 Kawaguchi T et al. FTY720, a novel immunosuppressant possessing unique mechanisms. III. Synergistic prolongation of canine renal allograft survival in combination with cyclosporin A. Transplant. Proc. 1996; 28: 1062-1063 PubMed Google Scholar , 12 Chiba K 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 Crossref PubMed Google Scholar , 13 Troncosco P et al. Prophylaxis of acute renal allograft rejection using FTY720 in combination with subtherapeutic doses of cyclosporine. Transplantation. 1999; 67: 145-151 Crossref PubMed Scopus (71) Google Scholar , 14 Wang M.E et al. Immunosuppressive effects of FTY720 alone or in combination with cyclosporine and/or sirolimus. Transplantation. 1998; 65: 899-905 Crossref PubMed Scopus (100) Google Scholar , 15 Stepkowski S.M et al. Synergistic interaction of FTY720 with cyclosporin or sirolimus to prolong heart allograft survival. Transplant. Proc. 1998; 30: 2214-2216 Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar , and prevents the development of pathology in graft-vs-host disease (GvHD) 14 Wang M.E et al. Immunosuppressive effects of FTY720 alone or in combination with cyclosporine and/or sirolimus. Transplantation. 1998; 65: 899-905 Crossref PubMed Scopus (100) Google Scholar , 16 Mitsusada M et al. Prevention of graft rejection and graft-versus-host reaction by a novel immunosuppressant, FTY720, in rat small bowel transplantation. Transpl. Int. 1997; 10: 343-349 PubMed Google Scholar , autoimmune type I diabetes 17 Suzuki K et al. Prevention of experimentally induced autoimmune type I diabetes in rats by the new immunosuppressive reagent FTY720. Transplant. Proc. 1998; 30: 1044-1045 Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar and rheumatoid arthritis (L. Feng, unpublished observations). It is now evident that FTY720 displays a novel mechanism of action that has not been observed with any other immunosuppressive agent. Unlike its structural analogue myriocin, FTY720 does not bind serine palmitoyl transferase and does not inhibit the sphingolipid pathway 18 Chen J.K et al. The identification of myriocin-binding proteins. Chem. Biol. 1999; 6: 221-235 Abstract Full Text PDF PubMed Scopus (93) Google Scholar . Therapeutic doses of FTY720 do not impair lymphocyte function but instead modulate the circulation of T and B cells between the blood and the secondary lymphoid organs. In transplantation situations this leads to a sequestration of T and B cells to the lymph nodes (LNs) and Peyer's patches (PPs) 6 Yanagawa Y et al. FTY720, a novel immunosuppressant possessing unique mechanisms. II. FTY720 prolongs skin allograft survival by decreasing T cell infiltration into grafts but not cytokine production in vivo. J. Immunol. 1998; 160: 5493-5499 PubMed Google Scholar , 12 Chiba K 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 Crossref PubMed Google Scholar and an inhibition of T-cell infiltration into grafted organs 6 Yanagawa Y et al. FTY720, a novel immunosuppressant possessing unique mechanisms. II. FTY720 prolongs skin allograft survival by decreasing T cell infiltration into grafts but not cytokine production in vivo. J. Immunol. 1998; 160: 5493-5499 PubMed Google Scholar , 7 Hwang M.-W et al. FTY720, a new immunosuppressant, promotes long term graft survival and inhibits the progression of graft coronary artery disease in a murine model of cardiac transplantation. Circulation. 1999; 100: 1322-1329 Crossref PubMed Scopus (77) Google Scholar . Recent evidence suggests that FTY720 acts on lymphocytes via G-protein-coupled receptors (GPCRs) 19 Brinkmann V et al. FTY720 suppresses immune responses by modulating G-protein coupled receptors on lymphocytes resulting in altered lymphocyte homing. Transplantation. 1999; 67: S226 Crossref Google Scholar , possibly chemokine receptors, and that the drug affects the responsiveness of T and B cells to chemokines, which results in altered cell migration. 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride
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