title: FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. II. FTY720 prolongs skin allograft survival by decreasing T cell infiltration into grafts but not cytokine production in vivo.
abstract: FTY720, a novel immunosuppressant, prolonged the survival of WKAH skin allografts transplanted into MHC-incompatible F344 rats. In this allograft model, the median survival time of the control group was 7 days, whereas those of the groups given FTY720 orally at 0.1 mg/kg and cyclosporin A (CsA) at 10 mg/kg were 10.5 and 11 days, respectively. In contrast, FTY720 (0.1 mg/kg) combined with CsA (10 mg/kg) synergistically prolonged allograft survival with a median survival time exceeding 70 days. To elucidate the mechanisms of this remarkable synergistic effect, mRNA expressions of IL-2 and IFN-gamma and that of CD3 (delta-chain), which reflects T cell infiltration, in allografts were temporally analyzed using a semiquantitative PCR method. In WKAH skin allografts, mRNA levels of IL-2, IFN-gamma, and CD3 were increased as compared with isograft controls, peaking on days 4 to 5. CsA (10 mg/kg) significantly inhibited elevations of IL-2 and IFN-gamma mRNA, while slightly inhibiting that of CD3 mRNA in allografts. On the contrary, FTY720 (0.1 mg/kg) markedly inhibited the elevation of CD3 mRNA, while slightly inhibiting those of IL-2 and IFN-gamma mRNA. FTY720 (0.1 mg/kg) combined with CsA (10 mg/kg) almost completely suppressed the intragraft expressions of mRNA for IL-2, IFN-gamma, and CD3. Immunohistochemical staining and flow cytometric analysis also confirmed that FTY720 decreased T cell infiltration into allografts. From these results, the synergistic effect of FTY720 combined with CsA on prolongation of allograft survival is presumably based on the respective inhibitions of T cell infiltration and cytokine production in grafts.
authors.affiliation: Research Laboratories, Yoshitomi Pharmaceutical Industries, Ltd., Saitama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yanagawa
authors.forename: K
authors.initials: K
authors.lastname: Sugahara
authors.forename: H
authors.initials: H
authors.lastname: Kataoka
authors.forename: T
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Masubuchi
authors.forename: K
authors.initials: K
authors.lastname: Chiba
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis*; D000068876:Fingolimod Hydrochloride; D006085:Graft Survival / Q000187:drug effects*; D006648:Histocompatibility / Q000235:genetics; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D007959:Lymphocyte Culture Test, Mixed; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D016133:Polymerase Chain Reaction; D011409:Propylene Glycols / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D016038:Skin Transplantation / Q000276:immunology*; D013110:Sphingosine / Q000031:analogs & derivatives; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors; D014184:Transplantation, Homologous
chemical_list: D017252:CD3 Complex; D016207:Cytokines; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011409:Propylene Glycols; D012333:RNA, Messenger; D007371:Interferon-gamma; D016572:Cyclosporine; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine