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

• Published in: The Journal of immunology (1950) 1998-06, Vol.160 (11), p.5493-5499
• Main Authors: Yanagawa, Yoshiki, Sugahara, Kunio, Kataoka, Hirotoshi, Kawaguchi, Takafumi, Masubuchi, Yumi, Chiba, Kenji
• Format: Article
• Language: English
• Subjects: Animals; CD3 Complex - drug effects; CD3 Complex - genetics; Cell Movement - drug effects; Cell Movement - immunology; Cyclosporine - pharmacology; Cytokines - biosynthesis; Fingolimod Hydrochloride; Graft Survival - drug effects; Histocompatibility - genetics; Immunosuppressive Agents - pharmacology; Interferon-gamma - biosynthesis; Interferon-gamma - drug effects; Interferon-gamma - genetics; Interleukin-2 - biosynthesis; Interleukin-2 - genetics; Lymphocyte Culture Test, Mixed; Major Histocompatibility Complex - genetics; Male; Polymerase Chain Reaction; Propylene Glycols - pharmacology; Rats; Rats, Inbred F344; Rats, Inbred Strains; RNA, Messenger - biosynthesis; RNA, Messenger - drug effects; RNA, Messenger - metabolism; Skin Transplantation - immunology; Sphingosine - analogs & derivatives; T-Lymphocytes - immunology; Time Factors; Transplantation, Homologous
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.160.11.5493

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.