FTY720 Immunosuppression Impairs Effector T Cell Peripheral Homing Without Affecting Induction, Expansion, and Memory1

FTY720 (2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol hydrochloride) prolongs survival of solid organ allografts in animal models. Mechanisms of FTY720 immunomodulation were studied in mice infected with lymphocytic choriomeningitis virus (LCMV) to assess T cell responses or with vesicular stomatitis virus to evaluate Ab responses. Oral FTY720 (0.3 mg/kg/day) did not affect LCMV replication and specific CTL and B cells were induced and expanded normally. Moreover, the anti-viral humoral immune responses were normal. However, FTY720 treatment showed first a shift of overall distribution of CTL from the spleen to peripheral lymph nodes and lymphocytopenia was observed. This effect was reversible within 7–21 days. Together with unimpaired T and B cell memory after FTY720 treatment, this finding rendered enhancement of lymphocyte apoptosis by FTY720 in vivo unlikely. Secondly, the delayed-type hypersensitivity reaction to a viral MHC class I-presented peptide was markedly reduced by FTY720. These results were supported by impaired circulation of LCMV specific TCR transgenic effector lymphocytes in the peripheral blood and reduced numbers of tissue infiltrating CTL in response to delayed-type hypersensitivity reaction. Thirdly, in a CD8+ T cell-mediated diabetes model in a transgenic mouse expressing the LCMV glycoprotein in the islets of the pancreas, FTY720 delayed or prevented disease by reducing islet-infiltrating CTL. Thus, FTY720 effectively reduced recirculation of CD8+ effector T cells and their recruitment to peripheral lesions without affecting the induction and expansion of immune responses in secondary lymphoid organs. These properties may offer the potential to treat ongoing organ-specific T cell-mediated immunopathologic disease.

[1]  L. Feng,et al.  FTY720: a novel transplantation drug that modulates lymphocyte traffic rather than activation. , 2000, Trends in pharmacological sciences.

[2]  S. Stepkowski,et al.  Synergistic interaction of FTY720 with cyclosporine or sirolimus to prolong heart allograft survival. , 1998, Transplantation proceedings.

[3]  K. Sugahara,et al.  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. , 1998, Journal of immunology.

[4]  H. Kataoka,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. , 1998, Journal of immunology.

[5]  S. Stepkowski,et al.  Immunosuppressive effects of FTY720 alone or in combination with cyclosporine and/or sirolimus. , 1998, Transplantation.

[6]  M. Bevan,et al.  Massive expansion of antigen-specific CD8+ T cells during an acute virus infection. , 1998, Immunity.

[7]  B. Odermatt,et al.  A simple method for evaluating the rejection of grafted spleen cells by flow cytometry and tracing adoptively transferred cells by light microscopy. , 1997, Journal of immunological methods.

[8]  H. Amemiya,et al.  An immunosuppressive agent, FTY720, increases intracellular concentration of calcium ion and induces apoptosis in HL‐60 , 1997, Immunology.

[9]  S. Enosawa,et al.  A new immunosuppressant, FTY720, induces bcl‐2‐associated apoptotic cell death in human lymphocytes , 1996, Immunology.

[10]  S. Enosawa,et al.  Induction of selective cell death targeting on mature T-lymphocytes in rats by a novel immunosuppressant, FTY720. , 1996, Immunopharmacology.

[11]  S. Enosawa,et al.  Long-term graft acceptance in allografted rats and dogs by treatment with a novel immunosuppressant, FTY720. , 1996, Transplantation proceedings.

[12]  R. Zinkernagel,et al.  Development of insulitis without diabetes in transgenic mice lacking perforin-dependent cytotoxicity , 1996, The Journal of experimental medicine.

[13]  R. Zinkernagel,et al.  Induction of long-lived germinal centers associated with persisting antigen after viral infection , 1996, The Journal of experimental medicine.

[14]  H. Pircher,et al.  Visualization, characterization, and turnover of CD8+ memory T cells in virus-infected hosts , 1996, The Journal of experimental medicine.

[15]  S. Enosawa,et al.  A novel immunosuppressant, FTY720, with a unique mechanism of action, induces long-term graft acceptance in rat and dog allotransplantation. , 1996, Transplantation.

[16]  R. Zinkernagel,et al.  Antiviral protection by vesicular stomatitis virus-specific antibodies in alpha/beta interferon receptor-deficient mice , 1995, Journal of virology.

[17]  P. Borrow,et al.  Virus-induced immunosuppression: immune system-mediated destruction of virus-infected dendritic cells results in generalized immune suppression , 1995, Journal of virology.

[18]  T. Okumoto,et al.  Fungal metabolites. Part 11. A potent immunosuppressive activity found in Isaria sinclairii metabolite. , 1994, The Journal of antibiotics.

[19]  R M Zinkernagel,et al.  Impairment and delay of neutralizing antiviral antibody responses by virus-specific cytotoxic T cells. , 1993, Journal of immunology.

[20]  R. Zinkernagel,et al.  Antivirally protective cytotoxic T cell memory to lymphocytic choriomeningitis virus is governed by persisting antigen , 1992, The Journal of experimental medicine.

[21]  R. Zinkernagel,et al.  Skin test to assess virus-specific cytotoxic T-cell activity. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[22]  R M Zinkernagel,et al.  Quantification of lymphocytic choriomeningitis virus with an immunological focus assay in 24- or 96-well plates. , 1991, Journal of virological methods.

[23]  C. Mackay,et al.  T-cell memory: the connection between function, phenotype and migration pathways. , 1991, Immunology today.

[24]  H. Pircher,et al.  Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice , 1991, Cell.

[25]  R. Zinkernagel,et al.  Analysis of the kinetics of antiviral memory T help in vivo: characterization of short‐lived cross‐reactive T help , 1990, European journal of immunology.

[26]  D. Moskophidis,et al.  Virus-induced delayed-type hypersensitivity reaction is sequentially mediated by CD8+ and CD4+ T lymphocytes. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Klaus Rajewsky,et al.  The half‐lives of serum immunoglobulins in adult mice , 1988, European journal of immunology.

[28]  R. Zinkernagel,et al.  Antibody mediated suppression of secondary IgM response in nude mice against vesicular stomatitis virus. , 1986, Journal of immunology.

[29]  R. Zinkernagel,et al.  Susceptibility to lymphocytic choriomeningitis virus isolates correlates directly with early and high cytotoxic T cell activity, as well as with footpad swelling reaction, and all three are regulated by H-2D , 1985, The Journal of experimental medicine.

[30]  R. Zinkernagel,et al.  Suppression by cyclosporin A of murine T-cell-mediated immunity against viruses in vivo and in vitro. , 1985, Cellular immunology.

[31]  H. Waldmann,et al.  Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo , 1984, Nature.

[32]  G. Curt,et al.  The pharmacology and clinical use of methotrexate. , 1983, The New England journal of medicine.

[33]  D. Kluepfel,et al.  Myriocin, a new antifungal antibiotic from Myriococcum albomyces. , 1972, The Journal of antibiotics.

[34]  R. Wagner,et al.  BIOLOGIC PROPERTIES OF TWO PLAQUE VARIANTS OF VESICULAR STOMATITIS VIRUS (INDIANA SEROTYPE). , 1963, Journal of immunology.

[35]  R. Zinkernagel,et al.  Neutralizing antiviral B cell responses. , 1997, Annual review of immunology.

[36]  B. Kahan Drug therapy: cyclosporine , 1989 .

[37]  M. Buchmeier,et al.  The virology and immunobiology of lymphocytic choriomeningitis virus infection. , 1980, Advances in immunology.

[38]  R M Zinkernagel,et al.  MHC-restricted cytotoxic T cells: studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness. , 1979, Advances in immunology.

[39]  J. Hotchin The biology of lymphocytic choriomeningitis infection: virus-induced immune disease. , 1962, Cold Spring Harbor symposia on quantitative biology.