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*
Institute of Experimental Immunology and
Laboratory for Special Techniques, Department of Pathology, University Hospital, Zurich, Switzerland; and
Novartis Pharma AG, Basel, Switzerland
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.
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A. Billich, F. Bornancin, P. Devay, D. Mechtcheriakova, N. Urtz, and T. Baumruker Phosphorylation of the Immunomodulatory Drug FTY720 by Sphingosine Kinases J. Biol. Chem., November 28, 2003; 278(48): 47408 - 47415. [Abstract] [Full Text] [PDF]
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A. C. Yopp, G. J. Randolph, and J. S. Bromberg Leukotrienes, Sphingolipids, and Leukocyte Trafficking J. Immunol., July 1, 2003; 171(1): 5 - 10. [Full Text] [PDF]
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M. Fujino, N. Funeshima, Y. Kitazawa, H. Kimura, H. Amemiya, S. Suzuki, and X.-K. Li Amelioration of Experimental Autoimmune Encephalomyelitis in Lewis Rats by FTY720 Treatment J. Pharmacol. Exp. Ther., April 1, 2003; 305(1): 70 - 77. [Abstract] [Full Text]
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J. H. Xie, N. Nomura, S. L. Koprak, E. J. Quackenbush, M. J. Forrest, and H. Rosen 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., April 1, 2003; 170(7): 3662 - 3670. [Abstract] [Full Text] [PDF]
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V. Brinkmann, M. D. Davis, C. E. Heise, R. Albert, S. Cottens, R. Hof, C. Bruns, E. Prieschl, T. Baumruker, P. Hiestand, et al. The Immune Modulator FTY720 Targets Sphingosine 1-Phosphate Receptors J. Biol. Chem., June 7, 2002; 277(24): 21453 - 21457. [Abstract] [Full Text] [PDF]
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H. Li, G. M. L. Meno-Tetang, K. Chiba, N. Arima, P. Heining, and W. J. Jusko Pharmacokinetics and Cell Trafficking Dynamics of 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol Hydrochloride (FTY720) in Cynomolgus Monkeys after Single Oral and Intravenous Doses J. Pharmacol. Exp. Ther., May 1, 2002; 301(2): 519 - 526. [Abstract] [Full Text] [PDF]
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 K. Budde, R. L. Schmouder, R. Brunkhorst, B. Nashan, P. W. Lucker, T. Mayer, S. Choudhury, A. Skerjanec, G. Kraus, and H. H. Neumayer First Human Trial of FTY720, a Novel Immunomodulator, in Stable Renal Transplant Patients J. Am. Soc. Nephrol., April 1, 2002; 13(4): 1073 - 1083. [Abstract] [Full Text] [PDF]
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Y. Bai, J. Liu, Y. Wang, S. Honig, L. Qin, P. Boros, and J. S. Bromberg L-Selectin-Dependent Lymphoid Occupancy Is Required to Induce Alloantigen-Specific Tolerance J. Immunol., February 15, 2002; 168(4): 1579 - 1589. [Abstract] [Full Text] [PDF]
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G. Henning, L. Ohl, T. Junt, P. Reiterer, V. Brinkmann, H. Nakano, W. Hohenberger, M. Lipp, and R. Forster CC Chemokine Receptor 7-dependent and -independent Pathways for Lymphocyte Homing: Modulation by FTY720 J. Exp. Med., December 17, 2001; 194(12): 1875 - 1881. [Abstract] [Full Text] [PDF]
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