FTY720 immunosuppression impairs effector T cell peripheral homing withoutaffecting induction, expansion, and memory

FTY720 (2-amino-2-2-[4-octylphenyl]ethyl)-1,3- hydrochloride) prolongs surv ival of solid organ allografts in animal models. Mechanisms of FTY720 immun omodulation 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, F TY720 treatment showed first a shift of overall distribution of CTL from th e spleen to peripheral lymph nodes and lymphocytopenia was observed. This e ffect was reversible within 7-21 days, Together with unimpaired T and B cel l memory after FTY720 treatment, this finding rendered enhancement of lymph ocyte apoptosis by FTY720 in vivo unlikely. Secondly, the delayed-type hype rsensitivity 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 mo del in a transgenic mouse expressing the LCMV glycoprotein in the islets of the pancreas, FTY720 delayed or prevented disease by reducing islet-infilt rating CTL. Thus, FTY720 effectively reduced recirculation of CD8(+) effect or T cells and their recruitment to peripheral lesions without affecting th e induction and expansion of immune responses in secondary lymphoid organs. These properties may offer the potential to treat ongoing organ-specific T fell-mediated immunopathologic disease.