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  • Title: Effect of FK506 on donor T-cell functions that are responsible for graft-versus-host disease and graft-versus-leukemia effect.
    Author: Imado T, Iwasaki T, Kuroiwa T, Sano H, Hara H.
    Journal: Transplantation; 2004 Feb 15; 77(3):391-8. PubMed ID: 14966413.
    Abstract:
    BACKGROUND: FK506 is a potent immunosuppressive agent that is used in human graft-versus-host disease (GvHD) prevention. However, the precise mechanisms for GvHD prevention and the effect on graft-versus-leukemia (GvL) activity are unknown. This study was undertaken to determine the effect of FK506, given at clinically relevant doses, on donor T-cell functions responsible for GvHD and GvL activity. METHODS: The effect of FK506 on GvHD prevention and GvL activity was investigated using a murine model of allogeneic bone-marrow transplantation in which mice were injected with a P815 leukemic cell line. The regulatory role of FK506 on donor T cells was tested by analysis of donor T-cell expansions in the spleen and donor anti-host T-cell proliferative and cytotoxic responses. mRNA expression of type 1 T helper (Th1), Fas ligand (L), and granzyme B were also evaluated in target organs of GvHD. RESULTS: FK506 significantly prolonged the survival of GvHD mice when given at the trough level of 17.6 ng/mL, whereas it also blocked GvL effect in P815-injected GvHD mice. FK506 reduced the expansion of donor CD8+ and, to a lesser extent, CD4+ T cells in the spleen and inhibited donor anti-host T-cell proliferative and cytotoxic responses. It also inhibited the induction of Th1, FasL, and granzyme B mRNA expression in target organs of GvHD. CONCLUSIONS: FK506 inhibits both GvHD and GvL activity when given at clinical doses by inhibiting donor T-cell expansion, donor anti-host T-cell reactivity, and Th1 immune responses.
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