Fty720 and Cyclosporin Protect Ovarian Tissue Grafted into Rabbits

OBJECTIVE: To determine whether FTY720 combined with CsA has immunomodulatory effects on human ovarian tissue transplanted to the back muscle of rabbits for an 8-week period. STUDY DESIGN: We selected rabbits as recipients of ovarian xenografts with and without treatment by CsA and FTY720. Ovarian fragments from twelve patients were cut into 2 mm × 2 mm, 1-2mm thick pieces and randomly distributed into four groups: Group 1 (FTY720 2 mg/kg/d+CsA 3 mg/kg/d), Group 2 (FTY720 1 mg/kg/d+CsA 3mg/kg/d), Group 3 (FTY720 0.5 mg/kg/d+CsA 3mg/kg/d) and Group 4 for control (CsA 3 mg/kg/d). FTY720 was started three days before transplantation and was given daily after transplantation. CsA was administrated post-transplantation. All the animals were killed 8 weeks post- transplantation. Levels of serum estrogen (E2), interferon-γ (IFN-γ) and interleukin-4 (IL-4) were detected by radioimmunoassay and ELISA. Anti-CD31 and anti-Ki-67 antibodies were used to evaluate neo-vascularization in xenografts and proliferation activity of ovarian follicles. Peripheral CD4+/CD8+ T cells were analyzed by flow cytometry. RESULTS: Combined treatment with cyclosporin A and FTY720 improved graft survival and reduced peripheral CD4+ and CD8+ T cell counts compared to treatment with cyclosporin A alone. Neovascularization took place in the peripheral zone of the xenograft while granulosa cells, positively stained by Ki-67, were found in early-stage follicles and stromal cells in the combined treatment groups. CONCLUSION: FTY720 in combination with cyclosporin A maintains human ovarian xenografts in these rabbit models.