Heart and liver xenotransplantation under low-dose tacrolimus - Graft survival after withdrawal of immunosuppression

Background. The hamster-to-rat xenotransplantation model is a useful model to investigate the features of extended host response to long-surviving xen ografts, Early xenoantibody responses are T-cell independent and resistant to tacrolimus. Treatment with the combination of mofetil mycophenolate plus FK506 avoids acute xenograft rejection completely but after withdrawal of immunosuppression hamster grafts are rejected by a process called late xeno graft rejection (LXR), Methods. Hamster hearts and livers were transplanted into Lewis rats. Graft ed rats were treated with mofetil mycophenolate (25 mg/kg/day) for 8 days a nd FK506 (0.2 mg/kg/day) for 31 days. Serum IgM and IgG levels were determi ned by flow cytometry and interferon-gamma levels by ELISA. IgM, IgG, and C 3 deposits were measured in tissue by immunofluorescence, and leukocyte inf iltration was measured by immunoperoxidase staining. Results. Survival of heart and liver xenografts in the rats was 48+/-4 days and 63+/-8 days, respectively. After cessation of all immunosuppression, h earts were rejected in 18+/-4 days and livers in 33+/-8 days. Production se quences of xenoantibodies in the two organs differed substantially, especia lly 7 days after transplantation and at the moment of rejection. Quantifica tion of interferon-gamma levels indicated that there were no significant ch anges after transplantation. Histological and immunohistochemical studies s howed signs of humoral mechanism of LXR in rats undergoing heart transplant ation and cellular mechanism of LXR in those that received a liver transpla nt. Conclusions. These observations suggest that rejection in the hamster-to-ra t heart xenotransplantation model is mediated by a T cell-independent B-cel l response to which a T cell-dependent B-cell response is added in LXR, In the liver xenotransplantation model, our hypothesis is that LXR is mediated by a mixed cell mechanism, involving lymphocytes CD4(+)CD45RC(+), macropha ges, and cytotoxic T lymphocytes, In summary, we have demonstrated and comp ared the peculiar features of LXR in two different organs.