Acute liver transplant rejection upon immunosuppression withdrawal in a tolerance induction trial: potential role of IFN-gamma-secreting CD8+ T cells.

We designed a pilot trial in cadaveric liver transplantation to determine whether induction with antithymocyte globulins (ATG) and sirolimus would allow immunosuppression withdrawal. Patients received ATG 3.75 mg/kg per day from day 1 to 5 after transplantation followed by sirolimus for 4 to 6 months. We monitored interleukin (IL)-7 serum levels, interferon (IFN)-gamma, and IL-2 mRNA accumulation in mixed leukocyte reaction and intragraft IFN-gamma mRNA expression. In the first three patients, immunosuppression discontinuation was followed by reversible acute rejection occurring on days 280, 246, and 163 posttransplantation, corresponding to days 140, 40, and 39 after drug withdrawal, respectively. At the time of rejection, blood CD8+ T-cells counts had returned to or above pretransplant levels in two of three patients, whereas CD4+ T-cell count remained low. IL-7 serum levels rose in all three patients in the first months after transplantation and IFN-gamma mRNA accumulated in mixed leukocyte reaction between recipient T cells and donor spleen cells at the time of rejection. High levels of IFN-gamma mRNA were consistently detected in liver biopsy performed at the time of rejection. In conclusion, lymphopenia-induced IL-7 production after induction with ATG and sirolimus might lead to emergence of IFN-gamma-secreting CD8+ T-cells responsible for acute rejection after immunosuppression withdrawal.