Induction of Regulatory T Cells and Indefinite Survival of Fully Allogeneic Cardiac Grafts by Ursodeoxycholic Acid in Mice

Abstract

Ursodeoxycholic acid (UDCA) has been used to treat patients with cholestatic and autoimmune liver diseases. Several studies have addressed whether UDCA can inhibit graft rejection in experimental and clinical transplantation, but the results have varied. We investigated the effect of UDCA and the mechanism of its effect on alloimmune responses in a murine model of cardiac transplantation. CBA mice underwent transplantation of a C57BL/10 heart and received a single dose of UDCA. Survival times of the allografts were recorded. An adoptive transfer study was conducted to determine whether regulatory cells were generated. The effects on graft survival of adding FK506 or cyclosporine A (CyA) to UDCA treatment were assessed. Histologic, cell proliferation, and cytokine assessments were performed. CBA recipients given UDCA (25 mg/kg) had indefinite allograft survival (median survival time [MST], >100 days). UDCA also suppressed proliferation of splenocytes and production of interleukin (IL)-2, IL-6, and interferon-gamma, and up-regulated IL-10 production. Adoptive transfer of either whole splenocytes or CD4+ cells from UDCA-treated allograft recipients resulted in indefinite survival of allografts in naive secondary recipients (MST, >100 days). Adoptive transfer of CD4+ CD25+ cells from UDCA-treated recipients significantly prolonged allograft survival in naive secondary recipients (MST, >80 days). FK506 (0.1 mg/kg/day) was compatible with the induction of indefinite allograft survival by UDCA, whereas CyA (10 mg/kg/day) abrogated the effect of UDCA. UDCA induced unresponsiveness to fully allogeneic cardiac allografts and generated CD4+ CD25+ regulatory cells in our model. FK506, but not CyA, was compatible with UDCA treatment.