Rapamycin combined with donor immature dendritic cells promotes liver allograft survival in association with CD4(+) CD25(+) Foxp3(+) regulatory T cell expansion

Aim: To determine whether donor immature dendritic cells (imDCs) combined with a short postoperative course of rapamycin (Rapa) has the ability to expand the CD4(+) CD25(+) Foxp3(+) regulatory T (Treg) cells and prolong liver allograft survival.

Methods: Orthotopic liver transplantation (OLT) was performed from Lewis rats to Brown Norway recipients. Three days before transplantation, animals were injected intravenously with 2 × 10(6) donor bone marrow-derived imDCs. Recipient rats (the combined treated group) also received Rapa for 7 d after liver transplantation. Additional groups received either imDCs alone, Rapa alone, or saline alone. Every six recipients from each group were killed at 14 days, 28 days after OLT. The changes of CD4(+) CD25(+) Foxp3(+) Treg cells in peripheral blood and spleen, histological changes of liver grafts, and serum cytokine levels were investigated. The other six recipients were left in each group to observe the animal survival.

Results: Donor imDCs followed by a short postoperative course of Rapa induced long-term allograft survival. The percentage of CD4(+) CD25(+) Foxp3(+) Treg cells in CD4(+) T cells in the combination treatment group were significantly higher compared with the acute rejection group. Moreover, within the CD4(+) CD25(+) T cell population the combination treatment recipients maintained a higher incidence of Foxp3(+) T cells compared with the other groups. Despite the lower serum levels of interleukin (IL)-2, IL-12, and interferon-γ in the combined treated group, the cytokine levels in the combined treated group at 7 days after OLT was nearly twice that at 3 days after OLT but decreased significantly compared with the other groups at 28 days after OLT. Serum IL-10 level in the combined treated group was higher than the other groups.

Conclusions: A single imDC infusion followed by a short postoperative course of Rapa prolongs liver allograft survival and enhances the expansion of Treg cells. This optimal protocol may be a promising administration protocol for the peritransplant tolerance induction.