Enhancement of NKT Cells and Increase in Regulatory T Cells Results in Improved Allograft Survival

Background Natural killer T (NKT) cells can serve as regulatory cells important in peripheral tolerance. In an experimental colitis model, it was shown that FK506 enhances the tolerizing effect of regulatory NKT cells induced by oral tolerance. We explored whether a subtherapeutic dose of FK506 could enhance the tolerizing effect of NKT cells induced by oral administration of donor spleen cells (SCs) in the pre-transplant period to prolong heart allograft survival. Methods Heterotopic heart transplantation was performed from BALB/c to B6 mice. The B6 recipients were pre-treated with either BALB/c SCs (2 × 10 7 /mouse), or FK506 (1.0 mg/kg/d), or BALB/c SCs + FK506 by gavage every other day for a total of five feedings before transplantation. Results Heart allograft survival was only significantly prolonged in the BALB/c SC + FK506 pre-fed mice. This was associated with a marked increase of NKT cells in both the liver and spleen of the recipients, and most importantly, 7 days after transplantation, an increase in CD25 + CD4 + T cells expressing CTLA4 in the spleen. Conclusions In our model it appears that a subtherapeutic dose of FK506 enhanced the tolerizing effect of NKT cells induced by oral tolerance, prolonging allograft survival by generating CD25 + CD4 + CTLA4 T cells. This appears to be an excellent in vivo model to generate regulatory T cells to allospecific transplant antigens.