Cardiac allograft tolerance induced by isogeneic CD4+CD25+ regulatory T cells.

OBJECTIVES: To evaluate the effect of isogeneic CD4+CD25+ regulatory T cells on cardiac allograft tolerance in heterotopic heart transplant from Balb/c to C57BL/6 mice. MATERIALS AND METHODS: Isogeneic and allogeneic CD4+CD25+ regulatory T cells were obtained from pregnant C57BL/6 mice crossed with male Balb/c mice and from regular Balb/c mice. Recipient C57BL/6 mice were treated with sublethal radiation (2 Gy) and an infusion of isogeneic CD4+CD25+ regulatory T cells, allogeneic CD4+CD25+ regulatory T cells, or phosphate-buffered saline alone 1 day before a Balb/c-to-C57BL/6 heterotopic heart transplant. At 10 days after the transplant, cardiac allografts and the sera of recipients were evaluated with histology and cytokine analysis. Splenocytes of recipients were collected to determine chimerism on the day of the cessation of allograft heartbeat. RESULTS: Mice that received an infusion of isogeneic CD4+CD25+ regulatory T cells had significantly greater mean median survival time, greater degree of chimerism, decreased levels of cytokines (monokine induced by interferon-γ, interleukin 6, interleukin 10, and regulated upon activation, normal T cell expressed and secreted protein), and decreased lymphocytic infiltration than did mice that received phosphate-buffered saline alone. The effects on allograft tolerance were stronger in mice that received the isogeneic than the allogeneic CD4+CD25+ regulatory T cells. CONCLUSIONS: Isogeneic CD4+CD25+ regulatory T cells may establish cardiac allograft tolerance by inducing mixed chimerism and suppressing immune responses. Infusion with isogeneic CD4+CD25+ regulatory T cells combined with radiation (sublethal dose, 2 Gy) may establish allograft tolerance in mice. Therefore, further study is warranted because isogeneic CD4+CD25+ regulatory T cells may have therapeutic benefits.