Immunotherapeutic strategy based on anti-OX40L and low dose of IL-2 to prolong graft survival in sensitized mice by inducing the generation of CD4+ and CD8+ Tregs.

Alloreactive memory cells play a critical role after a second transplant and are difficult to suppress. This study investigated the effect of an immunotherapeutic strategy that combines anti-OX40L, rapamycin (Rapa), and a low dose of IL-2 in a memory cell-based adoptive model. In this model, the median survival time (MST) of the grafts of the combined treatment group was significantly extended compared to that of the control group and other treatment groups. A similar effect was observed regarding a reduction in memory T cells (Tm) and inflammatory cytokines production. Also, the percentages of Foxp3+ regulatory T cells (Tregs) increased in our model. In addition, mounting evidence has shown CD8+CD122+ T cells are also Tregs. We found that the group of CD8+CD122+PD1+ T cells was markedly increased in the combined treatment group, especially in the graft. We further demonstrated that CD8+CD122+PD1+ T cells could suppress activated T cells. Our data suggest that anti-OX40L combined with Rapa and a low dose of IL-2 can suppress Tm, modulate CD4 and CD8 Tregs, and induce long-term heart allograft survival in sensitized mice.