Triazolopyrimidine Derivative Nk026680 And Donor-Specific Transfusion Induces Cd4(+)Cd25(-)Foxp3(+) T Cells And Ameliorates Allograft Rejection In An Antigen-Specific Manner

We have previously demonstrated the unique properties of a new triazolopyrimidine derivative, NK026680, which exerts immunosuppressive effects in rat heart transplant model and confers tolerogeneic properties on ex vivo-conditioned dendritic cells in mice. We herein demonstrate that NK026680 promotes the expansion of regulatory T cells (Tregs) with potent immunoregulatory effects when used in combination with donor-specific transfusion (DST).BALB/c (H-2(d)) heart graft were transplanted into C57BL/6 (H-2(b)) mice following intravenous injection of donor splenocytes (DST) and oral administration of NK026680. The NK026680 plus DST treatment markedly prolonged the survival time of the donor-graft, but not that of the 3rd party-graft (C3H; H-2(k)). Treg cells in the recipient spleen on day 0 expanded when stimulated with donor-antigens in vivo and in vitro. After heart transplantation, Treg cells accumulated into the graft and increased in the spleen. NK026680 plus DST also decreased activated CD8(+) T cells in the spleen and inhibited infiltration of CD8(+) T cells into the graft. Depletion of CD25(+) cells inhibited the graft prolonging effect of the NK026680 plus DST treatment.NK026680 administration together with DST induces potent immunoregulatory effects in an antigen-specific manner, likely due to the in vivo generation of donor-specific Tregs.