Triazolopyrimidine derivative NK026680 and donor-specific transfusion induces CD4+CD25+Foxp3+ T cells and ameliorates allograft rejection in an antigen-specific manner

• Published in: Transplant immunology 2021-04, Vol.65, p.101338-101338, Article 101338
• Main Authors: Emoto, Shin, Shibasaki, Susumu, Nagatsu, Akihisa, Goto, Ryoichi, Ono, Hitoshi, Fukasaku, Yasutomo, Igarashi, Rumi, Ota, Takuji, Fukai, Moto, Shimamura, Tsuyoshi, Saiga, Kan, Taketomi, Akinobu, Murakami, Masaaki, Todo, Satoru, Yamashita, Kenichiro
• Format: Article
• Language: English
• Subjects: Allografts; Animals; Cardiac transplantation; CD8-Positive T-Lymphocytes; Donor-specific transfusion; Forkhead Transcription Factors; Graft Rejection; Graft Survival; Heart Transplantation; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; NK026680; Pyrimidines; Rats; Regulatory T cells; T-Lymphocytes, Regulatory; Triazoles
• ISSN: 0966-3274; 1878-5492
• DOI: 10.1016/j.trim.2020.101338

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-2d) heart graft were transplanted into C57BL/6 (H-2b) 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-2k). 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. •Donor-specific transfusion with NK026680 prolongs cardiac allograft survival in mice.•Donor-specific transfusion with NK026680 induces donor-specific regulatory T cells.•Anti-CD25mAb abolishes the effect of donor-specific transfusion with NK026680.