TY - JOUR
T1 - Triazolopyrimidine derivative NK026680 and donor-specific transfusion induces CD4+CD25+Foxp3+ T cells and ameliorates allograft rejection in an antigen-specific manner
AU - Emoto, Shin
AU - Shibasaki, Susumu
AU - Nagatsu, Akihisa
AU - Goto, Ryoichi
AU - Ono, Hitoshi
AU - Fukasaku, Yasutomo
AU - Igarashi, Rumi
AU - Ota, Takuji
AU - Fukai, Moto
AU - Shimamura, Tsuyoshi
AU - Saiga, Kan
AU - Taketomi, Akinobu
AU - Murakami, Masaaki
AU - Todo, Satoru
AU - Yamashita, Kenichiro
N1 - Funding Information:
This study was supported in part by the funding from the Nippon Kayaku Co., Ltd., and Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, Japan. S. E. and K. Y. received the grant from Nippon Kayaku Co., Ltd. The other authors declare no conflict of interest.
Funding Information:
This study was in part supported by funding from the Nippon Kayaku Co., Ltd ., and by the Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science , Japan (# 26253068 to K.Y.).
Publisher Copyright:
© 2020 Elsevier B.V.
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85094814144&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85094814144&partnerID=8YFLogxK
U2 - 10.1016/j.trim.2020.101338
DO - 10.1016/j.trim.2020.101338
M3 - Article
C2 - 33022372
AN - SCOPUS:85094814144
VL - 65
JO - Transplant Immunology
JF - Transplant Immunology
SN - 0966-3274
M1 - 101338
ER -