A novel chemical compound, NK026680, targets dendritic cells to prolong recipient survival after rat liver grafting.
BACKGROUND
There is great interest in the recently developed immunosuppressant NK026680, which is a derivative of triazolopyrimidine. Its unique chemical structure and action mechanism are completely different from those of conventional immunosuppressants.


METHODS
The present study was designed to investigate the effects of NK026680 on rat bone-marrow-derived dendritic cell (BMDC) differentiation and maturation in an in vitro culture system and its applicability in liver transplantation.


RESULTS
NK026680 inhibited T-cell proliferation stimulated by alloantigen in a dose-dependent manner, but did not inhibit concanavalin A. The populations of OX6+CD161a cells and CD86+CD161a cells were suppressed in NK026680-treated dendritic cells (DCs). Exposure of DCs to NK026680 downregulated the interleukin (IL)-12 (p40, p35), interferon-gamma mRNA expression and upregulated IL-10, transforming growth factor-beta, in which impaired the ability of DC to stimulate T cell proliferation. Furthermore, oral administration of NK026680 for 14 days significantly prolonged liver allograft survival and limitation of T-cell responses and polarization toward a Th2 cytokine profile.


CONCLUSIONS
These results demonstrate that NK026680 may have therapeutic potential for preventing allo-rejection in organ transplantation, acting at the step of immune response through inhibiting BMDC differentiation and maturation into potent antigen-presenting cells.
Hara
Yoshiaki
Y
Laboratory of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
Funeshima-Fuji
Naoko
N
Fujino
Masayuki
M
Tokunaka
Kazuhiro
K
Abe
Fuminori
F
Sato
Yoshinobu
Y
Hatakeyama
Katsuyoshi
K
Takahara
Shiro
S
Ezaki
Taichi
T
Kimura
Hiromitsu
H
Li
Xiao-Kang
XK
D000818:Animals; D051940:B7-2 Antigen / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006085:Graft Survival / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007519:Isoantigens / Q000494:pharmacology; D016031:Liver Transplantation / Q000473:pathology / Q000502:physiology*; D008297:Male; D008934:Mitogens / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D014230:Triazoles / Q000494:pharmacology*
C509974:(S)-1-(5-hydroxy-1,5-dimethylhexyl)-3-(7-(4-methoxyphenyl)-(1,2,4-triazolo(1,5-a)pyrimidin-2-yl))urea; D051940:B7-2 Antigen; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D007519:Isoantigens; D008934:Mitogens; D011743:Pyrimidines; D014230:Triazoles; D003208:Concanavalin A