Document Detail

A novel chemical compound, NK026680, targets dendritic cells to prolong recipient survival after rat liver grafting.
MedLine Citation:
PMID:  17700168     Owner:  NLM     Status:  MEDLINE    
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.
Yoshiaki Hara; Naoko Funeshima-Fuji; Masayuki Fujino; Kazuhiro Tokunaka; Fuminori Abe; Yoshinobu Sato; Katsuyoshi Hatakeyama; Shiro Takahara; Taichi Ezaki; Hiromitsu Kimura; Xiao-Kang Li
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Transplantation     Volume:  84     ISSN:  0041-1337     ISO Abbreviation:  Transplantation     Publication Date:  2007 Aug 
Date Detail:
Created Date:  2007-08-16     Completed Date:  2007-09-26     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0132144     Medline TA:  Transplantation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  407-14     Citation Subset:  IM    
Laboratory of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
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MeSH Terms
Antigens, CD86 / genetics,  metabolism
Cell Differentiation / drug effects
Cell Proliferation / drug effects
Cells, Cultured
Concanavalin A / pharmacology
Dendritic Cells / cytology,  drug effects*,  physiology*
Dose-Response Relationship, Drug
Graft Survival / physiology*
Histocompatibility Antigens Class II / genetics,  metabolism
Immunosuppressive Agents / pharmacology*
Isoantigens / pharmacology
Liver Transplantation / pathology,  physiology*
Mitogens / pharmacology
Pyrimidines / pharmacology*
Rats, Inbred Lew
T-Lymphocytes / drug effects,  pathology,  physiology
Triazoles / pharmacology*
Reg. No./Substance:
0/(S)-1-(5-hydroxy-1,5-dimethylhexyl)-3-(7-(4-methoxyphenyl)-(1,2,4-triazolo(1,5-a)pyrimidin-2-yl))urea; 0/Antigens, CD86; 0/Histocompatibility Antigens Class II; 0/Immunosuppressive Agents; 0/Isoantigens; 0/Mitogens; 0/Pyrimidines; 0/Triazoles; 11028-71-0/Concanavalin A

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