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.