Norcantharidin modulates development of dendritic cells and prolongs skin allograft survival
Journal
Transplantation
Journal Volume
92
Journal Issue
8
Pages
848-857
Date Issued
2011
Author(s)
Abstract
Background. To examine the effects of norcantharidin (NCTD) on development of human myeloid dendritic cells (DCs) in vitro and in skin allograft transplantation in vivo. Methods. Human CD14+ monocytes were isolated and triggered differentiation and maturation toward myeloid DCs with and without NCTD. The cell morphology, viability, cell death, expression of surface markers and co-stimulatory molecules, allostimulatory activity, and cytokine production were examined for characterization of DCs. The rejection of mice skin allograft model was used to translate the in vitro effect of cantharidin (CTD) and NCTD on DCs. Results. DCs developed in the presence of NCTD showed decreased viability, cell death with necrosis, and lower expression of CD1a and CD83. DCs triggered in the presence of NCTD possessed a greater allostimulatory activity in naive CD4+CD45RA+ T cells. NCTD modulated DCs through calcineurin phosphatase but not through mammalian target of rapamycin or downstream molecule p70S6 kinase. In vivo, NCTD caused accumulation and co-localization of antigen-presenting cells and regulatory T cells in the interfollicular area of the recipients' spleens. CTD and NCTD prolonged skin allograft survival along with less severe histopathological inflammatory reactions. CTD, but not NCTD, treatment caused elevation of serum alanine aminotransferase and evident mortality of the recipients. Conclusion. NCTD modulated the differentiation and maturation of human myeloid DCs and caused deviation of standard DC differentiation toward a tolerogenic phenotype through calcineurin phosphatase inhibition. In vivo, both drugs effectively prolonged skin allograft survival. NCTD was less toxic than CTD, and thus, has potential for development as an immunosuppressant for transplant rejection. ? 2011 by Lippincott Williams & Wilkins.
SDGs
Other Subjects
alanine aminotransferase; calcineurin phosphatase; cantharidin; CD14 antigen; CD38 antigen; CD45RA antigen; cytokine; mammalian target of rapamycin; norcantharidin; phosphatase; S6 kinase; t6 antigen; unclassified drug; acute graft rejection; alanine aminotransferase blood level; animal cell; animal experiment; animal model; animal tissue; antigen expression; antigen presenting cell; article; bioaccumulation; cell activity; cell death; cell differentiation; cell maturation; cell structure; cell viability; controlled study; cytokine production; disease severity; dose response; drug mechanism; graft recipient; graft rejection; graft survival; histopathology; human; human cell; immunomodulation; immunostimulation; in vitro study; in vivo study; male; monocyte; mortality; mouse; myeloid dendritic cell; nonhuman; priority journal; protein expression; protein localization; regulatory T lymphocyte; skin allograft; skin inflammation; spleen; survival time; Animals; Bicyclo Compounds, Heterocyclic; Dendritic Cells; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Interleukin-10; Interleukin-12; Lymphocyte Activation; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Skin Transplantation; Transplantation, Homologous
Type
journal article