Enhanced maturation and functional capacity of monocyte-derived immature dendritic cells by the synthetic immunomodulator Murabutide

Murabutide is a safe synthetic immunomodulator derived from muramyl dipepti de, the smallest bioactive unit of bacterial peptidoglycan. Although it is well known that muramyl peptides modulate the functions of monocytes/macrop hages, their activity on dendritic cells is poorly documented. We thus inve stigated the effects of Murabutide on immunophenotype, endocytosis, T-cell stimulatory capacity, and cytokine secretion of human monocyte-derived imma ture dendritic cells (iDCs). We found that Murabutide triggers immunophenot ypic changes as upon treatment, iDCs up-regulate the surface expression of the major histocompatibility complex type II molecule human leucocyte antig en-DR, the co-stimulatory molecules CD80, CD86 and CD40 and the differentia tion marker CD83, and down-regulate the expression of the mannose receptor. These phenotypic changes are also mirrored by changes in their biological activity. Subsequent to treatment with the synthetic immunomodulator, DC ha ve a decreased endocytic capacity but exhibit enhanced stimulatory capacity for both allogeneic and autologous T cells. In addition, Murabutide-stimul ated iDCs have a greater cytostatic activity toward the tumour cell line TH P-1. Furthermore, in the presence of Murabutide, DCs transiently increased the release of macrophage inhibitory protein-1 beta, tumour necrosis factor -alpha and interleukin-10, whereas the enhanced production of macrophage-co lony stimulating factor was sustained over the 3-day period analysed. In ad dition, Murabutide triggers the phosphorylation of the three classes of mit ogen-activated protein kinases in iDCs. Altogether our results demonstrate that Murabutide triggers the maturation and activation of monocyte-derived iDCs. As this immunomodulator is approved for administration in humans, it could be a useful adjunct to boost the efficacy of DC-based vaccines design ed against tumours or virus-infected cells.