AM3, a natural glycoconjugate, induces the functional maturation of human dendritic cells

Abstract

Background and purpose: Dendritic cells (DCs) are dedicated antigen-presenting cells able to initiate specific immune responses and their maturation is critical for the induction of antigen-specific T-lymphocyte responses. Here, we have investigated the effects of Inmunoferon-active principle (AM3), the active agent of a commercial immunomodulatory drug, on human monocyte-derived DCs (MDDCs). Experimental approach: MDDCs derived from healthy and hepatitis C virus (HCV)-infected patients were stimulated with AM3. We analysed the expression of cell surface proteins by flow cytometry, that of cytokine production by ELISA, and the expression of chemokines and chemokine receptors by RNase protection assays. T-lymphocyte proliferation was assessed in mixed lymphocyte reactions, protein expression by western blot and luciferase-based reporter methods, and Toll-like receptor (TLR)-blocking antibodies were employed to analyse TLR activity. Key results: In MDDCs, AM3 induced or enhanced expression of CD54, CD83, CD86, HLA-DR, chemokines and chemokine receptors, interleukin (IL)-12p70 and IL-10. Furthermore, AM3 stimulated MDDCs to increase proliferation of allogenic T cells. AM3 triggered nuclear translocation of NF-kB and phosphorylation of p38 mitogen-activated protein kinase. AM3 promoted NF-kB activation in a TLR-4-dependent manner, and blocking TLR-4 activity attenuated the enhanced expression of CD80, CD83 and CD86 induced by AM3. AM3 enhanced the expression of maturation-associated markers in MDDCs from HCVinfected patients and increased the proliferation of T lymphocytes induced by these MDDCs. Conclusions and implications: These results underline the effects of AM3 in promoting maturation of MDDCs and suggest that AM3 might be useful in regulating immune responses in pathophysiological situations requiring DC maturation.

The biological response modifier AM3 attenuates the inflammatory cell response and hepatic fibrosis in rats with biliary cirrhosis

“…AM3 also improves the immune response to hepatitis B vaccination in patients with immune deficiency secondary to chronic renal failure 17. Moreover, AM3 suppresses the overproduction of TNFα by LPS and modulates the TLR4-induced maduration of dendritic cells in experimental models 23 24 35. In our study, AM3 abrogated the intense inflammatory bias of the immune system response observed in the peripheral blood and in the liver of cirrhotic rats.…”

Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis

“…In a mouse model of diabetes, HMGB1 upregulates CD40 expression and enhances IL-12 production by DCs, leading to natural killer (NK)T cell activation and subsequent NKT cell-dependent augmentation of IFN-γ production, with the early loss of transplanted islets [ 81 ]. AM3, a mixture containing immunoregulatory glycoconjugates, induces functional maturation of monocyte-derived DCs from patients with chronic HCV infection and healthy donors, and stimulates the secretion of molecules with antiviral properties in a TLR4-dependent manner [ 82 ].…”

Glycosphopeptical and Specific Immunotherapy Effect in Allergic Rhinitis

“…Glycophosphopeptical (GFP) is a molecule composed of polysaccharides of fungal origin and proteins of vegetable origin, adsorbed in an inorganic phosphate-sulfate-calcium matrix. It has been shown to stimulate innate immunity, mainly during infectious processes [7][8][9][10] as an adjuvant to specific immunotherapy accelerates the conversion of the Th response to the Th2 phenotype, [11][12][13][14][15] by stimulation to innate immunity (dendritic cells) via recognition of this molecule by non-specific receptors. The objective of the study was to analyze the clinical response, allergen SIT and the use of GFP immunomodulatory in patients with allergic rhinitis.…”