Project description:Dendritic cells (DC) play a crucial role in initiating, shaping and controlling the immune response. They are the most important antigen presenting cells in the immune system. DC can be divided in immature and mature DC. DCs reside in an immature state in most tissues or they circulate in the blood, where they recognize and phagocytose pathogens and other antigens. Direct contact with many pathogens leads to the maturation of DCs. The property to stimulate T cells is reserved for mature DC (O`Doherty, U. 1994). This functional maturation results in an up-regulation of the surface molecule MHC class II, adhesion molecules (CD54 and CD58) and co-stimulatory receptors (CD80 and CD86) as well as decreased antigen uptake capacity (CD206). (Banchereau, J. and Steinman, R.M. 1998). Immunosuppressive drugs have revolutionized organ transplantation and improved the therapeutic management of autoimmune diseases. These drugs interfere on lymphocytes but they also act at the earliest stage of immune response. They are targeting key functions of dendritic cells (Hackstein H. and Thomson A.W., 2004 review). Sanglifehrin A (SFA) is a new immunosuppressive drug. It is a representative of a class of macrolides produced by the actinomycetes strain Streptomyces A92-308110 that bind to cyclophilin A (CypA), the binding protein of cyclosporine A (CsA). Most studies about immunosuppressive effects of SFA took place on T and B lymphocytes. Unlike CsA, the cyclophilin-SFA-complex shows no effect on the calcium-dependent protein phosphatase calcineurin (Zenke, G. 2001). Unlike CsA and FK506, SFA shows no inhibition of IL-2 expression (Zenke, G. 2001; Zhang, L.H. 2001), nor does it suppress IL-2 receptor transcription (Zhang, L.H. 2001) in T lymphocytes. It could be shown that SFA reduces the Interleukin 12 production in dendritic cells (Steinschulte, C. 2003). IL-12p70 plays an important role in the pathogenesis of inflammation and autoimmune diseases. DCs generated in the presence of SFA show reduced macropinocytosis and lectin-mediated endocytosis. In contrast, CD89 und CD32 were increased by SFA. The effect of SFA on the expression of Ag uptake receptors and Ag capture by DCs makes SFA unique among other immunophilin-binding immunosuppressive drugs (Woltman, A. 2004). Our goal is to investigate the gene expression profile of SFA treated mature human monocyte-derived dendritic cells. Comparison of SFA-stimulated versus unstimulated cells. 7 biological replicates

Project description:Dendritic cells (DC) play a crucial role in initiating, shaping and controlling the immune response. They are the most important antigen presenting cells in the immune system. DC can be divided in immature and mature DC. DCs reside in an immature state in most tissues or they circulate in the blood, where they recognize and phagocytose pathogens and other antigens. Direct contact with many pathogens leads to the maturation of DCs. The property to stimulate T cells is reserved for mature DC (O`Doherty, U. 1994). This functional maturation results in an up-regulation of the surface molecule MHC class II, adhesion molecules (CD54 and CD58) and co-stimulatory receptors (CD80 and CD86) as well as decreased antigen uptake capacity (CD206). (Banchereau, J. and Steinman, R.M. 1998). Immunosuppressive drugs have revolutionized organ transplantation and improved the therapeutic management of autoimmune diseases. These drugs interfere on lymphocytes but they also act at the earliest stage of immune response. They are targeting key functions of dendritic cells (Hackstein H. and Thomson A.W., 2004 review). Sanglifehrin A (SFA) is a new immunosuppressive drug. It is a representative of a class of macrolides produced by the actinomycetes strain Streptomyces A92-308110 that bind to cyclophilin A (CypA), the binding protein of cyclosporine A (CsA). Most studies about immunosuppressive effects of SFA took place on T and B lymphocytes. Unlike CsA, the cyclophilin-SFA-complex shows no effect on the calcium-dependent protein phosphatase calcineurin (Zenke, G. 2001). Unlike CsA and FK506, SFA shows no inhibition of IL-2 expression (Zenke, G. 2001; Zhang, L.H. 2001), nor does it suppress IL-2 receptor transcription (Zhang, L.H. 2001) in T lymphocytes. It could be shown that SFA reduces the Interleukin 12 production in dendritic cells (Steinschulte, C. 2003). IL-12p70 plays an important role in the pathogenesis of inflammation and autoimmune diseases. DCs generated in the presence of SFA show reduced macropinocytosis and lectin-mediated endocytosis. In contrast, CD89 und CD32 were increased by SFA. The effect of SFA on the expression of Ag uptake receptors and Ag capture by DCs makes SFA unique among other immunophilin-binding immunosuppressive drugs (Woltman, A. 2004). Our goal is to investigate the gene expression profile of SFA treated mature human monocyte-derived dendritic cells.

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Cdc42 controls DC-maturation - Cdc42-dependent actin dynamics controls maturation and secretory activity of dendritic cells

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Cdc42-dependent actin dynamics controls maturation and secretory activity of dendritic cells.

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