Dendritic Cells in Human Atherosclerosis: From Circulation to Atherosclerotic Plaques

Background. Atherosclerosis is a chronic inflammatory disease with atherosclerotic plaques containing inflammatory infiltrates predominantly consisting of monocytes/macrophages and activated T cells. More recent is the implication of dendritic cells (DCs) in the disease. Since DCs were demonstrated in human arteries in 1995, numerous studies in humans suggest a role for these professional antigen-presenting cells in atherosclerosis. Aim. This paper focuses on the observations made in blood and arteries of patients with atherosclerosis. In principal, flow cytometric analyses show that circulating myeloid (m) and plasmacytoid (p) DCs are diminished in coronary artery disease, while immunohistochemical studies describe increased intimal DC counts with evolving plaque stages. Moreover, mDCs and pDCs appear to behave differently in atherosclerosis. Yet, the origin of plaque DCs and their relationship with blood DCs are unknown. Therefore, several explanations for the observed changes are postulated. In addition, the technical challenges and discrepancies in the research field are discussed. Future. Future studies in humans, in combination with experimental animal studies will unravel mechanisms leading to altered blood and plaque DCs in atherosclerosis. As DCs are crucial for inducing but also dampening immune responses, understanding their life cycle, trafficking and function in atherosclerosis will determine potential use of DCs in antiatherogenic therapies

Optimizing Dendritic Cell-Based Immunotherapy: Tackling the Complexity of Different Arms of the Immune System

Earlier investigations have revealed a surprising complexity and variety in the range of interaction between cells of the innate and adaptive immune system. Our understanding of the specialized roles of dendritic cell (DC) subsets in innate and adaptive immune responses has been significantly advanced over the years. Because of their immunoregulatory capacities and because very small numbers of activated DC are highly efficient at generating immune responses against antigens, DCs have been vigorously used in clinical trials in order to elicit or amplify immune responses against cancer and chronic infectious diseases. A better insight in DC immunobiology and function has stimulated many new ideas regarding the potential ways forward to improve DC therapy in a more fundamental way. Here, we discuss the continuous search for optimal in vitro conditions in order to generate clinical-grade DC with a potent immunogenic potential. For this, we explore the molecular and cellular mechanisms underlying adequate immune responses and focus on most favourable DC culture regimens and activation stimuli in humans. We envisage that by combining each of the features outlined in the current paper into a unified strategy, DC-based vaccines may advance to a higher level of effectiveness

Decreased numbers of peripheral blood dendritic cells in patients with coronary artery disease are associated with diminished plasma Flt3 ligand levels and impaired plasmacytoid dendritic cell function

International audienceBackground: We investigate whether activation of circulating DCs or levels of FMS-like tyrosine kinase 3 ligand (Flt3L) and granulocyte-macrophage colony stimulating factor (GM-CSF), haematopoietic growth factors important for dendritic cell (DC) differentiation, could account for reduced blood DC numbers in coronary artery disease (CAD) patients. Methods: Concentrations of Flt3L and GM-CSF were measured in plasma from CAD patients (n=15) and controls (n=12). Frequency and phenotype of myeloid (mDCs) and plasmacytoid (p)DCs were analysed by multicolour flow cytometry in fresh blood, and after overnight incubation with Toll-like receptor-4 or -7 ligands lipopolysaccharide or imiquimod. DC function was measured by interleukin (IL)-12 and interferon (IFN)-alpha secretion. Results: Circulating numbers of CD11c+ mDCs and CD123+ pDCs and frequencies of CD86+ and CCR-7+ mDCs, but not pDCs, were declined in CAD. Also plasma Flt3L, but not GM-CSF, was lower in patients and positively correlated with blood DC counts. In response to lipopolysaccharide, mDCs upregulated CD83 and CD86, but CCR-7 expression and IL-12 secretion remained unchanged, similarly in patients and controls. Conversely, pDCs from patients displayed lower CD83 and CCR-7 expression after overnight incubation and showed a weaker imiquimod-induced upregulation of CD83 and IFN-alpha secretion. Conclusions: Our data suggest that reduced blood DC counts in CAD are, at least partly, due to impaired DC differentiation from bone marrow progenitors. Decreased mDCs are presumably also explained by activation and subsequent migration to atherosclerotic plaques or lymph nodes. Although mDCs are functioning normally, pDCs from patients seemed to be both numerically and functionally impaired