[Show abstract][Hide abstract] ABSTRACT: The limited efficacy of monocyte-derived dendritic cell (mo-DC)-based vaccines is primarily attributed to the reduced mo-DC migratory capacity. One undefined aspect is the initial binding of mo-DCs to endothelial cells and vascular selectins. In this study, we investigated the role and modulation of the selectin binding determinant sialyl Lewis(x) (sLe(x)) in selectin-dependent mo-DC binding. Our data reveal that sLe(x) is required for maximal binding of mo-DCs to tumor necrosis factor (TNF)-α-activated endothelial cells under static conditions, as evidenced by the use of sialidase. Sialidase treatment also abrogated mo-DC cell tethering to immobilized, purified P-, L-, or E-selectin under flow. The requirement of sLe(x)-dependent binding of mo-DC to selectins was further substantiated by using sLe(x) free sugar and anti-sLe(x) antibody, which significantly suppressed mo-DC-selectin binding. P-selectin glycoprotein ligand-1 is required for mo-DC binding to both P- and L-selectin, but it is dispensable for E-selectin recognition. Interestingly, the extent of mo-DC tethering was maximal on P-selectin, followed by E- and L- selectin. Accordingly, L-selectin mediated faster mo-DC rolling than E- or P-selectin. Interferon (IFN)-γ induces a significant increase in mo-DC surface sLe(x) expression, which is probably due to the enhanced synthesis of C2GnT-I. These findings may contribute to improving mo-DC-based vaccination protocols.
Biochemical and Biophysical Research Communications 06/2011; 409(3):459-64. DOI:10.1016/j.bbrc.2011.05.026 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prostate adenocarcinoma is present in over 80% of men over the age of 80 and is by far the most common cancer of men. Although radical prostatectomy is curative in early disease, the risks of incontinence and impotence can affect the quality of life of patients. Early intervention with localized immunotherapy represents a potential solution as lymphocyte infiltration does occur in prostate cancer lesions, and immunotherapy with dendritic cell vaccines can significantly increase survival in late stage disease. However, lymphocytic infiltrates in the cancerous prostates have an anergic character arising from the suppressive effects of the microenvironment resulting from a conversion of effector cells into regulatory T-cells. Although TGFβ (transforming growth factor β) and IL-10 (interleukin-10) are known to be strong suppressor molecules associated with prostate cancer, they are among many possible suppressive factors. We discuss the possible role of alternative suppressor molecules, including the WAP (whey acidic protein) homologue ps20 that is expressed on prostate stroma and other WAP domain-containing proteins in the immunosuppressive prostate cancer milieu and discuss novel immunotherapeutic strategies to combat this disease.
Biochemical Society Transactions 10/2011; 39(5):1433-6. DOI:10.1042/BST0391433 · 3.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dendritic cells (DCs) are crucial components of the immune response, strategically positioned as immune sentinels. Complex trafficking and accurate positioning of DCs are indispensable for both immunity and tolerance. This is particularly evident for their therapeutic application where an unmet clinical need exists for DCs with improved migratory capacity upon adoptive transfer into patients. One critical step that directs the trafficking of DCs throughout the body is their egress from the vasculature, starting with their adhesive interactions with vascular endothelium under shear flow. Both tethering and rolling rely on interactions mediated by specific glycans attached to glycoproteins and glycolipids present on the DC surface. In DCs, surface glycosylation, including the expression of selectin ligands, changes significantly depending on the local microenvironment and the functional state of the cells. These changes have been documented and have potential implications in important cell functions such as migration. In this article, we review the glycobiological aspects in the context of DC interaction with endothelium, and offer insights on how it can be applied to modulate DC applicability in therapy.
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