| 1. |
- Oosterhoff, Dinja, et al.
(författare)
-
Intradermal Delivery of TLR Agonists in a Human Explant Skin Model: Preferential Activation of Migratory Dendritic Cells by Polyribosinic-Polyribocytidylic Acid and Peptidoglycans
- 2013
-
Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 190:7, s. 3338-3345
-
Tidskriftsartikel (refereegranskat)abstract
- TLR agonists are attractive candidate adjuvants for therapeutic cancer vaccines as they can induce a balanced humoral and T cell-mediated immune response. With a dense network of dendritic cells (DCs) and draining lymphatics, the skin provides an ideal portal for vaccine delivery. Beside direct DC activation, TLR agonists may also induce DC activation through triggering the release of inflammatory mediators by accessory cells in the skin microenvironment. Therefore, a human skin explant model was used to explore the in vivo potential of intradermally delivered TLR agonists to stimulate Langerhans cells and dermal DCs in their natural complex tissue environment. The skin-emigrated DCs were phenotyped and analyzed for T cell stimulatory capacity. We report that, of six tested TLR-agonists, the TLR2 and -3 agonists peptidoglycan (PGN) and polyribosinic-polyribocytidylic acid (Poly I:C) were uniquely able to enhance the T cell-priming ability of skin-emigrated DCs, which, in the case of PGN, was accompanied by Th1 polarization. The enhanced priming capacity of Poly I:C-stimulated DCs was associated with a strong upregulation of appropriate costimulatory molecules, including CD70, whereas that of PGN-stimulated DCs was associated with the release of a broad array of proinflammatory cytokines. Transcriptional profiling further supported the notion that the PGN- and Poly I:C-induced effects were mediated through binding to TLR2/nucleotide-binding oligomerization domain 2 and TLR3/MDA5, respectively. These data warrant further exploration of PGN and Poly I:C, alone or in combination, as DC-targeted adjuvants for intradermal cancer vaccines. The Journal of Immunology, 2013, 190:3338-3345.
|
|
| 2. |
- Saeland, Eirikur, et al.
(författare)
-
The C-type lectin MGL expressed by dendritic cells detects glycan changes on MUC1 in colon carcinoma
- 2007
-
Ingår i: Cancer Immunol Immunother. ; 56:8, s. 1225-1236
-
Tidskriftsartikel (refereegranskat)abstract
- The epithelial mucin MUC1 is a high molecular weight membrane glycoprotein frequently overexpressed and aberrantly glycosylated in adenocarcinoma. Mucins normally contain high amounts of O-linked carbohydrate structures that may influence immune reactions to this antigen. During malignant transformation, certain glyco-epitopes of MUC1, such as Tn-antigen, TF-antigen and their sialylated forms become exposed. The role of these glycan structures in tumor biology is unknown, but their presence is known to correlate with poor prognosis in several adenocarcinomas. We analyzed the potency of MUC1 containing Tn-antigens (MUC1-Tn) to target C-type lectins that function as carbohydrate recognition and uptake molecules on dendritic cells (DC). We identified the macrophage galactose type C-type lectin (MGL), expressed by both DC and macrophages, as the receptor for recognition and binding of MUC1-Tn. To validate the occurrence of MGL–MUC1 interactions in situ, we studied the binding of MGL to MUC1 in primary colon carcinoma tissue. Isolation of MUC1 out of colon carcinoma tissue showed strong binding activity to MGL. Interestingly, MGL binding to MUC1 was highly correlated to binding by the lectin Helix pomatia agglutinin (HPA), which is associated with poor prognosis in colorectal cancer. The detection of MGL positive cells in situ at the tumor site together with the modified glycosylation status of MUC1 to target MGL on DC suggests that MGL positive antigen presenting cells may play a role in tumor progression.
|
|
| 3. |
- Bax, Marieke, et al.
(författare)
-
Dendritic cell maturation results in pronounced changes in glycan expression affecting recognition by siglecs and galectins
- 2007
-
Ingår i: Journal of Immunology. - 1550-6606. ; 179:12, s. 8216-8224
-
Tidskriftsartikel (refereegranskat)abstract
- Dendritic cells (DC) are the most potent APC in the organism. Immature dendritic cells (iDC) reside in the tissue where they capture pathogens whereas mature dendritic cells (mDC) are able to activate T cells in the lymph node. This dramatic functional change is mediated by an important genetic reprogramming. Glycosylation is the most common form of posttranslational modification of proteins and has been implicated in multiple aspects of the immune response. To investigate the involvement of glycosylation in the changes that occur during DC maturation, we have studied the differences in the glycan profile of iDC and mDC as well as their glycosylation machinery. For information relating to glycan biosynthesis, gene expression profiles of human monocyte-derived iDC and mDC were compared using a gene microarray and quantitative real-time PCR. This gene expression profiling showed a profound maturation-induced up-regulation of the glycosyltransferases involved in the expression of LacNAc, core 1 and sialylated structures and a down-regulation of genes involved in the synthesis of core 2 O-glycans. Glycosylation changes during DC maturation were corroborated by mass spectrometric analysis of N- and O-glycans and by flow cytometry using plant lectins and glycan-specific Abs. Interestingly, the binding of the LacNAc-specific lectins galectin-3 and -8 increased during maturation and up-regulation of sialic acid expression by mDC correlated with an increased binding of siglec-1, -2, and -7.
|
|
| 4. |
- de Jong, Marein A. W. P., et al.
(författare)
-
Dendritic cells mediate herpes simplex virus infection and transmission through the C-type lectin DC-SIGN
- 2008
-
Ingår i: Journal of General Virology. - : Microbiology Society. - 0022-1317 .- 1465-2099. ; 89, s. 2398-2409
-
Tidskriftsartikel (refereegranskat)abstract
- Dendritic cells (DCs) are essential for the induction of specific immune responses against invading pathogens. Herpes simplex virus (HSV) is a common human pathogen that causes painful but mild infections of the skin and mucosa, and which results in latency and recurrent infections. Of the two HSV subtypes described, HSV-1 causes mainly oral–facial lesions, whilst HSV-2 is associated with genital herpes. DCs are involved in HSV-induced immune suppression, but little is known about the molecular interactions between DCs and HSV. This study demonstrated that HSV-1 and -2 both interact with the DC-specific C-type lectin DC-SIGN. Further analyses demonstrated that DC-SIGN interacts with the HSV glycoproteins gB and gC. Binding of HSV-1 to immature DCs depended on both DC-SIGN and heparan sulfate proteoglycans. Strikingly, HSV-1 infection of DCs was almost completely inhibited by blocking antibodies against DC-SIGN. Thus, DC-SIGN is an important attachment receptor for HSV-1 on immature DCs and enhances infection of DCs in cis. In addition, DC-SIGN captures HSV-1 for transmission to permissive target cells. These data strongly suggest that DC-SIGN is a potential target to prevent HSV infection and virus dissemination. Further studies will show whether these interactions are involved in HSV-induced immune suppression.
|
|
