Publications (14) View all
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Article: Alginate-coated chitosan nanogel capacity to modulate the effect of TLR ligands on blood dendritic cells.
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ABSTRACT: Biodegradable nanoparticles have been employed for vaccine delivery, frequently admixed with adjuvants. Surprisingly, there is little information on their modulation of immune responses, speculated to be negligible. We analysed the immunomodulatory capacity of alginate-coated chitosan-nanogels (Ng), on porcine and human blood dendritic cells (DCs), when applied with defined adjuvants targeting different DC subpopulations. DC maturation, cytokine production and cell migration were assessed. Ng differentially influenced the immunomodulatory characteristics of individual Toll-like receptor (TLR) ligands: Pam(3)Cys-SK4-induced IL-1β was enhanced; CpG-oligodeoxynucleotides (CpG-ODN)-induced IFN-α, IL-6 and TNFα were impaired; CpG-ODN-induced CD86 and CCR7, and cell migration, were diminished - plasmacytoid DCs (pDCs) were particularly sensitive. Therein, the Ng influence on DC endocytosis of the TLR ligands was apparently a major contributory element. This demonstrates the importance of predefining the interplay between delivery vehicles and admixed immunostimulatory moieties, for ensuring appropriate immune activation and efficacious combinations.Nanomedicine: nanotechnology, biology, and medicine 01/2013; · 5.44 Impact Factor -
Article: Prognostic value of arginase-II expression and regulatory T-cell infiltration in head and neck squamous cell carcinoma.
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ABSTRACT: Tumor-infiltrating lymphocytes are present in a variety of tumors and play a central role in antitumor immune responses. Nevertheless, most cancers progress probably because tumors are only weakly immunogenic and develop multiple immunosuppressive mechanisms. In the present study, on head and neck squamous cell carcinoma, we found high intraepithelial infiltration of regulatory FOXP3(+) T cells, and relatively high levels of BDCA2(+) and FOXP3(+) cells in stromal (peripheral) regions of the tumors. Tumor-infiltrating (intraepithelial) FOXP3(+) T cells were significantly more frequent in patients with oropharynx and oral cavity squamous cell carcinoma and in patients without lymph node metastasis. Furthermore, arginase-II (ARG2) was expressed by 60%, inducible nitric oxide synthetase by 9%, cyclooxygenase-2 by 43%, and B-cell lymphoma 2 (BCL2) by 26% of tumors. Interestingly, the absence of ARG2 expression, enhanced stromal infiltration of CD11c(+) myeloid dendritic cells, and high numbers of FOXP3(+) T cells were each significantly associated with prolonged overall survival, and the latter two parameters were also confirmed by multivariate analysis. For disease-free survival, multivariate analysis revealed significant negative correlations with BCL2 and ARG2 expression by tumor cells. These findings shed new light on mechanisms of cancer progression, and provide rationales for therapeutic inhibition of immunosuppressive mechanisms in head and neck squamous cell carcinoma.International Journal of Cancer 07/2012; · 5.44 Impact Factor -
Article: Virus-like particles induce robust human T-helper cell responses.
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ABSTRACT: Among synthetic vaccines, virus-like particles (VLPs) are used for their ability to induce strong humoral responses. Very little is reported on VLP-based-vaccine-induced CD4(+) T-cell responses, despite the requirement of helper T cells for antibody isotype switching. Further knowledge on helper T cells is also needed for optimization of CD8(+) T-cell vaccination. Here, we analysed human CD4(+) T-cell responses to vaccination with MelQbG10, which is a Qβ-VLP covalently linked to a long peptide derived from the melanoma self-antigen Melan-A. In all analysed patients, we found strong antibody responses of mainly IgG1 and IgG3 isotypes, and concomitant Th1-biased CD4(+) T-cell responses specific for Qβ. Although less strong, comparable B- and CD4(+) T-cell responses were also found specific for the Melan-A cargo peptide. Further optimization is required to shift the response more towards the cargo peptide. Nevertheless, the data demonstrate the high potential of VLPs for inducing humoral and cellular immune responses by mounting powerful CD4(+) T-cell help.European Journal of Immunology 11/2011; 42(2):330-40. · 5.10 Impact Factor -
Article: Vaccination-induced functional competence of circulating human tumor-specific CD8 T-cells.
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ABSTRACT: T-cells specific for foreign (e.g., viral) antigens can give rise to strong protective immune responses, whereas self/tumor antigen-specific T-cells are thought to be less powerful. However, synthetic T-cell vaccines composed of Melan-A/MART-1 peptide, CpG and IFA can induce high frequencies of tumor-specific CD8 T-cells in PBMC of melanoma patients. Here we analyzed the functionality of these T-cells directly ex vivo, by multiparameter flow cytometry. The production of multiple cytokines (IFNγ, TNFα, IL-2) and upregulation of LAMP-1 (CD107a) by tumor (Melan-A/MART-1) specific T-cells was comparable to virus (EBV-BMLF1) specific CD8 T-cells. Furthermore, phosphorylation of STAT1, STAT5 and ERK1/2, and expression of CD3 zeta chain were similar in tumor- and virus-specific T-cells, demonstrating functional signaling pathways. Interestingly, high frequencies of functionally competent T-cells were induced irrespective of patient's age or gender. Finally, CD8 T-cell function correlated with disease-free survival. However, this result is preliminary since the study was a Phase I clinical trial. We conclude that human tumor-specific CD8 T-cells can reach functional competence in vivo, encouraging further development and Phase III trials assessing the clinical efficacy of robust vaccination strategies.International Journal of Cancer 07/2011; 130(11):2607-17. · 5.44 Impact Factor -
Article: Targeting siglecs--a novel pharmacological strategy for immuno- and glycotherapy.
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ABSTRACT: The immune system must be tightly held in check to avoid bystander tissue damage as well as autoreactivity caused by overwhelming immune reactions. A novel family of immunoregulatory, carbohydrate-binding receptors, the Siglecs (sialic acid binding immunoglobulin-like lectins), has received particular attention in light of their capacity to mediate cell death, anti-proliferative effects and to regulate a variety of cellular activities. Siglec receptors are mainly expressed on leukocytes in a cell type-specific and differentiation-dependent manner. Siglecs might potentially be exploited as targets of novel immune- and glycotherapeutics for cell-directed therapies in autoimmune and allergic diseases, as well as in haematologic malignancies. Here we present novel insights on structural and functional characteristics, expression patterns and evolutionary aspects of Siglecs and their ligands. Pharmacological strategies using Siglec agonistic cross-linking therapeutics, such as monoclonal or engineered antibodies, intravenous immunoglobulin (IVIG), or glycomimetics are discussed. Modulation of immune responses by targeting Siglecs using agonistic or antagonistic therapeutics may have important clinical implications and may pave the way for novel pharmacological avenues for the treatment of autoimmune and allergic diseases or for tumor immunotherapy.Biochemical pharmacology 05/2011; 82(4):323-32. · 4.25 Impact Factor
