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Increasing the tolerogenic potential of dendritic cells by targeted interference with chemokine function

Projectomschrijving

Na een (nier)transplantatie moeten patiënten medicijnen gebruiken ter voorkoming dat het transplantaat wordt afgestoten. Deze medicijnen onderdrukken het immuunsysteem aspecifiek waardoor er een verhoogde kans is op infecties. Bepaalde immuuncellen  (dendritische) kunnen door een kweekmethode tolerantie inducerende (tolerogene) eigenschappen krijgen. Door voorafgaande aan de transplantatie tolerogene dendritische cellen van de donor toe te dienen, kan het immuunsysteem van de ontvanger selectief onderdrukt worden. Dit leidt tot betere acceptatie van het getransplanteerde orgaan zonder nadelige effecten op de rest van  het afweersysteem. In het creëren van tolerantie door dendritische cellen spelen chemokines en T-cellen en een cruciale rol. In dit project bestuderen wij de rol van chemokines bij het bepalen van de tolerogene eigenschappen van dendritische cellen.

Producten

Auteur: M Kouwenberg, J van der Vlag, L Hilbrands
Auteur: M Kouwenberg, J van der Vlag, L Hilbrands
Titel: The role of syndecan-1 in the interaction between dendritic cells and T cells
Auteur: M Kouwenberg, A. Rops, M. Götte, J. van der Vlag, L. Hilbrands
Titel: The role of syndecan-1 in the interaction between dendritic cells and T cells
Auteur: M Kouwenberg, A. Rops, M. Götte, J. van der Vlag, L. Hilbrands
Auteur: M Kouwenberg, J van der Vlag, L Hilbrands
Titel: Dendritic cell derived CXCL1: no role in T cell activation or differentiation
Auteur: M Kouwenberg, J van der Vlag, L Hilbrands
Titel: The role of syndecan-1 in the interaction between dendritic cells and T cells
Auteur: M Kouwenberg, A. Rops, M. Götte, J. van der Vlag, L. Hilbrands
Titel: The role of heparan sulphate, heparanase and alpha-1 antitrypsin in immune response and transplantation.
Titel: Heparan sulphate and heparan sulphate proteoglycans: underexposed mediators in dendritic cell – T cell interaction
Titel: Allostimulatory effects of dendritic cells with a regulatory phenotype
Titel: High levels of CXCL1 produced by immunogenic dendritic cells do not activate T cells
Titel: The role of syndecan-1 in dendritic cell - T cell interaction
Titel: Allostimulatory Effects of Dendritic Cells with Characteristic Features of a Regulatory Phenotype
Auteur: Kouwenberg, M., Jacobs, C. W. M., van der Vlag, J., Hilbrands, L. B.
Magazine: PLoS ONE

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Samenvatting van de aanvraag

Dendritic cells (DC) are antigen-presenting cells that initiate and regulate immune responses. These responses can be either immunogenic or tolerogenic. Tolerogenic DC have therapeutic potential in preventing undesirable immune responses such as autoimmunity and allograft rejection. Successful DC-based immunotherapy would alleviate the burden of complications that is associated with the current treatment with non-specific immunosuppressive drugs. In animal models, infusion of tolerogenic DC prior to organ transplantation has been shown to prolong allograft survival. Common features of these tolerogenic DC are a low expression of costimulatory molecules and a cytokine production profile that polarizes the T cell response towards a regulatory phenotype. The cytokine profile of DC is largely regulated by signaling via pattern recognition receptors, like Toll-like receptors (TLRs). By targeted interference in TLR signaling, we generated mouse DC with a highly tolerogenic phenotype, i.e. a low expression of costimulatory molecules and a high IL-10:IL-12 production ratio. Surprisingly, these DC induced strong T cell responses in vitro and markedly shortened graft survival in a heart transplantation model. Using a cytokine/chemokine protein array, we found a high expression of the chemokine CXCL1 (KC) by this unique type of highly immunogenic DC. In this proposal we will further elaborate on the role of DC-derived chemokines in determining the immunoregulatory properties of DC. Firstly, we will generate tolerogenic and immunogenic DC, and perform a thorough analysis of the chemokine expression profiles of each type of DC. Secondly, we will evaluate strategies that interfere with the interaction between chemokines and their receptors in order to increase the tolerogenic potential of DC. We will in particular address the specific role of the negatively charged glycosaminoglycans (GAG), which frequently serve as co-receptors for chemokines, including CXCL1. We also will test available blocking antibodies and small molecular receptor antagonists. We expect that our research will reveal new targets that increase the tolerogenic capacities of DC. This can be translated to novel treatment strategies of patients with organ transplants or autoimmune disease.

Onderwerpen

Kenmerken

Projectnummer:
92003567
Looptijd: 100%
Looptijd: 100 %
2011
2019
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. L.B. Hilbrands
Verantwoordelijke organisatie:
Radboudumc