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Nuclear receptors in dendritic cell biology: it's time to foster the orphans

Projectomschrijving

Ons afweersysteem is essentieel voor het opruimen van ziekteverwekkers en kankercellen. Dendritische cellen zijn cellen van
ons afweersysteem die andere afweercellen kunnen aansturen. In dit project hebben wij onderzocht wat de rol is van het eiwit
Nur77 in deze cellen. Nur77 blijkt een belangrijke rol te spelen in de activiteit van dendritische cellen. Zodra we Nur77
uitschakelen worden de dendritische cellen beter in het activeren van andere afweercellen, terwijl ze andere afweercellen
remmen als we Nur77 activeren. Deze kennis opent nieuwe perspectieven voor de optimalisatie van de werking van
dendritische cellen in de behandeling van kanker en auto- immuunziektes.

Producten

Titel: Radiotherapie en immunotherapie in de behandeling van kanker, hoe halen we het beste uit beide
Auteur: Marleen Ansems
Titel: Nur77, a new target to boost DC vaccination?
Auteur: Marleen Ansems
Titel: The function of antigen presenting Dendritic Cells in the immune system in health and disease
Auteur: Marleen Ansems
Titel: Nur77 deficiency alters dendritic cell function
Auteur: Marleen Ansems
Titel: Microenvironmental derived factors modulating dendritic cell function and vaccine efficacy: the effect of prostanoid receptor and nuclear receptor ligands
Auteur: Raaijmakers, Tonke K., Ansems, Marleen
Magazine: cancer immunology immunotherapy
Titel: Nuclear Receptor Nur77 Deficiency Alters Dendritic Cell Function
Auteur: Tel-Karthaus, Nina, Kers-Rebel, Esther D., Looman, Maaike W., Ichinose, Hiroshi, de Vries, Carlie J., Ansems, Marleen
Magazine: Frontiers in Immunology

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Samenvatting van de aanvraag

Dendritic cells (DC) are the professional antigen presenting cells of the immune system. Proper function of DCs is crucial in eliciting an effective immune response against pathogens, but DCs also play a decisive role in inducing anti-tumor immunity. Different members of the type I and type II Nuclear Receptor (NR) family of transcription factors have been reported to affect proper function of the immune cells. The NR4A subfamily is part of the type III NR group of orphan NRs and consists of Nur77/NR4A1, Nurr1/NR4A2 and Nor-1/NR4A3. Recently, the NR4A subfamily of NRs has been reported to be expressed and function within the immune system. Our recently published and preliminary data show that the NR4As are also potently induced in mature DCs. Intriguingly, in the absence of Nur77 DCs are hyperactivated. Based on these data I now hypothesize that the NR4A orphan NRs play a dominant role in modulating the magnitude of activation of professional antigen presenting DCs. To unravel the role of NR4A transcriptional pathways in DCs and to explore their ability to direct the DC activation program at the interface of immunity and tolerance I will 1) elucidate the impact of the NR4A1/Nur77 pathway on immunity and tolerance in vivo using mice uniquely lacking this receptor in DCs, 2) define the genomic and non-genomic mode of action of NR4A in human DCs using Chromatin ImmunoPrecipitation (ChIP)-sequencing and cell biological approaches and 3) explore the function of human NR4A modified DCs for use in future DC-based vaccination therapies. Ultimately, targeting these receptors may prove to be efficacious in boosting DC function and may lead to the development of improved DC-based immunotherapies.

Onderwerpen

Kenmerken

Projectnummer:
91615093
Looptijd: 100%
Looptijd: 100 %
2015
2019
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Dr. ir. M. Ansems
Verantwoordelijke organisatie:
Radboudumc