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TARG-SUP SIGNED

Targeting TGF-β activation, likely the core mechanism of immunosuppression by human regulatory T cells.

Total Cost €

EC-Contrib. €

Partnership

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Outcomes and
results

TARG-SUP project word cloud

Explore the words cloud of the TARG-SUP project. It provides you a very rough idea of what is the project "TARG-SUP" about.

mice pathological lymphocytes molecular unknown functional anti largely complexes expression toxicities immunotherapies structural predict mabs expressing tools chimeric tgf dimensional cells inhibitory garp express microbial membrane chronic alternative cancer blocking antibodies mutant tregs inhibit treatment tolerance cell release proteins regulatory humans infections immunological human functions tri mediated diseases protein bearing tested displays derive sufficient immune physiological surface clinical implicated immunosuppression immunostimulatory beta generate active dependent modulate inhibition tumour explore murine treg vaccines notably transient mouse implies latent activation appears understand unravel perform roles additional

Project "TARG-SUP" data sheet

The following table provides information about the project.

Coordinator	UNIVERSITE CATHOLIQUE DE LOUVAIN Organization address address: PLACE DE L UNIVERSITE 1 city: LOUVAIN LA NEUVE postcode: 1348 website: www.uclouvain.be contact info title: n.a. name: n.a. surname: n.a. function: n.a. email: n.a. telephone: n.a. fax: n.a.
Coordinator Country	Belgium [BE]
Total cost	1˙993˙125 €
EC max contribution	1˙993˙125 € (100%)
Programme	1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
Code Call	ERC-2015-CoG
Funding Scheme	ERC-COG
Starting year	2016
Duration (year-month-day)	from 2016-04-01 to 2021-03-31

Partnership

Take a look of project's partnership.

#	participants	country	role	EC contrib. [€]
1	UNIVERSITE CATHOLIQUE DE LOUVAIN UNIVERSITE CATHOLIQUE DE LOUVAIN Organization address address: PLACE DE L UNIVERSITE 1 city: LOUVAIN LA NEUVE postcode: 1348 website: www.uclouvain.be contact info title: n.a. name: n.a. surname: n.a. function: n.a. email: n.a. telephone: n.a. fax: n.a.	BE (LOUVAIN LA NEUVE)	coordinator	1˙993˙125.00

Map

Project objective

Regulatory T lymphocytes (Tregs) inhibit immune responses and are required to maintain immune tolerance. Tregs express membrane protein GARP, which displays latent TGF-β1 on the cell surface. Immunosuppression by human Tregs appears to require GARP-mediated activation of TGF-β1. My objectives are to unravel the molecular aspects of TGF-β1 activation by GARP and determine the functional importance of this process in physiological and pathological conditions where Tregs or other GARP-expressing cells are present. As this implies the development of new tools to modulate GARP-dependent TGF-β1 activation and Treg immunosuppression, we will also explore their potential for the treatment of immune-related human diseases, and notably cancer. More specifically, I will: - Derive antibodies that modulate GARP-mediated TGF-β1 production by human Tregs and perform structural analyses in the presence of these antibodies to identify tri-dimensional changes in GARP/TGF-β1 complexes that lead to the release of active TGF-β1. - Identify and characterize additional proteins implicated in TGF-β1 activation by human Tregs, as GARP is required but not sufficient for TGF-β1 activation by Tregs. - Determine the immunological and clinical impact of inhibitory anti-GARP mAbs on cancer in mice. We will derive anti-murine GARP mAbs. As an alternative, we will generate mutant mice expressing a chimeric mouse/human GARP that is recognized by anti-human GARP mAbs. The antibodies will be tested in tumour-bearing mice treated or not with other immunotherapies including vaccines or immunostimulatory antibodies. - Determine whether blocking anti-GARP mAbs improve immune responses to microbial vaccines or to chronic infections, as these represent important applications for transient inhibition of Treg activity in humans. - Analyse the expression and roles of GARP in non-Treg cells to better understand GARP functions, which remain largely unknown, and predict potential toxicities of anti-GARP mAbs.

Publications

List of publications.
year	authors and title	journal	last update
2018	StÃ©phanie LiÃ©nart, Romain Merceron, Christophe Vanderaa, Fanny Lambert, Didier Colau, Julie Stockis, Bas van der Woning, Hans De Haard, Michael Saunders, Pierre G. Coulie, Savvas N. Savvides, Sophie Lucas Structural basis of latent TGF-Î²1 presentation and activation by GARP on human regulatory T cells published pages: 952-956, ISSN: 0036-8075, DOI: 10.1126/science.aau2909	Science 362/6417	2019-04-18

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