Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation
Lidia Yshii
(1)
,
Emanuela Pasciuto
(1)
,
Pascal Bielefeld
(2, 3)
,
Loriana Mascali
(1)
,
Pierre Lemaitre
(1)
,
Marika Marino
(1)
,
James Dooley
(3)
,
Lubna Kouser
(4, 3)
,
Stijn Verschoren
(1)
,
Vasiliki Lagou
(1)
,
Hannelore Kemps
(5)
,
Pascal Gervois
(5)
,
Antina de Boer
(1)
,
Oliver Burton
(3)
,
Jérôme Wahis
(6, 1)
,
Jens Verhaert
(1)
,
Samar Tareen
(3)
,
Carlos Roca
(3)
,
Kailash Singh
(3)
,
Carly Whyte
(3)
,
Axelle Kerstens
(1, 7)
,
Zsuzsanna Callaerts-Vegh
(1)
,
Suresh Poovathingal
(1)
,
Teresa Prezzemolo
(1)
,
Keimpe Wierda
(1)
,
Amy Dashwood
(3)
,
Junhua Xie
(8, 9)
,
Elien van Wonterghem
(1, 8, 9)
,
Eline Creemers
(1)
,
Meryem Aloulou
(3, 10)
,
Willy Gsell
(1)
,
Oihane Abiega
(2)
,
Sebastian Munck
(1, 7)
,
Roosmarijn Vandenbroucke
(8, 9)
,
Annelies Bronckaers
(5)
,
Robin Lemmens
(1, 11)
,
Bart de Strooper
(1, 12)
,
Ludo van den Bosch
(1)
,
Uwe Himmelreich
(1)
,
Carlos Fitzsimons
(2)
,
Matthew Holt
(1, 13)
,
Adrian Liston
(1, 3)
1
KU Leuven -
Catholic University of Leuven = Katholieke Universiteit Leuven
2 UvA - University of Amsterdam [Amsterdam] = Universiteit van Amsterdam
3 The Babraham Institute [Cambridge, UK]
4 Brunel University London [Uxbridge]
5 UHasselt - Hasselt University
6 INCI - Institut des Neurosciences Cellulaires et Intégratives
7 VIB [Belgium]
8 IRC - VIB-UGent Center for Inflammation Research [Gand, Belgique]
9 UGENT - Universiteit Gent = Ghent University = Université de Gand
10 Infinity - Institut Toulousain des Maladies Infectieuses et Inflammatoires
11 University Hospitals Leuven [Leuven]
12 UCL - University College of London [London]
13 I3S - Instituto de Investigação e Inovação em Saúde
2 UvA - University of Amsterdam [Amsterdam] = Universiteit van Amsterdam
3 The Babraham Institute [Cambridge, UK]
4 Brunel University London [Uxbridge]
5 UHasselt - Hasselt University
6 INCI - Institut des Neurosciences Cellulaires et Intégratives
7 VIB [Belgium]
8 IRC - VIB-UGent Center for Inflammation Research [Gand, Belgique]
9 UGENT - Universiteit Gent = Ghent University = Université de Gand
10 Infinity - Institut Toulousain des Maladies Infectieuses et Inflammatoires
11 University Hospitals Leuven [Leuven]
12 UCL - University College of London [London]
13 I3S - Instituto de Investigação e Inovação em Saúde
Emanuela Pasciuto
- Fonction : Auteur
- PersonId : 1232626
- ORCID : 0000-0002-5391-9585
Marika Marino
- Fonction : Auteur
- PersonId : 1232627
- ORCID : 0000-0001-6773-6176
James Dooley
- Fonction : Auteur
- PersonId : 1232628
- ORCID : 0000-0003-3154-4708
Stijn Verschoren
- Fonction : Auteur
- PersonId : 1232629
- ORCID : 0000-0001-6733-3481
Oliver Burton
- Fonction : Auteur
- PersonId : 1232632
- ORCID : 0000-0003-3884-7373
Kailash Singh
- Fonction : Auteur
- PersonId : 1232633
- ORCID : 0000-0002-6771-7757
Carly Whyte
- Fonction : Auteur
- PersonId : 1232634
- ORCID : 0000-0001-6556-6855
Zsuzsanna Callaerts-Vegh
- Fonction : Auteur
- PersonId : 1232635
- ORCID : 0000-0001-9091-2078
Amy Dashwood
- Fonction : Auteur
- PersonId : 1232636
- ORCID : 0000-0002-4340-377X
Willy Gsell
- Fonction : Auteur
- PersonId : 1232637
- ORCID : 0000-0001-7334-6107
Roosmarijn Vandenbroucke
- Fonction : Auteur
- PersonId : 757949
- ORCID : 0000-0002-8327-620X
Adrian Liston
- Fonction : Auteur
- PersonId : 793067
- ORCID : 0000-0002-6272-4085
- IdRef : 152640231
Résumé
The ability of immune-modulating biologics to prevent and reverse pathology has transformed recent clinical practice. Full utility in the neuroinflammation space, however, requires identification of both effective targets for local immune modulation and a delivery system capable of crossing the blood–brain barrier. The recent identification and characterization of a small population of regulatory T (T reg ) cells resident in the brain presents one such potential therapeutic target. Here, we identified brain interleukin 2 (IL-2) levels as a limiting factor for brain-resident T reg cells. We developed a gene-delivery approach for astrocytes, with a small-molecule on-switch to allow temporal control, and enhanced production in reactive astrocytes to spatially direct delivery to inflammatory sites. Mice with brain-specific IL-2 delivery were protected in traumatic brain injury, stroke and multiple sclerosis models, without impacting the peripheral immune system. These results validate brain-specific IL-2 gene delivery as effective protection against neuroinflammation, and provide a versatile platform for delivery of diverse biologics to neuroinflammatory patients.