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CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.ORCID iD: 0000-0002-7045-1806
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2012 (English)In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 9, 112- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). In the murine experimental autoimmune encephalomyelitis (EAE) model of MS, T regulatory (Treg) cell therapy has proved to be beneficial, but generation of stable CNS-targeting Tregs needs further development. Here, we propose gene engineering to achieve CNS-targeting Tregs from naive CD4 cells and demonstrate their efficacy in the EAE model.

METHODS

CD4+T cells were modified utilizing a lentiviral vector system to express a chimeric antigen receptor (CAR) targeting myelin oligodendrocyte glycoprotein (MOG) in trans with the murine FoxP3 gene that drives Treg differentiation. The cells were evaluated in vitro for suppressive capacity and in C57BL/6 mice to treat EAE. Cells were administered by intranasal (i.n.) cell delivery.

RESULTS

The engineered Tregs demonstrated suppressive capacity in vitro and could efficiently access various regions in the brain via i.n cell delivery. Clinical score 3 EAE mice were treated and the engineered Tregs suppressed ongoing encephalomyelitis as demonstrated by reduced disease symptoms as well as decreased IL-12 and IFNgamma mRNAs in brain tissue. Immunohistochemical markers for myelination (MBP) and reactive astrogliosis (GFAP) confirmed recovery in mice treated with engineered Tregs compared to controls. Symptomfree mice were echallenged with a second EAE-inducing inoculum but remained healthy, demonstrating the sustained effect of engineered Tregs.

CONCLUSION

CNS-targeting Tregs delivered i.n. localized to the CNS and efficiently suppressed ongoing inflammation leading to diminished disease symptoms.

Place, publisher, year, edition, pages
2012. Vol. 9, 112- p.
Keyword [en]
MS, redirected cells, T regulatory cells, EAE, FoxP3, myelin oligodendrocyte glycoprotein
National Category
Neurology
Research subject
Neurology
Identifiers
URN: urn:nbn:se:uu:diva-175383DOI: 10.1186/1742-2094-9-112ISI: 000307014500001PubMedID: 22647574OAI: oai:DiVA.org:uu-175383DiVA: diva2:531109
Note

De två första författarna delar första författarskapet.

Available from: 2012-06-05 Created: 2012-06-05 Last updated: 2017-12-07Bibliographically approved

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Fransson, MoaPiras, ElenaBurman, JoachimNilsson, BerithEssand, MagnusMagnusson, Peetra UBrittebo, EvaLoskog, Angelica Si
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