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CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.ORCID-id: 0000-0002-7045-1806
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
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2012 (engelsk)Inngår i: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 9, s. 112-Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
2012. Vol. 9, s. 112-
Emneord [en]
MS, redirected cells, T regulatory cells, EAE, FoxP3, myelin oligodendrocyte glycoprotein
HSV kategori
Forskningsprogram
Neurologi
Identifikatorer
URN: urn:nbn:se:uu:diva-175383DOI: 10.1186/1742-2094-9-112ISI: 000307014500001PubMedID: 22647574OAI: oai:DiVA.org:uu-175383DiVA, id: diva2:531109
Merknad

De två första författarna delar första författarskapet.

Tilgjengelig fra: 2012-06-05 Laget: 2012-06-05 Sist oppdatert: 2018-05-18bibliografisk kontrollert

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

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