CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery

Fransson, M and Piras, E and Burman, J and Nilsson, B and Essand, M and Lu, BF and Harris, RA and Magnusson, PU and Brittebo, E and Loskog, ASI (2012) CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery. Journal of Neuroinflammation, 9.

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Abstract

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 naïve 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. Symptom-free mice were rechallenged 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. © 2012 Fransson et al.; licensee BioMed Central Ltd.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Fransson, M Piras, E Burman, J Nilsson, B Essand, M Lu, BF binfeng@pitt.edu BINFENG Harris, RA Magnusson, PU Brittebo, E Loskog, ASI
Date:	30 May 2012
Date Type:	Publication
Journal or Publication Title:	Journal of Neuroinflammation
Volume:	9
DOI or Unique Handle:	10.1186/1742-2094-9-112
Schools and Programs:	School of Medicine > Immunology
Refereed:	Yes
Date Deposited:	14 Oct 2016 15:26
Last Modified:	24 Jun 2021 04:55
URI:	http://d-scholarship.pitt.edu/id/eprint/29887

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