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

Journal of Neuroinflammation

Angelica SI Loskog⁵  Eva Brittebo⁴  Peetra U Magnusson⁵  Robert A Harris²  BinFeng Lu¹  Magnus Essand⁵  Berith Nilsson⁵  Joachim Burman³  Elena Piras⁴  Moa Fransson⁵ 

[1] Department of Immunology, University of Pittsburgh, 320 East North Avenue, Pittsburgh, PA, 15212, USA;Applied Immunology, Department of Clinical Neurosciences, Karolinska Institutet, Center for Molecular Medicine, Karolinska Hospital at Solna, Solna, Sweden;Department of Neuroscience, Uppsala University, Uppsala University Hospital Entr 70, SE-75185, Uppsala, Sweden;Department of Pharmaceutical Biosciences, Uppsala University, BMC, Husarg 3, SE-75124, Uppsala, Sweden;Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck Laboratory C11, Dag Hammarskjoldsv 20, SE-75185, Uppsala, Sweden

关键词: Myelin oligodendrocyte glycoprotein (MOG);    FoxP3;    EAE;    T regulatory cells;    redirected cells;    MS;   

Others  :  1212566
DOI  :  10.1186/1742-2094-9-112

 received in 2011-12-19, accepted in 2012-05-30,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Fransson et al.; licensee BioMed Central Ltd.

【 图 表 】

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