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Systemic lentivirus-mediated delivery of short hairpin RNA targeting calcium release-activated calcium channel 3 as gene therapy for collagen-induced arthritis.

Authors :
Liu S
Kiyoi T
Takemasa E
Maeyama K
Source :
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2015 Jan 01; Vol. 194 (1), pp. 76-83. Date of Electronic Publication: 2014 Nov 24.
Publication Year :
2015

Abstract

Immune cells, including T cells, B cells, and osteoclasts, in conjunction with their associated cytokines, have been studied as primary molecular therapeutic targets for the management of rheumatoid arthritis (RA) patients. The increase in cytosolic Ca(2+) levels through the activation of store-operated Ca(2+) release-activated channels (CRACs) is involved in mediating a disparate array of cellular responses by these immune cells. This study was undertaken to investigate the feasibility and efficiency of the regulation of Ca(2+) entry in the treatment of RA. To moderately suppress Ca(2+) entry via CRACs, we gene silenced CRACM3, which was induced by systemic application of specific short hairpin RNAs (shRNAs) using a lentiviral-delivery system, in a murine model of collagen-induced arthritis (CIA). The inflammatory responses were determined by measuring the levels of a panel of cytokines and chemokines in the joints and serum. Ag-specific responses were evaluated by determining the cytokine profile of T cells stimulated with autoantigen. We also analyzed the ability of specific CRACM3-shRNA to regulate mature osteoclast function in CIA mice. The therapeutic effect of lentiviral-delivered CRACM3-shRNA was associated with gene silencing of CRACM3, along with the successful biodistribution of the virus. Extracellular Ca(2+) influx in the splenocytes, thymocytes, and knee joint synovial cells was moderately suppressed. Inflammatory responses and autoimmune responses were reduced by CRACM3 gene silencing. A decrease in mature osteoclast activity also was observed in CRACM3-shRNA-treated CIA mice. These results indicate that regulation of Ca(2+) entry through lentivirus-mediated CRACM3 gene silencing is beneficial in the treatment of RA.<br /> (Copyright © 2014 by The American Association of Immunologists, Inc.)

Details

Language :
English
ISSN :
1550-6606
Volume :
194
Issue :
1
Database :
MEDLINE
Journal :
Journal of immunology (Baltimore, Md. : 1950)
Publication Type :
Academic Journal
Accession number :
25422506
Full Text :
https://doi.org/10.4049/jimmunol.1401976