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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.
- 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.)
- Subjects :
- Animals
Calcium Signaling genetics
Cytokines biosynthesis
Cytokines blood
Cytosol metabolism
HEK293 Cells
Humans
Knee Joint metabolism
Lentivirus
Male
Mice
Mice, Inbred DBA
Osteoclasts metabolism
RNA Interference
Spleen cytology
Synovial Fluid cytology
T-Lymphocytes immunology
Thymocytes metabolism
Arthritis, Experimental therapy
Arthritis, Rheumatoid therapy
Calcium metabolism
Calcium Channels genetics
Genetic Therapy methods
RNA, Small Interfering genetics
Subjects
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