Modulation of collagen-induced arthritis by adenovirus-mediated intra-articular expression of modified collagen type II
1 Department of Medicine, University of Tennessee Health Science Center, 956 Court Avenue, Memphis, Tennessee 38163, USA
2 Department of Biomedical Engineering, University of Tennessee Health Science Center, 920 Madison, Suite 407, Memphis, Tennessee 38163 USA
3 Department of Orthopedics, University of Tennessee Health Science Center, 1211 Union Avenue, Suite 520, Memphis, Tennessee 38104 USA
4 Research Service, Veterans Affairs Medical Center, 1030 Jefferson Avenue, Memphis TN 38104 USA
5 Department of Pediatrics, University of Tennessee Health Science Center, 50 North Dunlap, Room 401, Memphis TN 38163 USA
Arthritis Research & Therapy 2010, 12:R136 doi:10.1186/ar3074Published: 8 July 2010
Rheumatoid arthritis (RA) is a systemic disease manifested by chronic inflammation in multiple articular joints, including the knees and small joints of the hands and feet. We have developed a unique modification to a clinically accepted method for delivering therapies directly to the synovium. Our therapy is based on our previous discovery of an analog peptide (A9) with amino acid substitutions made at positions 260 (I to A), 261 (A to B), and 263 (F to N) that could profoundly suppress immunity to type II collagen (CII) and arthritis in the collagen-induced arthritis model (CIA).
We engineered an adenoviral vector to contain the CB11 portion of recombinant type II collagen and used PCR to introduce point mutations at three sites within (CII124-402, 260A, 261B, 263D), (rCB11-A9) so that the resulting molecule contained the A9 sequence at the exact site of the wild-type sequence.
We used this construct to target intra-articular tissues of mice and utilized the collagen-induced arthritis model to show that this treatment strategy provided a sustained, local therapy for individual arthritic joints, effective whether given to prevent arthritis or as a treatment. We also developed a novel system for in vivo bioimaging, using the firefly luciferase reporter gene to allow serial bioluminescence imaging to show that luciferase can be detected as late as 18 days post injection into the joint.
Our therapy is unique in that we target synovial cells to ultimately shut down T cell-mediated inflammation. Its effectiveness is based on its ability to transform potential inflammatory T cells and/or bystander T cells into therapeutic (regulatory-like) T cells which secrete interleukin (IL)-4. We believe this approach has potential to effectively suppress RA with minimal side effects.