Modulation of collagen-induced arthritis by adenovirus-mediated intra-articular expression of modified collagen type II.
BACKGROUND
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).


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Tang
Bo
B
Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA. Bo.Tang@stjude.org
Cullins
David L
DL
Zhou
Jing
J
Zawaski
Janice A
JA
Park
Hyelee
H
Brand
David D
DD
Hasty
Karen A
KA
Gaber
M Waleed
MW
Stuart
John M
JM
Kang
Andrew H
AH
Myers
Linda K
LK
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy; D016367:Baculoviridae / Q000235:genetics; D024043:Collagen Type II / Q000235:genetics* / Q000494:pharmacology*; D015316:Genetic Therapy / Q000379:methods*; D007165:Immunosuppression Therapy / Q000379:methods; D007270:Injections, Intra-Articular; D015847:Interleukin-4 / Q000276:immunology; D007596:Joints / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D013583:Synovial Membrane / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D024043:Collagen Type II; D011994:Recombinant Proteins; D015847:Interleukin-4