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

Bo Tang, David L. Cullins, Jing Zhou, Janice A. Zawaski, Hyelee Park, David Brand, Karen Hasty, M. Waleed Gaber, John Stuart, Andrew Kang, Linda Myers

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Introduction: 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.

Original languageEnglish (US)
Article numberR136
JournalArthritis Research and Therapy
Volume12
Issue number4
DOIs
StatePublished - Jul 8 2010

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Experimental Arthritis
Collagen Type II
Adenoviridae
Joints
T-Lymphocytes
Therapeutics
Arthritis
Rheumatoid Arthritis
Inflammation
Firefly Luciferases
Synovial Membrane
Regulatory T-Lymphocytes
Amino Acid Substitution
Knee Joint
Luciferases
Reporter Genes
Point Mutation
Interleukin-4
Foot
Immunity

All Science Journal Classification (ASJC) codes

  • Rheumatology
  • Immunology and Allergy
  • Immunology

Cite this

Modulation of collagen-induced arthritis by adenovirus-mediated intra-articular expression of modified collagen type II. / Tang, Bo; Cullins, David L.; Zhou, Jing; Zawaski, Janice A.; Park, Hyelee; Brand, David; Hasty, Karen; Gaber, M. Waleed; Stuart, John; Kang, Andrew; Myers, Linda.

In: Arthritis Research and Therapy, Vol. 12, No. 4, R136, 08.07.2010.

Research output: Contribution to journalArticle

Tang, Bo ; Cullins, David L. ; Zhou, Jing ; Zawaski, Janice A. ; Park, Hyelee ; Brand, David ; Hasty, Karen ; Gaber, M. Waleed ; Stuart, John ; Kang, Andrew ; Myers, Linda. / Modulation of collagen-induced arthritis by adenovirus-mediated intra-articular expression of modified collagen type II. In: Arthritis Research and Therapy. 2010 ; Vol. 12, No. 4.
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AU - Zhou, Jing

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AU - Park, Hyelee

AU - Brand, David

AU - Hasty, Karen

AU - Gaber, M. Waleed

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AU - Kang, Andrew

AU - Myers, Linda

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N2 - Introduction: 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.

AB - Introduction: 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.

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