Abstract
Collagen-induced arthritis (CIA) is an experimental model of arthritis widely used to dissect the pathogenesis of human rheumatoid arthritis and to identify potential therapeutic targets. Among these, TNF-alpha has been recognized to play an important role. Here we investigate the feasibility and therapeutic efficacy of prolonged blockade of TNF-alpha activity through the adenovirus-mediated gene delivery of a dimeric chimeric human p55 TNFR-IgG fusion protein and compare it to protein therapy in established CIA. A single i.v. administration of the replication-deficient adenovirus yielded microgram serum levels of the chimeric fusion protein and ameliorated CIA for 10 days. Subsequently, benefit was lost and a rebound to greater inflammatory activity was observed despite the continual presence of bioactive TNFR fusion protein. A similar trend was also observed in mice injected directly with comparable amounts of a human TNFR-IgG fusion protein, whereas the administration of a control adenovirus-encoding beta-galactosidase or of a control human IgG1 protein did not significantly affect the disease course. The mechanisms of the rebound of CIA were investigated, and augmented Ab response to collagen type II and TNFR were identified as potential causes. Our results confirm the feasibility of adenovirus-mediated gene delivery of cytokine inhibitors in animal models of autoimmune diseases for investigational purposes and highlight the importance of prolonged studies. Further investigations are needed to optimize ways of exploiting the potential of adenoviral gene therapy in RA.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Abatacept
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Adenoviruses, Human / genetics
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Adenoviruses, Human / immunology*
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Animals
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Antibodies, Monoclonal / pharmacology
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Antigens, CD / administration & dosage
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Antigens, CD / genetics
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Antigens, CD / therapeutic use
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Antigens, Differentiation / administration & dosage
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Antigens, Differentiation / therapeutic use
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Arthritis, Experimental / genetics
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Arthritis, Experimental / immunology*
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Arthritis, Experimental / pathology
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Arthritis, Experimental / prevention & control
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CTLA-4 Antigen
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Cell Line
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Collagen / immunology*
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Gene Transfer Techniques
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Humans
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Immunoconjugates*
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Immunoglobulin G / biosynthesis
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Immunoglobulin Isotypes / biosynthesis
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Immunosuppressive Agents / administration & dosage
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Immunosuppressive Agents / therapeutic use
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Injections, Intravenous
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Joints / pathology
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology
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Male
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Mice
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Mice, Inbred DBA
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Receptors, Tumor Necrosis Factor / administration & dosage
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / therapeutic use
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Receptors, Tumor Necrosis Factor, Type I
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Recombinant Fusion Proteins / administration & dosage
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / pharmacology
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Solubility
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Time Factors
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Tumor Necrosis Factor-alpha / antagonists & inhibitors*
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / immunology
Substances
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Antibodies, Monoclonal
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Antigens, CD
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Antigens, Differentiation
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CTLA-4 Antigen
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CTLA4 protein, human
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Ctla4 protein, mouse
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Immunoconjugates
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Immunoglobulin G
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Immunoglobulin Isotypes
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Immunosuppressive Agents
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Type I
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Recombinant Fusion Proteins
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Tumor Necrosis Factor-alpha
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Abatacept
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Collagen