title: Modulation of immune and inflammatory responses on experimental arthritis following intraarticular gene transfer of tumor necrosis factor receptor-immunoglobulin Fc.
abstract: In spite of popularity of TNF-α antagonist in the treatment of rheumatoid arthritis (RA), their modes of action are not fully understood. In the present study, we further explore the effects of gene transfer route of a TNF-α antagonist on arthritis. Recombinant adeno-associated virus 2 (rAAV2) encoding rat TNF receptor-immunoglobulin Fc (ratTNFR:Fc) fusion gene was injected intraarticularly in rats with collagen-induced arthritis (CIA). As revealed by examination of the clinical, radiographical, and histological aspects, local gene transfer of rAAV2/ratTNFR:Fc ameliorated the arthritis symptoms and inhibited the development of CIA. Compared with the vector control group, expressions of TNF-α, IL-1, and IFN-γ were down-regulated, and IL-10 release was up-regulated in the rAAV2/ratTNFR:Fc-treated group. Furthermore, administration of rAAV2/ratTNFR:Fc ameliorated the enlargement of spleen and significantly reduced spleen cell proliferation. Low level of nitric oxide (NO) in spleen was observed in CIA rats following the delivery of rAAV2/ratTNFR:Fc when compared to the vector control group. This study provides the evidence that intraarticular delivery of rAAV2/ratTNFR:Fc suppress the progression of arthritis by restoring the balance between pro-inflammatory and anti-inflammatory cytokines and inhibiting spleen cell proliferation. Our findings also implicate that the down-regulation of NO release on arthritis is involved in the anti-inflammatory mechanisms of TNF-α antagonist.
authors.affiliation: National Center for Safety Evaluation of Drugs, National Institute for the Control of Pharmaceutical and Biological Products, Hongda Middle Street A8, Beijing Economic and Technological Development Area, Beijing 100083, China.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Zhou
authors.forename: Kai
authors.initials: K
authors.lastname: Gao
authors.forename: Lianzhong
authors.initials: L
authors.lastname: Shen
authors.forename: Aizhi
authors.initials: A
authors.lastname: Zhao
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Wu
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Junzhi
authors.initials: J
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Li
mesh_terms: D056704:Adaptive Immunity / Q000502:physiology*; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D000068800:Etanercept; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000235:genetics* / Q000627:therapeutic use*; D007249:Inflammation / Q000503:physiopathology*; D007270:Injections, Intra-Articular; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000235:genetics* / Q000627:therapeutic use*; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D009569:Nitric Oxide; D000068800:Etanercept