Rheumatology International

, Volume 32, Issue 9, pp 2605–2614

Modulation of immune and inflammatory responses on experimental arthritis following intraarticular gene transfer of tumor necrosis factor receptor-immunoglobulin Fc

Original Article

DOI: 10.1007/s00296-011-1974-z

Cite this article as:
Zhou, X., Gao, K., Shen, L. et al. Rheumatol Int (2012) 32: 2605. doi:10.1007/s00296-011-1974-z

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.

Keywords

TNFRRheumatoid arthritisModulationInflammationGene therapyTNF-α

Supplementary material

296_2011_1974_MOESM1_ESM.ppt (52 kb)
Supplementary Fig 1 Expression and bioactivity of ratTNFR:Fc. (a). The supernatants of ratTNFR:Fc-transduced cells were collected, and TNF-α inhibition bioassay were performed to analyze the bioactivity of expressed fusion protein. (b). TNFR Level in the joint homogenates of rats (nonarthritic) injected intraarticularly with rAAV2/ratTNFR:Fc at different times. The rats of control group were injected with only PBS (n = 3 rats in each time point; ** p<0.01 versus the control group). (PPT 51 kb)
296_2011_1974_MOESM2_ESM.jpg (649 kb)
Supplementary Fig 2Immunohistochemical analysis of joint tissue of rats with collagen-induced arthritis (CIA) after rAAV2/ratTNFR:Fc gene transfer. At the termination of the experiments (days 35), ankle joints of rats were collected and embedded in paraffin wax. The section samples were immunostained using specific antibodies against rat IgG Fc and counterstained with Mayer’s hemalum. (a). Representative untreated joint showing normal architecture of joint. (b). Representative vector-treated joint section (c). rAAV2/ratTNFR:Fc-treated joint sections.

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Xiaobing Zhou
    • 1
  • Kai Gao
    • 2
  • Lianzhong Shen
    • 1
  • Aizhi Zhao
    • 3
  • Xiaobing Wu
    • 3
  • Chao Wang
    • 1
  • Junzhi Wang
    • 1
    • 2
    • 5
  • Bo Li
    • 1
    • 4
  1. 1.National Center for Safety Evaluation of DrugsNational Institute for the Control of Pharmaceutical and Biological ProductsBeijingChina
  2. 2.Division of BiopharmaceuticsNational Institute for the Control of Pharmaceutical and Biological ProductsBeijingChina
  3. 3.AGTC Gene Technology Company LtdBeijing Economic and Technological Development AreaBeijingChina
  4. 4.National center for Safety Evaluation of Drugs, National Institute for the Control of Pharmaceutical and Biological ProductsBeijing Economic and Technological Development AreaBeijingChina
  5. 5.National Institute for the Control of Pharmaceutical and Biological ProductsBeijingPeople’s Republic of China