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

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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.

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Acknowledgments

We would like to thank Hua Jiang, Peng Qian, Shuhui Lang, and Yanwei Yang for excellent technical assistant in animal assays and histological studies. This work was supported by the National Science & Technology Pillar Program (No: 2002AA2Z3421) and Scientific and Technological Major Special Project for. ‘‘Significant Creation of New Drugs’’ (No. 2008ZX09305-002) from the Ministry of Science and Technology, People’s Republic of China.

Conflict of interest

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. 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

    Xiaobing Zhou, Lianzhong Shen, Chao Wang, Junzhi Wang & Bo Li

  2. Division of Biopharmaceutics, National Institute for the Control of Pharmaceutical and Biological Products, Temple of Heaven, Beijing, 100050, China

    Kai Gao & Junzhi Wang

  3. AGTC Gene Technology Company Ltd, Beijing Economic and Technological Development Area, Yongchang Middle Street No.6, Beijing, 100176, China

    Aizhi Zhao & Xiaobing Wu

  4. National center for Safety Evaluation of Drugs, National Institute for the Control of Pharmaceutical and Biological Products, Beijing Economic and Technological Development Area, Hongda Middle Street A8, Beijing, 100176, China

    Bo Li

  5. National Institute for the Control of Pharmaceutical and Biological Products, Temple of Heaven, Beijing, 100050, People’s Republic of China

    Junzhi Wang

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  1. Xiaobing Zhou
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Correspondence to Junzhi Wang or Bo Li.

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The authors X. Zhou and K. Gao are contributed equally to this work.

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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)

Supplementary Fig 2

Immunohistochemical 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.

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Zhou, X., Gao, K., Shen, L. et al. Modulation of immune and inflammatory responses on experimental arthritis following intraarticular gene transfer of tumor necrosis factor receptor-immunoglobulin Fc. Rheumatol Int 32, 2605–2614 (2012). https://doi.org/10.1007/s00296-011-1974-z

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