caa a22 4500 605506523 CHVBK 20210128100627.0 cr unu---uuuuu 210128e20150801xx s 000 0 eng 10.1007/s00253-015-6459-7 doi (NATIONALLICENCE)springer-10.1007/s00253-015-6459-7 Combination therapy with TNFR-Fc and CTLA4-FasL using the recombinant adeno-associated virus potently suppresses adjuvant-induced arthritis in rats [Elektronische Daten] [Fang Wang, Jiyun Yu, Yu Wang, Yunbo Jiang, Ning Guo, Wei Zhang] The complexity of rheumatoid arthritis (RA) pathogenesis makes combined blockade of key pathogenic factors an attractive therapeutic strategy. We have previously reported a novel recombinant adeno-associated virus (AAV) vector, AAV.TFCF, which mediates separate coexpression of TNFα antagonist TNFR-Fc and T cell antagonist CTLA4-FasL both in vitro and in vivo (the injected joints). The purpose of this study was to examine the efficacy of TNFR-Fc/CTLA4-FasL combination therapy mediated by AAV.TFCF in experimental model of RA. Adjuvant-induced arthritis (AIA) was induced in Lewis rats, and the recombinant AAV.TFCF was injected into rat ankle joints. AAV vector encoding CTLA4-FasL (AAV.CTFA) or TNFR-Fc (AAV.TRFC) was used as the monotherapy control, and an AAV vector mediating the expression of enhanced green fluorescent protein (AAV.EGFP) was used as the negative control. The combination treatment mediated by AAV.TFCF demonstrated a more effective suppression of AIA compared with those monotherapy controls, as reflected in the clinical and histological observations. The synergistic anti-inflammatory effect of TNFR-Fc combining with CTLA4-FasL was proved to be associated with the greater reductions of inflammatory CD4+ T cell infiltration and proinflammatory cytokine TNFα level in the arthritic joints. In addition, the combination therapy was found to be able to increase the frequency of CD4 + CD25 + FoxP3+ regulatory T cell population in rat draining lymph nodes and suppress splenic inflammatory responses. These results suggest that combination treatment with TNFR-Fc and CTLA4-FasL may achieve superior efficacy in suppressing RA, and using this novel recombinant AAV.TFCF to obtain the combined counteraction of both pathogenic T cells and the key proinflammatory cytokine TNFα may provide a more effective and desirable strategy for treatment of RA. Springer-Verlag Berlin Heidelberg, 2015 Rheumatoid arthritis nationallicence Combination therapy nationallicence CTLA4-FasL nationallicence TNFR-Fc nationallicence Wang Fang Department of Translational Medicine, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, 100850, Beijing, China aut Yu Jiyun Department of Translational Medicine, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, 100850, Beijing, China aut Wang Yu Department of Translational Medicine, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, 100850, Beijing, China aut Jiang Yunbo Department of Translational Medicine, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, 100850, Beijing, China aut Guo Ning Department of Translational Medicine, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, 100850, Beijing, China aut Zhang Wei Department of Translational Medicine, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, 100850, Beijing, China aut Applied Microbiology and Biotechnology Springer Berlin Heidelberg 99/15(2015-08-01), 6327-6337 0175-7598 99:15<6327 2015 99 253 https://doi.org/10.1007/s00253-015-6459-7 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00253-015-6459-7 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Wang Fang Department of Translational Medicine, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, 100850, Beijing, China aut NATIONALLICENCE 700 1- Yu Jiyun Department of Translational Medicine, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, 100850, Beijing, China aut NATIONALLICENCE 700 1- Wang Yu Department of Translational Medicine, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, 100850, Beijing, China aut NATIONALLICENCE 700 1- Jiang Yunbo Department of Translational Medicine, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, 100850, Beijing, China aut NATIONALLICENCE 700 1- Guo Ning Department of Translational Medicine, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, 100850, Beijing, China aut NATIONALLICENCE 700 1- Zhang Wei Department of Translational Medicine, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, 100850, Beijing, China aut NATIONALLICENCE 773 0- Applied Microbiology and Biotechnology Springer Berlin Heidelberg 99/15(2015-08-01), 6327-6337 0175-7598 99:15<6327 2015 99 253