title: Interleukin-35 gene therapy exacerbates experimental rheumatoid arthritis in mice.
abstract: Interleukin (IL)-35 was initially described as an immunosuppressive cytokine specifically produced by CD4(+)FoxP3(+) regulatory T cells (Treg). Since Treg play a major role in autoimmunity control and protect from inflammation, we aimed at evaluating the role of IL-35 in collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA), using a non-viral gene transfer strategy. The clinical and histological effect of IL-35 was assessed in mice with CIA receiving an injection of two distinct plasmids encoding IL-35 gene (pIGneo-mIL-35 or pORF-mIL-35) 3 and 18 days after CIA induction. Treg and Th17 were characterized by flow cytometry in the spleen and lymph nodes of treated mice. Our results showed that whatever the plasmid used, IL-35 gene transfer resulted in a statistically significant increase in clinical scores of CIA compared to results with empty plasmid. The underlying cellular mechanisms of this effect were shown to be related to an increased Th17/Treg ratio in the spleen of pORF-mIL-35 treated mice. In conclusion, we show an unexpected but clear exacerbating effect of IL-35 gene transfer in an autoimmune and inflammatory RA model, associated with a modification of the Th17/Treg balance. Altogether, these result shows that this cytokine can promote chronic inflammation.
authors.affiliation: INSERM, U1125, F-93017 Bobigny, France; Sorbonne Paris Cité Université Paris 13, F-93017 Bobigny, France.
authors.forename: A
authors.initials: A
authors.lastname: Thiolat
authors.affiliation: INSERM, U1125, F-93017 Bobigny, France; Sorbonne Paris Cité Université Paris 13, F-93017 Bobigny, France.
authors.forename: A
authors.initials: A
authors.lastname: Denys
authors.affiliation: INSERM, U1125, F-93017 Bobigny, France; Sorbonne Paris Cité Université Paris 13, F-93017 Bobigny, France.
authors.forename: M
authors.initials: M
authors.lastname: Petit
authors.affiliation: INSERM, U1125, F-93017 Bobigny, France; Sorbonne Paris Cité Université Paris 13, F-93017 Bobigny, France.
authors.forename: J
authors.initials: J
authors.lastname: Biton
authors.affiliation: INSERM, U1125, F-93017 Bobigny, France; Sorbonne Paris Cité Université Paris 13, F-93017 Bobigny, France.
authors.forename: D
authors.initials: D
authors.lastname: Lemeiter
authors.affiliation: INSERM, U1125, F-93017 Bobigny, France; Sorbonne Paris Cité Université Paris 13, F-93017 Bobigny, France.
authors.forename: R
authors.initials: R
authors.lastname: Herve
authors.affiliation: UMR 7244, Paris 13 University, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93000 Bobigny, France.
authors.forename: D
authors.initials: D
authors.lastname: Lutomski
authors.affiliation: INSERM, U1125, F-93017 Bobigny, France; Sorbonne Paris Cité Université Paris 13, F-93017 Bobigny, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Avicenne Hospital, Rheumatology Dpt, F-93009 Bobigny, France.
authors.forename: M-C
authors.initials: MC
authors.lastname: Boissier
authors.affiliation: INSERM, U1125, F-93017 Bobigny, France; Sorbonne Paris Cité Université Paris 13, F-93017 Bobigny, France. Electronic address: natacha.bessis@univ-paris13.fr.
authors.forename: N
authors.initials: N
authors.lastname: Bessis
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology*; D003094:Collagen; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D007249:Inflammation / Q000235:genetics* / Q000276:immunology; D007378:Interleukins / Q000235:genetics*; D019041:L-Selectin / Q000096:biosynthesis; D051379:Mice; D008811:Mice, Inbred DBA; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology
chemical_list: D007378:Interleukins; C569375:interleukin-35, mouse; D019041:L-Selectin; D003094:Collagen
keywords: Gene therapy; Interleukin-35; Regulatory T cells; Rheumatoid arthritis