Amelioration of rat collagen-induced arthritis through CD4+ T cells apoptosis and synovial interleukin-17 reduction by indoleamine 2,3-dioxygenase gene therapy.
Indoleamine 2,3-dioxygenase (IDO) has been known as an emerging therapeutic target in autoimmunity-related arthritis. The treatment responses of adenoviral vectors encoding IDO (AdIDO) gene therapy in rat collagen-induced arthritis (CIA) were examined in this study. The therapeutic effects on ankle circumference, articular index, and radiographic and histological scores were evaluated in AdIDO-injected ankle joints. We further determined CD4+ T-cell numbers and their apoptotic status, CD68(+) macrophage numbers, kynurenine (a downstream tryptophan metabolite) concentrations, interleukin-17 (IL-17) levels, and retinoic acid-related orphan receptor γt (RORγt) expression in synovial tissues of CIA rats receiving AdIDO treatment. Reduction of ankle circumference, articular index, and radiographic and histological scores were noted in AdIDO-treated ankles, as compared with those receiving injection of control vectors. Furthermore, IDO gene transfer led to decreased infiltrating CD4+ T cells with enhanced apoptosis, reduced CD68+ macrophage numbers, increased kynurenine levels, lower IL-17 concentrations, and decreased RORγt expression within the ankle joints. In addition, such a therapy diminished type II collagen-specific IL-17 production and RORγt expression in CD4+ T cells from draining lymph nodes of CIA rats. Our results demonstrate for the first time that intra-articular delivery of IDO gene ameliorated ankle arthritis of CIA rats by induction of CD4+ T-cell apoptosis and reduction of synovial IL-17 production through the supplement of kynurenine. Taken together, these findings implicate the novel strategy of using IDO gene as a therapeutic approach in treating patients with rheumatoid arthritis.
Chen
Shih-Yao
SY
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, No. 1 University Road, Tainan, Taiwan.
Wu
Chao-Liang
CL
Lai
Ming-Derg
MD
Lin
Chi-Chen
CC
Yo
Yi-Te
YT
Jou
I-Ming
IM
Lee
Che-Hsin
CH
Weng
Chia-Tse
CT
Shiau
Ai-Li
AL
Wang
Chrong-Reen
CR
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000843:Ankle Joint / Q000378:metabolism; D017209:Apoptosis; D001169:Arthritis, Experimental / Q000628:therapy*; D001172:Arthritis, Rheumatoid / Q000628:therapy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics* / Q000378:metabolism*; D020381:Interleukin-17 / Q000032:analysis*; D007737:Kynurenine / Q000032:analysis; D008264:Macrophages / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013583:Synovial Membrane / Q000378:metabolism; D014364:Tryptophan / Q000032:analysis
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D020381:Interleukin-17; D007737:Kynurenine; D014364:Tryptophan