類風濕性關節炎 (rheumatoid arthritis, RA)是一種複雜且病因不明的人類自體免疫疾病。目前為人所認知RA的可能致病原因包含T細胞依賴與獨立的路徑 (T cell-dependent and independent pathway)，而所牽涉的即是T細胞與滑膜細胞 (synoviocyte)在RA發病過程所可能扮演的調控角色。根據T細胞理論，活化的CD4+ T浸潤至關節內藉由釋放干擾素γ (interferon-γ，IFN-γ)或介白素17號 (interleukin-17，IL-17)促進滑膜細胞表現促發炎細胞素 (pro-inflammatory cytokine)如腫瘤壞死因子α(tumor necrosis factor α)、介白素1號β(interleukin-1β, IL-1β)與介白素6號 (interleukin-6, IL-6)促進關節發炎; 反之，T細胞獨立的理論則認為滑膜細胞如巨噬細胞 (macrophage)或滑膜纖維母細胞 (synovial fibroblast, SF)才是促成慢性關節發炎的主要細胞，T細胞的浸潤只是滑膜細胞主導發炎反應中的一個現象而已。在本次的研究中我們設計特異性促進T細胞與SF死亡的策略來探討未來可能的治療方向。針對T細胞依賴的路徑我們利用腺病毒載體攜帶吲哚胺2,3雙加氧酶 (indoleamine 2,3-dioxygenase, IDO)，此病毒載體命名為AdIDO，並將其以關節內注射的方式打進膠原蛋白誘發關節炎(collagen-induced arthritis, CIA)大鼠踝關節內並發現能藉由控制色胺酸 (tryptophan)代謝路徑促進CD4+ T細胞進行細胞凋亡與降低retinoic acid related orphan receptorγt (RORγt)與IL-17的表現而減緩關節炎的症狀; 然而，在T細胞獨立的路徑我們則是利用一隻端粒酶所調控的E1B-55-kd缺失的條件性複製腺病毒 (telomerase-dependent E1B-55-kd-deleted conditionally replicating adenovirus)，命名為Ad.GS1，來治療大鼠關節炎。Ad.GS1能選擇性地在大鼠SF細胞中進行複製並促進其細胞溶解，對於免疫細胞與正常細胞則沒有毒殺能力。這樣的治療方式能降低CIA大鼠關節內纖維母細胞所表現的酵素prolyl 4-hydroxylase (P4H)，抑制發炎細胞素IL-1β與基質金屬蛋白酶9號 (matrix metalloproteinase 9, MMP-9)的量來達到治療大鼠關節炎的目的。雖然我們在目前的研究中仍無法歸納出T細胞依賴或獨立路徑中的任何一個所可能扮演在RA致病機轉的角色，本研究卻提供了兩個未來對於RA治療的新穎方向: 一是藉由調控色胺酸代謝路徑促進CD4+T細胞凋亡與降低IL-17的量; 二是利用條件性複製腺病毒特異性毒殺SF以抑制IL-1β與MMP-9表現來避免骨頭的破壞而達到治療RA的目的。

Rheumatoid arthritis (RA) is a complex, human autoimmune disease with unknown etiology. According to current knowledge, two possible pathogenic mechanisms, T cell dependent and independent pathways are involved in RA. In T cell theory, activated CD4+ T cells infiltrate into rheumatoid joints and release interferon-γ(IFN-γ) or interleukin-17 (IL-17) to trigger synoviocytes expressing pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin-1β(IL-1β) or interleukin-6 (IL-6). In contrast, non-T cell theory describes that synoviocytes, such as macrophages and synovial firoblasts (SFs) play important roles in regulating chronic joint inflammation process. The phenomenon of T cell infiltration is more than a by-pass effect. Therefore in this study, we designed two therapeutic strategies through specifically targeting T cells and SFs. Toward the T cell mechanism, we constructed an adenoviral vector expressing indoleamine 2,3-dioxygenase (IDO), designated AdIDO, to treat rats with collagen-induced arthritis (CIA). We found that after injection of AdIDO into ankle joints of the arthritic rats, IDO regulated tryptophan-metabolism pathway to induce CD4+ T apoptosis and downregulated the expression of retinoic acid related orphan receptorγt (RORγt) and IL-17. However, in the T cell-independent theory, we used a telomerase-dependent E1B-55-kd-deleted conditionally replicating adenovirus, designated Ad.GS1, to selectively induce SF cytolysis but spare immune or normal cells, to treat rat CIA. Intraarticular administration of Ad.GS1 decreased the production of prolyl 4-hydroxylase (P4H), IL-1β, and matrix metalloproteinase 9 (MMP-9) in rats with CIA. Although our present studies can’t conclude whether T cell dependent or independent pathway is involved in the pathogenic mechanism of RA, we provide two potential therapeutic strategies for RA: one is by regulating tryptophan-metabolism pathway to trigger CD4+ T apoptosis and IL-17 reduction; the other is through ultilizing conditionally replicating adenovirus to selectively induce SF cytolysis and inhibit the production of IL-1βand MMP-9.

Altomare,D.A. and Testa,J.R. (2005). Perturbations of the AKT signaling pathway in human cancer. Oncogene 24, 7455-7464.
Annunziato,F., Cosmi,L., Liotta,F., Maggi,E., and Romagnani,S. (2009). Type 17 T helper cells-origins, features and possible roles in rheumatic disease. Nat. Rev. Rheumatol. 5, 325-331.
Auckland,G. (1969). Psoriasis and arthritis: treatment with low tryptophan diet. Br. J. Dermatol. 81, 388-389.
Bakker,A.C., Van de Loo,F.A., Joosten,L.A., Bennink,M.B., Arntz,O.J., Dmitriev,I.P., Kashentsera,E.A., Curiel,D.T., and van den Berg,W.B. (2001). A tropism-modified adenoviral vector increased the effectiveness of gene therapy for arthritis. Gene Ther. 8, 1785-1793.
Bhattacharya,R., Mukherjee,P., Xiong,Z., Atala,A., Soker,S., and Mukhopadhyay,D. (2004). Gold nanoparticles inhibit VEGF165-induced proliferation of HUVEC cells. Nano Lett. 4, 2479-2481.
Bianco,N.R., Kim,S.H., Ruffner,M.A., and Robbins,P.D. (2009). Therapeutic effect of exosomes from indoleamine 2,3-dioxygenase-positive dendritic cells in collagen-induced arthritis and delayed-type hypersensitivity disease models. Arthritis Rheum. 60, 380-389.
Bischoff,J.R., Kirn,D.H., Williams,A., Heise,C., Horn,S., Muna,M., Ng,L., Nye,J.A., Sampson-Johannes,A., Fattaey,A., and McCormick,F. (1996). An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 274, 373-376.
Cattaneo,R., Miest,T., Shashkova,E.V., and Barry,M.A. (2008). Reprogrammed viruses as cancer therapeutics: targeted, armed and shielded. Nat. Rev. Microbiol. 6, 529-540.
Chabaud,M., Durand,J.M., Buchs,N., Fossiez,F., Page,G., Frappart,L., and Miossec,P. (1999). Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum. 42, 963-970.
Courtenay,J.S., Dallman,M.J., Dayan,A.D., Martin,A., and Mosedale,B. (1980). Immunisation against heterologous type II collagen induces arthritis in mice. Nature 283, 666-668.
Coyne,C.B. and Bergelson,J.M. (2005). CAR: a virus receptor within the tight junction. Adv. Drug Deliv. Rev. 57, 869-882.
Criado,G., Simelyte,E., Inglis,J.J., Essex,D., and Williams,R.O. (2009). Indoleamine 2,3 dioxygenase-mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen-induced arthritis. Arthritis Rheum. 60, 1342-1351.
Dooley,S., Herlitzka,I., Hanselmann,R., Ermis,A., Henn,W., Remberger,K., Hopf,T., and Welter,C. (1996). Constitutive expression of c-fos and c-jun, overexpression of ets-2, and reduced expression of metastasis suppressor gene nm23-H1 in rheumatoid arthritis. Ann. Rheum. Dis. 55, 298-304.
Fava,R.A., Olsen,N.J., Spencer-Green,G., Yeo,K.T., Yeo,T.K., Berse,B., Jackman,R.W., Senger,D.R., Dvorak,H.F., and Brown,L.F. (1994). Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue. J. Exp. Med. 180, 341-346.
Firestein,G.S. (2003). Evolving concepts of rheumatoid arthritis. Nature 423, 356-361.
Firestein,G.S. (2007). Biomedicine. Every joint has a silver lining. Science 315, 952-953.
Firestein,G.S., Echeverri,F., Yeo,M., Zvaifler,N.J., and Green,D.R. (1997). Somatic mutations in the p53 tumor suppressor gene in rheumatoid arthritis synovium. Proc. Natl. Acad. Sci. U. S. A 94, 10895-10900.
Firestein,G.S., Nguyen,K., Aupperle,K.R., Yeo,M., Boyle,D.L., and Zvaifler,N.J. (1996). Apoptosis in rheumatoid arthritis: p53 overexpression in rheumatoid arthritis synovium. Am. J. Pathol. 149, 2143-2151.
Firestein,G.S. and Zvaifler,N.J. (2002). How important are T cells in chronic rheumatoid synovitis?: II. T cell-independent mechanisms from beginning to end. Arthritis Rheum. 46, 298-308.
Firestein,G.S. and Zvaifler,N.J. (1990). How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum. 33, 768-773.
Fox,D.A. (1997). The role of T cells in the immunopathogenesis of rheumatoid arthritis: new perspectives. Arthritis Rheum. 40, 598-609.
Furuzawa-Carballeda,J., Vargas-Rojas,M.I., and Cabral,A.R. (2007). Autoimmune inflammation from the Th17 perspective. Autoimmun. Rev. 6, 169-175.
Goossens,P.H., Schouten,G.J., 't Hart,B.A., Bout,A., Brok,H.P., Kluin,P.M., Breedveld,F.C., Valerio,D., and Huizinga,T.W. (1999). Feasibility of adenovirus-mediated nonsurgical synovectomy in collagen-induced arthritis-affected rhesus monkeys. Hum. Gene Ther. 10, 1139-1149.
Gregersen,P.K., Silver,J., and Winchester,R.J. (1987). The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 30, 1205-1213.
Grohmann,U., Orabona,C., Fallarino,F., Vacca,C., Calcinaro,F., Falorni,A., Candeloro,P., Belladonna,M.L., Bianchi,R., Fioretti,M.C., and Puccetti,P. (2002). CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat. Immunol. 3, 1097-1101.
Houpt,J.B., Ogryzlo,M.A., and Hunt,M. (1973). Tryptophan metabolism in man (with special reference to rheumatoid arthritis and scleroderma). Semin. Arthritis Rheum. 2, 333-353.
Hoyhtya,M., Myllyla,R., Piuva,J., Kivirikko,K.I., and Tryggvason,K. (1984). Monoclonal antibodies to human prolyl 4-hydroxylase. Eur. J. Biochem. 141, 472-482.

Hwu,P., Du,M.X., Lapointe,R., Do,M., Taylor,M.W., and Young,H.A. (2000). Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation. J. Immunol. 164, 3596-3599.
Ivanov,S. and Linden,A. (2009). Interleukin-17 as a drug target in human disease. Trends Pharmacol. Sci. 30, 95-103.
Izcue,A., Coombes,J.L., and Powrie,F. (2009). Regulatory lymphocytes and intestinal inflammation. Annu. Rev. Immunol. 27, 313-338.
Janossy,G., Panayi,G., Duke,O., Bofill,M., Poulter,L.W., and Goldstein,G. (1981). Rheumatoid arthritis: a disease of T-lymphocyte/macrophage immunoregulation. Lancet 2, 839-842.
Jimenez,B., Volpert,O.V., Crawford,S.E., Febbraio,M., Silverstein,R.L., and Bouck,N. (2000). Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat. Med. 6, 41-48.
Jou,I.M., Shiau,A.L., Chen,S.Y., Wang,C.R., Shieh,D.B., Tsai,C.S., and Wu,C.L. (2005). Thrombospondin 1 as an effective gene therapeutic strategy in collagen-induced arthritis. Arthritis Rheum. 52, 339-344.
Kiener,H.P., Niederreiter,B., Lee,D.M., Jimenez-Boj,E., Smolen,J.S., and Brenner,M.B. (2009). Cadherin 11 promotes invasive behavior of fibroblast-like synoviocytes. Arthritis Rheum. 60, 1305-1310.
Kirn,D. (2000). Replication-selective oncolytic adenoviruses: virotherapy aimed at genetic targets in cancer. Oncogene 19, 6660-6669.
Klareskog,L., Catrina,A.I., and paget, S. (2009). Rheumatoid arthritis. Lancet. 373, 659-672.
Koch,A.E. (2003). Angiogenesis as a target in rheumatoid arthritis. Ann. Rheum. Dis. 62 Suppl 2, ii60-ii67.
Koch,A.E., Harlow,L.A., Haines,G.K., Amento,E.P., Unemori,E.N., Wong,W.L., Pope,R.M., and Ferrara,N. (1994). Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J. Immunol. 152, 4149-4156.
Kontny,E., Ziolkowska,M., Dudzinka,E., Filipowicz-Sosnowska,A., and Ryzewska,A. (1995). Modified expression of c-Fos and c-Jun proteins and production of interleukin-1 beta in patients with rheumatoid arthritis. Clin. Exp. Rheumatol. 13, 51-57.
Kullmann,F., Judex,M., Neudecker,I., Lechner,S., Justen,H.P., Green,D.R., Wessinghage,D., Firestein,G.S., Gay,S., Scholmerich,J., and Muller-Ladner,U. (1999). Analysis of the p53 tumor suppressor gene in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 42, 1594-1600.
Lafyatis,R., Remmers,E.F., Roberts,A.B., Yocum,D.E., Sporn,M.B., and Wilder,R.L. (1989). Anchorage-independent growth of synoviocytes from arthritic and normal joints. Stimulation by exogenous platelet-derived growth factor and inhibition by transforming growth factor-beta and retinoids. J. Clin. Invest 83, 1267-1276.
Lee,D.M., Kiener,H.P., Agarwal,S.K., Noss,E.H., Watts,G.F., Chisaka,O., Takeichi,M., and Brenner,M.B. (2007). Cadherin-11 in synovial lining formation and pathology in arthritis. Science 315, 1006-1010.
Lemmel,E.M., Franke,M., Gaus,W., Hartl,P.W., Hofschneider,P.H., Miehlke,K., Machalke,K., and Obert,H.J. (1987). Results of a phase-II clinical trial on treatment of rheumatoid arthritis with recombinant interferon-gamma. Rheumatol. Int. 7, 127-132
Leung,P.S., Dhirapong,A., Wu,P.Y., and Tao,M.H. (2009). Gene therapy in autoimmune diseases: Challenges and opportunities. Autoimmun. Rev. 9, 170-174.
Li,N.L., Zhang,D.Q., Zhou,K.Y., Cartman,A., Leroux,J.Y., Poole,A.R., and Zhang,Y.P. (2000). Isolation and characteristics of autoreactive T cells specific to aggrecan G1 domain from rheumatoid arthritis patients. Cell Res. 10, 39-49.
Li,Y., Tredget,E.E., Ghaffari,A., Lin,X., Kilani,R.T., and Ghahary,A. (2006). Local expression of indoleamine 2,3-dioxygenase protects engraftment of xenogeneic skin substitute. J. Invest Dermatol. 126, 128-136.
Lu,J., Kasama,T., Kobayashi,K., Yoda,Y., Shiozawa,F., Hanyuda,M., Negishi,M., Ide,H., and Adachi,M. (2000). Vascular endothelial growth factor expression and regulation of murine collagen-induced arthritis. J. Immunol. 164, 5922-5927.
Luross,J.A. and Williams,N.A. (2001). The genetic and immunopathological processes underlying collagen-induced arthritis. Immunology 103, 407-416.
Marinova-Mutafchieva,L., Williams,R.O., Mason,L.J., Mauri,C., Feldmann,M., and Maini,R.N. (1997). Dynamics of proinflammatory cytokine expression in the joints of mice with collagen-induced arthritis (CIA). Clin. Exp. Immunol. 107, 507-512.
Matin,A., Streete,I.M., Jamie,I.M., Truscott,R.J., and Jamie,J.F. (2006). A fluorescence-based assay for indoleamine 2,3-dioxygenase. Anal. Biochem. 349, 96-102.
Mauri,C., Williams,R.O., Walmsley,M., and Feldmann,M. (1996). Relationship between Th1/Th2 cytokine patterns and the arthritogenic response in collagen-induced arthritis. Eur. J. Immunol. 26, 1511-1518.
McConnell,M.J. and Imperiale,M.J. (2004). Biology of adenovirus and its use as a vector for gene therapy. Hum. Gene Ther. 15, 1022-1033.
Mease,P.J., Hobbs,K., Chalmers,A., El-Gabalawy,H., Bookman,A., Keystone,E., Furst,D.E., Anklesaria,P., and Heald,A.E. (2009). Local delivery of a recombinant adenoassociated vector containing a tumour necrosis factor alpha antagonist gene in inflammatory arthritis: a phase 1 dose-escalation safety and tolerability study. Ann. Rheum. Dis. 68, 1247-1254.
Miao,R.Q., Agata,J., Chao,L., and Chao,J. (2002). Kallistatin is a new inhibitor of angiogenesis and tumor growth. Blood 100, 3245-3252.
Miossec,P. (2007). Interleukin-17 in fashion, at last: ten years after its description, its cellular source has been identified. Arthritis Rheum. 56, 2111-2115.
Muller-Ladner,U., Kriegsmann,J., Franklin,B.N., Matsumoto,S., Geiler,T., Gay,R.E., and Gay,S. (1996). Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am. J. Pathol. 149, 1607-1615.
Mulley,W.R. and Nikolic-Paterson,D.J. (2008). Indoleamine 2,3-dioxygenase in transplantation. Nephrology. (Carlton. ) 13, 204-211.
Munn,D.H., Shafizadeh,E., Attwood,J.T., Bondarev,I., Pashine,A., and Mellor,A.L. (1999). Inhibition of T cell proliferation by macrophage tryptophan catabolism. J. Exp. Med. 189, 1363-1372.
Munn,D.H., Zhou,M., Attwood,J.T., Bondarev,I., Conway,S.J., Marshall,B., Brown,C., and Mellor,A.L. (1998). Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281, 1191-1193.
Munz,C., Lunemann,J.D., Getts,M.T., and Miller,S.D. (2009). Antiviral immune responses: triggers of or triggered by autoimmunity? Nat. Rev. Immunol. 9, 246-258.
Nonomura,Y., Kohsaka,H., Nasu,K., Terada,Y., Ikeda,M., and Miyasaka,N. (2001). Suppression of arthritis by forced expression of cyclin-dependent kinase inhibitor p21(Cip1) gene into the joints. Int. Immunol. 13, 723-731.
O'Shea,C.C., Johnson,L., Bagus,B., Choi,S., Nicholas,C., Shen,A., Boyle,L., Pandey,K., Soria,C., Kunich,J., Shen,Y., Habets,G., Ginzinger,D., and McCormick,F. (2004). Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity. Cancer Cell 6, 611-623.
Oda,A., Miyata,M., Kodama,E., Satoh,H., Sato,Y., Nishimaki,T., Nomaguchi,H., and Kasukawa,R. (1994). Antibodies to 65Kd heat-shock protein were elevated in rheumatoid arthritis. Clin. Rheumatol. 13, 261-264.
Okamoto,K., Asahara,H., Kobayashi,T., Matsuno,H., Hasunuma,T., Kobata,T., Sumida,T., and Nishioka,K. (1998). Induction of apoptosis in the rheumatoid synovium by Fas ligand gene transfer. Gene Ther. 5, 331-338.
Olsen,N.J. and Stein,C.M. (2004). New drugs for rheumatoid arthritis. N. Engl. J. Med. 350, 2167-2179.
Panayi,G.S., Lanchbury,J.S., and Kingsley,G.H. (1992). The importance of the T cell in initiating and maintaining the chronic synovitis of rheumatoid arthritis. Arthritis Rheum. 35, 729-735.
Pap,T., Aupperle,K.R., Gay,S., Firestein,G.S., and Gay,R.E. (2001). Invasiveness of synovial fibroblasts is regulated by p53 in the SCID mouse in vivo model of cartilage invasion. Arthritis Rheum. 44, 676-681.
Pap,T., Franz,J.K., Hummel,K.M., Jeisy,E., Gay,R., and Gay,S. (2000). Activation of synovial fibroblasts in rheumatoid arthritis: lack of Expression of the tumour suppressor PTEN at sites of invasive growth and destruction. Arthritis Res. 2, 59-64.
Park,M.J., Min,S.Y., Park,K.S., Cho,Y.G., Cho,M.L., Jung,Y.O., Park,H.S., Chang,S.H., Cho,S.G., Min,J.K., Park,S.H., and Kim,H.Y. (2008). Indoleamine 2,3-dioxygenase-expressing dendritic cells are involved in the generation of CD4+CD25+ regulatory T cells in Peyer's patches in an orally tolerized, collagen-induced arthritis mouse model. Arthritis Res. Ther. 10, R11.
Rowley,M., Tait,B., Mackay,I.R., Cunningham,T., and Phillips,B. (1986). Collagen antibodies in rheumatoid arthritis. Significance of antibodies to denatured collagen and their association with HLA-DR4. Arthritis Rheum. 29, 174-184.
Salvador,G., Sanmarti,R., Garcia-Peiro,A., Rodriguez-Cros,J.R., Munoz-Gomez,J., and Canete,J.D. (2005). p53 expression in rheumatoid and psoriatic arthritis synovial tissue and association with joint damage. Ann. Rheum. Dis. 64, 183-187.
Sant,S.M., Suarez,T.M., Moalli,M.R., Wu,B.Y., Blaivas,M., Laing,T.J., and Roessler,B.J. (1998). Molecular lysis of synovial lining cells by in vivo herpes simplex virus-thymidine kinase gene transfer. Hum. Gene Ther. 9, 2735-2743.
Schroecksnadel,K., Kaser,S., Ledochowski,M., Neurauter,G., Mur,E., Herold,M., and Fuchs,D. (2003). Increased degradation of tryptophan in blood of patients with rheumatoid arthritis. J. Rheumatol. 30, 1935-1939.
Shahrara,S., Huang,Q., Mandelin,A.M., and Pope,R.M. (2008). TH-17 cells in rheumatoid arthritis. Arthritis Res. Ther. 10, R93.
Shiau,A.L., Chen,S.Y., Chang,M.Y., Su,C.H., Chung,S.Y., Yo,Y.T., Wang,C.R., and Wu,C.L. (2007). Prothymosin alpha lacking the nuclear localization signal as an effective gene therapeutic strategy in collagen-induced arthritis. J. Immunol. 178, 4688-4694.
Shieh,G.S., Shiau,A.L., Yo,Y.T., Lin,P.R., Chang,C.C., Tzai,T.S., and Wu,C.L. (2006). Low-dose etoposide enhances telomerase-dependent adenovirus-mediated cytosine deaminase gene therapy through augmentation of adenoviral infection and transgene expression in a syngeneic bladder tumor model. Cancer Res. 66, 9957-9966.
Smolen,J.S. and Steiner,G. (2003). Therapeutic strategies for rheumatoid arthritis. Nat. Rev. Drug Discov. 2, 473-488.
Stastny,P. (1976). Mixed lymphocyte cultures in rheumatoid arthritis. J. Clin. Invest 57, 1148-1157.
Stuart,J.M., Townes,A.S., and Kang,A.H. (1985). Type II collagen-induced arthritis. Ann. N. Y. Acad. Sci. 460, 355-362.
Szanto,S., Koreny,T., Mikecz,K., Glant,T.T., Szekanecz,Z., and Varga,J. (2007). Inhibition of indoleamine 2,3-dioxygenase-mediated tryptophan catabolism accelerates collagen-induced arthritis in mice. Arthritis Res. Ther. 9, R50.
Tak,P.P., Smeets,T.J., Boyle,D.L., Kraan,M.C., Shi,Y., Zhuang,S., Zvaifler,N.J., Breedveld,F.C., and Firestein,G.S. (1999). p53 overexpression in synovial tissue from patients with early and longstanding rheumatoid arthritis compared with patients with reactive arthritis and osteoarthritis. Arthritis Rheum. 42, 948-953.
Taniguchi,K., Kohsaka,H., Inoue,N., Terada,Y., Ito,H., Hirokawa,K., and Miyasaka,N. (1999). Induction of the p16INK4a senescence gene as a new therapeutic strategy for the treatment of rheumatoid arthritis. Nat. Med. 5, 760-767.
Thomaidis,T., Schorn,C., Flaig,W., Lingg,G., Schonhals,E., Klingel,R., Galle,P.R., and Schwarting,A. (2009). Immunoadsorption with tryptophan columns: a therapeutic option for the treatment of rheumatoid arthritis with septic complications. J. Clin. Apher. 24, 37-41.
Traister,R.S. and Hirsch,R. (2008). Gene therapy for arthritis. Mod. Rheumatol. 18, 2-14.
Trentham,D.E., Townes,A.S., and Kang,A.H. (1977). Autoimmunity to type II collagen an experimental model of arthritis. J. Exp. Med. 146, 857-868.
Tsai,C.Y., Shiau,A.L., Chen,S.Y., Chen,Y.H., Cheng,P.C., Chang,M.Y., Chen,D.H., Chou,C.H., Wang,C.R., and Wu,C.L. (2007). Amelioration of collagen-induced arthritis in rats by nanogold. Arthritis Rheum. 56, 544-554.
Tsumuki,H., Hasunuma,T., Kobata,T., Kato,T., Uchida,A., and Nishioka,K. (2000). Basic FGF-induced activation of telomerase in rheumatoid synoviocytes. Rheumatol. Int. 19, 123-128.
Van Boxel,J.A. and Paget,S.A. (1975). Predominantly T-cell infiltrate in rheumatoid synovial membranes. N. Engl. J. Med. 293, 517-520.
Verheijden,G.F., Rijnders,A.W., Bos,E., Coenen-de Roo,C.J., van Staveren,C.J., Miltenburg,A.M., Meijerink,J.H., Elewaut,D., de,K.F., Veys,E., and Boots,A.M. (1997). Human cartilage glycoprotein-39 as a candidate autoantigen in rheumatoid arthritis. Arthritis Rheum. 40, 1115-1125.
Vermeire,K., Heremans,H., Vandeputte,M., Huang,S., Billiau,A., and Matthys,P. (1997). Accelerated collagen-induced arthritis in IFN-gamma receptor-deficient mice. J. Immunol. 158, 5507-5513.
Wang,C.R., Chen,S.Y., Wu,C.L., Liu,M.F., Jin,Y.T., Chao,L., and Chao,J. (2005). Prophylactic adenovirus-mediated human kallistatin gene therapy suppresses rat arthritis by inhibiting angiogenesis and inflammation. Arthritis Rheum. 52, 1319-1324.
Wang,C.R., Shiau,A.L., Chen,S.Y., Lin,L.L., Tai,M.H., Shieh,G.S., Lin,P.R., Yo,Y.T., Lee,C.H., Kuo,S.M., Liu,M.F., Jou,I.M., Yang,C.Y., Shen,P.C., Lee,H.L., and Wu,C.L. (2008). Amelioration of collagen-induced arthritis in rats by adenovirus-mediated PTEN gene transfer. Arthritis Rheum. 58, 1650-1656.
Wu,C.L., Shieh,G.S., Chang,C.C., Yo,Y.T., Su,C.H., Chang,M.Y., Huang,Y.H., Wu,P., and Shiau,A.L. (2008). Tumor-selective replication of an oncolytic adenovirus carrying oct-3/4 response elements in murine metastatic bladder cancer models. Clin. Cancer Res. 14, 1228-1238.
Yang,H.T., Jirholt,J., Svensson,L., Sundvall,M., Jansson,L., Pettersson,U., and Holmdahl,R. (1999). Identification of genes controlling collagen-induced arthritis in mice: striking homology with susceptibility loci previously identified in the rat. J. Immunol. 163, 2916-2921.
Yao,Q., Wang,S., Gambotto,A., Glorioso,J.C., Evans,C.H., Robbins,P.D., Ghivizzani,S.C., and Oligino,T.J. (2003). Intra-articular adenoviral-mediated gene transfer of trail induces apoptosis of arthritic rabbit synovium. Gene Ther. 10, 1055-1060.
Yao,Q., Wang,S., Glorioso,J.C., Evans,C.H., Robbins,P.D., Ghivizzani,S.C., and Oligino,T.J. (2001). Gene transfer of p53 to arthritic joints stimulates synovial apoptosis and inhibits inflammation. Mol. Ther. 3, 901-910.
Yen,M.C., Lin,C.C., Chen,Y.L., Huang,S.S., Yang,H.J., Chang,C.P., Lei,H.Y., and Lai,M.D. (2009). A novel cancer therapy by skin delivery of indoleamine 2,3-dioxygenase siRNA. Clin. Cancer Res. 15, 641-649.
Zhang,H., Yang,Y., Horton,J.L., Samoilova,E.B., Judge,T.A., Turka,L.A., Wilson,J.M., and Chen,Y. (1997). Amelioration of collagen-induced arthritis by CD95 (Apo-1/Fas)-ligand gene transfer. J. Clin. Invest 100, 1951-1957.