類風濕性關節炎是一種慢性發炎的疾病，伴隨著單核球細胞、淋巴球細胞進入滑液膜關節，主要特徵是多發性關節炎和骨頭毀壞。在關節發炎增殖的滑液膜稱為血管翳，會侵犯和破壞局部骨頭結構。滑液膜增殖是由於嗜菌球細胞及滑液纖維母細胞明顯的增加，且局部表現腫瘤壞死因子及介白素-1等發炎激素，而且也分泌金屬蛋白脢。甚且這些細胞也分泌不正常的趨化性激素，如嗜菌球細胞發炎蛋白。我們實驗室構築帶有缺乏入核序列的前胸腺激素腺病毒 (突變株)，此蛋白只表現在核外且削弱細胞增生能力。我們也發現處裡缺乏入核序列的前胸腺激素腺病毒會降低嗜菌球細胞發炎蛋白啟動子的表現。因此我們想探討腺病毒突變株對膠質誘發關節炎模式的改善如何。結果顯示相對於對照組，腺病毒突變株治療組能改善關節炎的臨床嚴重度。在腺病毒突變株治療組發現嗜菌球細胞數量減低及嗜菌球細胞發炎蛋白量減少。腫瘤壞死因子及介白素-1等發炎激素表現量也相對的減少。金屬蛋白脢-9的活性下降及淋巴球增生獲得改善。這些數據顯示缺乏入核序列的前胸腺激素的基因治療對膠質誘發關節炎的改善，可能由降低發炎滑液膜關節中嗜菌球細胞發炎蛋白表現量。對於類風濕性關節炎病人，缺乏入核序列的前胸腺激素可能是個有潛力的治療策略。

　　Rheumatoid arthritis is a chronic inflammatory disease characterized with polyarthritis and bone destruction followed with infiltration of monocytes, and T cells into the synovial joints. Inflammatory synovium in the joint lining called pannus invades and destroys local bone structure. Synovial hyperplasia results from a marked increase in macrophages and synoviofibroblasts, locally expressed inflammatory mediators, TNF- and IL-1, and secreted matetalloproteinases, to digest the extracellular matrix in bone. However, those cells also secreted abnormal chemotactic cytokines, RANTES and MIP-1, are crucial for T cell chemotaxic from the circulation to inflamed tissue and also play an important role in the regulation of transendotherial migration of monocytes. Our laboratory have constructed an adenovirus encoding prothymosin (ProT) deletion mutant lacking the nuclear localization signal (NLS), exhibited a punctured nuclear distribution and reduced cell proliferation. Data of our experiment indicated that MIP-1 promoter expression was reduced by AdProTNLS treatment. In this study, we investigated the effect of AdProTNLS treatment in a rat model of collagen-induced arthritis (CIA). Our resulted showed that the clinical severity of ankle joint arthritis in CIA rats was ameliorated by the AdProTΔNLS treatment in comparison with that of the AdLacZ-injected group. The lower number of the synovial macrophages and a decreased level of macrophage inflammatory protein 1(MIP-1 found in the AdProTΔNLS-injected group. Reduced levels of proinflammatory cytokines, TNF- and IL-1were observed in the ProTΔNLS gene therapy. The activity of MMP-9 was reduced and the proliferation of lymphocytes was improved by ProTΔNLS gene transfers in CIA animal model. Therefore, these data suggested that suppression of the ProTΔNLS gene therapy in CIA rats may be attributable to the down expression of MIP-1in the synovial joints. Thymic peptide, ProTΔNLS, may be used as therapeutic strategy for rheumatoid arthritis pateints.

Baxevanis,C.N., Frillingos,S., Seferiadis,K., Reclos,G.J., Arsenis,P., Katsiyiannis,A., Anastasopoulos,E., Tsolas,O., and Papamichail,M. (1990). Enhancement of human T lymphocyte function by prothymosin alpha: increased production of interleukin-2 and expression of interleukin-2 receptors in normal human peripheral blood T lymphocytes. Immunopharmacol. Immunotoxicol. 12, 595-617.
Baxevanis,C.N., Reclos,G.J., Papamichail,M., and Tsokos,G.C. (1987). Prothymosin alpha restores the depressed autologous and allogeneic mixed lymphocyte responses in patients with systemic lupus erythematosus. Immunopharmacol. Immunotoxicol. 9, 429-440.
Chen,Q. and Wei,W. (2003c). Effects and mechanisms of glucosides of chaenomeles speciosa on collagen-induced arthritis in rats. Int. Immunopharmacol. 3, 593-608.
Chen,Q. and Wei,W. (2003b). Effects and mechanisms of glucosides of chaenomeles speciosa on collagen-induced arthritis in rats. Int. Immunopharmacol. 3, 593-608.
Chen,Q. and Wei,W. (2003a). Effects and mechanisms of glucosides of chaenomeles speciosa on collagen-induced arthritis in rats. Int. Immunopharmacol. 3, 593-608.
Choy,E.H. and Panayi,G.S. (2001). Cytokine pathways and joint inflammation in rheumatoid arthritis. N. Engl. J. Med. 344, 907-916.
Cordero,O.J., Sarandeses,C., and Nogueira,M. (1995). Prothymosin alpha receptors on lymphocytes. J. Interferon Cytokine Res. 15, 731-737.
Cordero,O.J., Sarandeses,C.S., Lopez,J.L., Cancio,E., Regueiro,B.J., and Nogueira,M. (1991). Prothymosin alpha enhances interleukin 2 receptor expression in normal human T-lymphocytes. Int. J. Immunopharmacol. 13, 1059-1065.
Cordero,O.J., Sarandeses,C.S., and Nogueira,M. (1996). Binding of 125I-prothymosin alpha to lymphoblasts through the non-thymosin alpha 1 sequence. Life Sci. 58, 1757-1770.
Cotter,M.A. and Robertson,E.S. (2000). Modulation of histone acetyltransferase activity through interaction of epstein-barr nuclear antigen 3C with prothymosin alpha. Mol. Cell Biol. 20, 5722-5735.
Eckert,K., Grunberg,E., Immenschuh,P., Garbin,F., Kreuser,E.D., and Maurer,H.R. (1997). Interleukin-2-activated killer cell activity in colorectal tumor patients: evaluation of in vitro effects by prothymosin alpha1. J. Cancer Res. Clin. Oncol. 123, 420-428.
Firestein,G.S. (1996). Invasive fibroblast-like synoviocytes in rheumatoid arthritis. Passive responders or transformed aggressors? Arthritis Rheum. 39, 1781-1790.
Firestein,G.S. and Zvaifler,N.J. (1990). How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum. 33, 768-773.
Freire,J., Covelo,G., Sarandeses,C., az-Jullien,C., and Freire,M. (2001). Identification of nuclear-import and cell-cycle regulatory proteins that bind to prothymosin alpha. Biochem. Cell Biol. 79, 123-131.
Grassi,F., Cristino,S., Toneguzzi,S., Piacentini,A., Facchini,A., and Lisignoli,G. (2004). CXCL12 chemokine up-regulates bone resorption and MMP-9 release by human osteoclasts: CXCL12 levels are increased in synovial and bone tissue of rheumatoid arthritis patients. J. Cell Physiol 199, 244-251.
Holmdahl,R., Andersson,M., Goldschmidt,T.J., Gustafsson,K., Jansson,L., and Mo,J.A. (1990). Type II collagen autoimmunity in animals and provocations leading to arthritis. Immunol. Rev. 118, 193-232.
Kim,W.U., Lee,W.K., Ryoo,J.W., Kim,S.H., Kim,J., Youn,J., Min,S.Y., Bae,E.Y., Hwang,S.Y., Park,S.H., Cho,C.S., Park,J.S., and Kim,H.Y. (2002). Suppression of collagen-induced arthritis by single administration of poly(lactic-co-glycolic acid) nanoparticles entrapping type II collagen: a novel treatment strategy for induction of oral tolerance. Arthritis Rheum. 46, 1109-1120.
Koetz,K., Bryl,E., Spickschen,K., O'Fallon,W.M., Goronzy,J.J., and Weyand,C.M. (2000). T cell homeostasis in patients with rheumatoid arthritis. Proc. Natl. Acad. Sci. U. S. A 97, 9203-9208.
Lu,K.H., Yang,S.F., Chu,S.C., Chen,P.N., Chou,M.C., Hsiao,T.Y., and Hsieh,Y.S. (2004). The significance of altered gelatinase expression in the synovium of patient with arthritic effusions. Clin. Rheumatol. 23, 21-26.
Luross,J.A. and Williams,N.A. (2001b). The genetic and immunopathological processes underlying collagen-induced arthritis. Immunology 103, 407-416.
Luross,J.A. and Williams,N.A. (2001a). The genetic and immunopathological processes underlying collagen-induced arthritis. Immunology 103, 407-416.
Manrow,R.E., Sburlati,A.R., Hanover,J.A., and Berger,S.L. (1991). Nuclear targeting of prothymosin alpha. J. Biol. Chem. 266, 3916-3924.
Naylor,P.H., Oates,K.K., Coss,M.C., Erdos,M.R., Naylor,C.W., and Goldstein,A.L. (1992). Identification of immunoreactive forms of thymosin alpha 1 in serum and supernatants by combining HPLC and RIA. Int. J. Immunopharmacol. 14, 1267-1278.
Panneerselvam,C., Haritos,A.A., Caldarella,J., and Horecker,B.L. (1987). Prothymosin alpha in human blood. Proc. Natl. Acad. Sci. U. S. A 84, 4465-4469.
Pineiro,A., Cordero,O.J., and Nogueira,M. (2000). Fifteen years of prothymosin alpha: contradictory past and new horizons. Peptides 21, 1433-1446.
Sarandeses,C.S., Covelo,G., az-Jullien,C., and Freire,M. (2003). Prothymosin alpha is processed to thymosin alpha 1 and thymosin alpha 11 by a lysosomal asparaginyl endopeptidase. J. Biol. Chem. 278, 13286-13293.
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.
Woods,J.M., Katschke,K.J., Volin,M.V., Ruth,J.H., Woodruff,D.C., Amin,M.A., Connors,M.A., Kurata,H., Arai,K., Haines,G.K., Kumar,P., and Koch,A.E. (2001b). IL-4 adenoviral gene therapy reduces inflammation, proinflammatory cytokines, vascularization, and bony destruction in rat adjuvant-induced arthritis. J. Immunol. 166, 1214-1222.
Woods,J.M., Katschke,K.J., Volin,M.V., Ruth,J.H., Woodruff,D.C., Amin,M.A., Connors,M.A., Kurata,H., Arai,K., Haines,G.K., Kumar,P., and Koch,A.E. (2001a). IL-4 adenoviral gene therapy reduces inflammation, proinflammatory cytokines, vascularization, and bony destruction in rat adjuvant-induced arthritis. J. Immunol. 166, 1214-1222.
Wu,C.L., Shiau,A.L., and Lin,C.S. (1997). Prothymosin alpha promotes cell proliferation in NIH3T3 cells. Life Sci. 61, 2091-2101.

Yoshihara, Y., H. Nakamura, K. Obata, H. Yamada, T. Hayakawa, K. Fujikawa, Y. Okada. (2000). Matrix metalloproteinases and tissue inhibitors of metalloproteinases in synovial fluids from patients with rheumatoid arthritis or osteoarthritis. Ann. Rheum. Dis. 59, 455.

Youssef PP, Kraan M, Breedveld F, Bresnihan B, Cassidy N, Cunnane G, et al. (1998). Quantitative microscopic analysis of inflammation in rheumatoid arthritis synovial membrane samples selected at arthroscopy compared with samples obtained blindly by needle biopsy. Arthritis Rheum 41, 663–9.