臺灣博碩士論文加值系統

類風濕性關節炎是一種關節慢性發炎的疾病，特徵為免疫細胞，包括淋巴細胞、巨噬細胞等浸潤到關節中，伴隨著滑液膜細胞活化、增殖，這些細胞產生大量許多分解性酵素，及Th1細胞激素刺激巨噬細胞等分化為蝕骨細胞，導致軟骨與硬骨被侵蝕破壞。Galectin是一群數目成長中的β半乳糖結合凝集蛋白，其中Galectin-1 (Gal-1)可以引起活化的T淋巴細胞凋亡，並抑制T淋巴細胞產生第二型白介素與巨噬細胞產生腫瘤壞死因子α、干擾素γ；家族中的另一個成員，Galentin-3 (Gal-3)則是淋巴細胞、巨噬細胞、中性白血球的化趨物質，除此之外，Gal-3會抑制T細胞凋亡、促進血管新生，且在類風濕性關節炎病人的關節中被大量表現。在本研究中我們假設透過增加Gal-1表現與抑制Gal-3表現或許能夠改善關節炎的發生與病程，我們篩選出能夠有效抑制Gal-3表現的RNA干擾素，並將Gal-1的表現基因與Gal-3的RNA干擾素分別建構於假型外套膜慢病毒載體中，治療由第二型膠原蛋白引起的大鼠關節炎，研究結果顯示我們建構的慢病毒能有效的使Gal-1過量表現，也有效降低Gal-3的表現，並且相對於給予食鹽水或是表現GFP的對照病毒，給予Gal-1基因或是Gal-3 RNA干擾素的大鼠都在臨床症狀有顯著改善，我們也經由病理學評估與X光攝影評估確認療效，因此Gal-1表現增加或抑制Gal-3表現能改善大鼠關節炎，總而言之，希望我們的研究能夠對於Gal-1與Gal-3在類風濕性關節炎中扮演的角色提供一些線索，並且對治療類風濕性關節炎能有新方向的療法。

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterized by blood-derived cells, such as macrophages and lymphocytes, infiltrating into joints, and in conjunction with activated synovial cells, production of inflammatory and T helper 1 (Th1) cytokines together with degradative enzymes that progressively lead to the destruction of cartilage and bone. Galectins are a growing family of β-galactoside-binding animal lectins. Galectin-1 (Gal-1) can induce apoptosis of activated but not resting human T cells as well as suppress Tumor necrosis factor α (TNF-α) and Interferon γ (IFN-γ) production by macrophages and Interleukin 2 (IL-2) production by T cells. In contrast to Gal-1, galectin-3 (Gal-3) is chemotactic for lymphocytes, macrophages, and neutrophils. Furthermore, Gal-3 promotes angiogenesis and serves as an inhibitor of T cell apoptosis, and is expressed in the synovial tissue of patients with RA, particularly at sites of joint destruction. In this study, we investigated whether increase of Gal-1 gene expression and reduction of Gal-3 gene expression may be beneficial in ameliorating arthritis onset and progression. We screened efficient short-hairpin RNA (shGal-3) to knockdown rat Gal-3 gene expression by the Gal-3 fusion with eGFP. We generated two VSV-G pseudotyped lentiviral vectors expressing Gal-1 (Lt.Gal-1) and shGal-3 (Lt.shGal-3) for gene therapy in the rat model of collagen-induced arthritis (CIA). Our results demonstrated that Lt.Gal-1 and Lt-shGal-3 efficiently increased Gal-1 and knocked down Gal-3 gene expression. We also administered Lt.Gal-1, Lt.shGal-3, or the control virus, Lt.GFP, to CIA rats to evaluate their therapeutic efficacy. Furthermore, histological and radiological analyses of the rat ankle were evaluated. We found that clinical symptoms and histological scores were ameliorated when Gal-1 expression was increased or Gal-3 was reduced. Taken together, this study may provide a novel therapeutic approach for the treatment of RA.

中文摘要　..................................................................I
Abstract　..................................................................III
誌謝 ......................................................................V
目錄　......................................................................VI
圖表目錄　..................................................................IX
附錄　......................................................................XI
縮寫　......................................................................XII
緒論(Introduction)　........................................................1
類風濕性關節炎 (rheumatoid arthritis, RA)　.................................1
RA致病機轉　................................................................1
RA與基因治療　..............................................................3
Galectin-1 (Gal-1)　........................................................4
Galectin-3 (Gal-3)　........................................................6
慢病毒載體 (Lentiviral vector)　............................................9
核醣核酸干擾 (RNA interference)　...........................................10
膠原蛋白誘導關節炎 (Collagen-induced arthritis, CIA)　......................11
研究動機與實驗設計　........................................................12
材料與方法(Materials and Methods)　.........................................13
材料　.....................................................................13
質體(plasmids)　..........................................................13
寡去氧核苷酸(oligodeoxynucleotides, ODN)　..................................14
細胞株　....................................................................16
實驗動物　..................................................................16
方法　......................................................................16
細胞株與細胞培養　..........................................................16
構築表現Gal-1的慢病毒載體　.................................................17
選殖大鼠的Gal-3 cDNA　......................................................17
Gal-3融合綠螢光質體建構與設計篩選Gal-3的RNA干擾素　.........................18
質體的轉染　................................................................18
RNA 的分離與RT-PCR　........................................................19
西方墨點法(Western blot) 　.................................................20
生產重組慢病毒載體　........................................................21
定量病毒的效價(titer)　.....................................................22
第二型膠原蛋白誘發關節炎(type II collagen-induced arthritis; CIA)　.........23
大鼠臨床上關節炎的病徵評估　................................................23
組織病理學分析(Histopathologic analysis)　..................................24
X光攝影評估　...............................................................24
免疫組織化學染色分析(Immunohistochemical analysis) 　.......................24
統計分析　..................................................................25
實驗結果(Results)　.........................................................26
大鼠Gal-3 cDNA的選殖　......................................................26
篩選有效的Gal-3 shRNA　.....................................................26
生產重組慢病毒載體Lt.Gal-1與Gal-1基因表現　.................................27
生產重組慢病毒載體Lt.shGal-3與抑制Gal-3蛋白表現　...........................28
探討Gal-1與Gal-3的表現與疾病的相關性　......................................29
重組慢病毒攜帶基因於關節內的表現　..........................................29
CIA大鼠中Lt.Gal-1與Lt.shGal-3的預防性治療效果(prophylactic effects)　.......30
Lt.Gal-1與Lt.shGal-3治療後的CIA大鼠之組織病理學分析　.......................30
Lt.Gal-1與Lt.shGal-3治療後的CIA大鼠之X光攝影分析　..........................31
淋巴節細胞在增加Gal-1表現與降低Gal-3表現後更容易受到抗原刺激死亡　..........31
經由給予Gal-1基因或Gal-3 shRNA降低大鼠關節炎之血管新生　....................32
藉由增加Gal-1基因表現或減少Gal-3 基因表現降低大鼠關節炎之T細胞浸潤　........32
討論(Discussion)　..........................................................34
參考文獻(References)　......................................................37
圖表(Figures)　.............................................................47
附錄(Appendix)　............................................................63
自述　......................................................................67

Allione, A., Wells, V., Forni, G., Mallucci, L., and Novelli, F. (1998). Beta-galactoside-binding protein (beta GBP) alters the cell cycle, up-regulates expression of the alpha- and beta-chains of the IFN-gamma receptor, and triggers IFN-gamma-mediated apoptosis of activated human T lymphocytes. J. Immunol. 161, 2114-2119.
Almkvist, J., and Karlsson, A. (2004). Galectins as inflammatory mediators. Glycoconj. J. 19, 575-581.
Bagasra, O., and Prilliman, K.R. (2004). RNA interference: the molecular immune system. J. Mol. Histol. 35, 545-553.
Barondes, S.H., Castronovo, V., Cooper, D.N., Cummings, R.D., Drickamer, K., Feizi, T., Gitt, M.A., Hirabayashi, J., Hughes, C., Kasai, K., et al. (1994a). Galectins: a family of animal beta-galactoside-binding lectins. Cell 76, 597-598.
Barondes, S.H., Cooper, D.N., Gitt, M.A., and Leffler, H. (1994b). Galectins. Structure and function of a large family of animal lectins. J. Biol. Chem. 269, 20807-20810.
Baum, L.G., Blackall, D.P., Arias-Magallano, S., Nanigian, D., Uh, S.Y., Browne, J.M., Hoffmann, D., Emmanouilides, C.E., Territo, M.C., and Baldwin, G.C. (2003). Amelioration of graft versus host disease by galectin-1. Clin. Immunol. 109, 295-307.
Baum, L.G., Pang, M., Perillo, N.L., Wu, T., Delegeane, A., Uittenbogaart, C.H., Fukuda, M., and Seilhamer, J.J. (1995). Human thymic epithelial cells express an endogenous lectin, galectin-1, which binds to core 2 O-glycans on thymocytes and T lymphoblastoid cells. J. Exp. Med. 181, 877-887.
Blaser, C., Kaufmann, M., Muller, C., Zimmermann, C., Wells, V., Mallucci, L., and Pircher, H. (1998). Beta-galactoside-binding protein secreted by activated T cells inhibits antigen-induced proliferation of T cells. Eur. J. Immunol. 28, 2311-2319.
Brummelkamp, T.R., Bernards, R., and Agami, R. (2002). A system for stable expression of short interfering RNAs in mammalian cells. Science 296, 550-553.
Caron, M., Joubert, R., and Bladier, D. (1987). Purification and characterization of a beta-galactoside-binding soluble lectin from rat and bovine brain. Biochim. Biophys. Acta 925, 290-296.
Chung, C.D., Patel, V.P., Moran, M., Lewis, L.A., and Miceli, M.C. (2000). Galectin-1 induces partial TCR zeta-chain phosphorylation and antagonizes processive TCR signal transduction. J. Immunol. 165, 3722-3729.
Colnot, C., Ripoche, M.A., Milon, G., Montagutelli, X., Crocker, P.R., and Poirier, F. (1998). Maintenance of granulocyte numbers during acute peritonitis is defective in galectin-3-null mutant mice. Immunology 94, 290-296.
Colnot, C., Sidhu, S.S., Poirier, F., and Balmain, N. (1999). Cellular and subcellular distribution of galectin-3 in the epiphyseal cartilage and bone of fetal and neonatal mice. Cell Mol. Biol. (Noisy-le-grand) 45, 1191-1202.
Craig, S.S., Krishnaswamy, P., Irani, A.M., Kepley, C.L., Liu, F.T., and Schwartz, L.B. (1995). Immunoelectron microscopic localization of galectin-3, an IgE binding protein, in human mast cells and basophils. Anat. Rec. 242, 211-219.
Crowston, J.G., Salmon, M., Khaw, P.T., and Akbar, A.N. (1997). T-lymphocyte-fibroblast interactions. Biochem. Soc. Trans. 25, 529-531.
Dasuri, K., Antonovici, M., Chen, K., Wong, K., Standing, K., Ens, W., El-Gabalawy, H., and Wilkins, J.A. (2004). The synovial proteome: analysis of fibroblast-like synoviocytes. Arthritis Res. Ther. 6, R161-168.
Dayer, J.M., Graham, R., Russell, G., and Krane, S.M. (1977). Collagenase production by rheumatoid synovial cells: stimulation by a human lymphocyte factor. Science 195, 181-183.
Dietz, A.B., Bulur, P.A., Knutson, G.J., Matasic, R., and Vuk-Pavlovic, S. (2000). Maturation of human monocyte-derived dendritic cells studied by microarray hybridization. Biochem. Biophys. Res. Commun. 275, 731-738.
Dolhain, R.J., van der Heiden, A.N., ter Haar, N.T., Breedveld, F.C., and Miltenburg, A.M. (1996). Shift toward T lymphocytes with a T helper 1 cytokine-secretion profile in the joints of patients with rheumatoid arthritis. Arthritis Rheum. 39, 1961-1969.
Dumic, J., Dabelic, S., and Flogel, M. (2006). Galectin-3: an open-ended story. Biochim. Biophys. Acta 1760, 616-635.
Elbashir, S.M., Harborth, J., Lendeckel, W., Yalcin, A., Weber, K., and Tuschl, T. (2001). Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494-498.
Firestein, G.S. (2003). Evolving concepts of rheumatoid arthritis. Nature 423, 356-361.
Firestein, G.S., Alvaro-Gracia, J.M., and Maki, R. (1990). Quantitative analysis of cytokine gene expression in rheumatoid arthritis. J. Immunol. 144, 3347-3353.
Folkman, J. (1995). Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat. Med. 1, 27-31.
Frigeri, L.G., Zuberi, R.I., and Liu, F.T. (1993). Epsilon BP, a beta-galactoside-binding animal lectin, recognizes IgE receptor (Fc epsilon RI) and activates mast cells. Biochemistry 32, 7644-7649.
Frisbie, D.D., Ghivizzani, S.C., Robbins, P.D., Evans, C.H., and McIlwraith, C.W. (2002). Treatment of experimental equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor antagonist gene. Gene Ther. 9, 12-20.
Fukumori, T., Takenaka, Y., Oka, N., Yoshii, T., Hogan, V., Inohara, H., Kanayama, H.O., Kim, H.R., and Raz, A. (2004). Endogenous galectin-3 determines the routing of CD95 apoptotic signaling pathways. Cancer Res. 64, 3376-3379.
Fukushi, J., Makagiansar, I.T., and Stallcup, W.B. (2004). NG2 proteoglycan promotes endothelial cell motility and angiogenesis via engagement of galectin-3 and alpha3beta1 integrin. Mol. Biol. Cell 15, 3580-3590.
Gould, D.J., and Favorov, P. (2003). Vectors for the treatment of autoimmune disease. Gene Ther. 10, 912-927.
Ho, M.K., and Springer, T.A. (1982). Mac-2, a novel 32,000 Mr mouse macrophage subpopulation-specific antigen defined by monoclonal antibodies. J. Immunol. 128, 1221-1228.
Houzelstein, D., Goncalves, I.R., Fadden, A.J., Sidhu, S.S., Cooper, D.N., Drickamer, K., Leffler, H., and Poirier, F. (2004). Phylogenetic analysis of the vertebrate galectin family. Mol. Biol. Evol. 21, 1177-1187.
Hsu, D.K., Hammes, S.R., Kuwabara, I., Greene, W.C., and Liu, F.T. (1996). Human T lymphotropic virus-I infection of human T lymphocytes induces expression of the beta-galactoside-binding lectin, galectin-3. Am. J. Pathol. 148, 1661-1670.
Hsu, D.K., Yang, R.Y., Pan, Z., Yu, L., Salomon, D.R., Fung-Leung, W.P., and Liu, F.T. (2000). Targeted disruption of the galectin-3 gene results in attenuated peritoneal inflammatory responses. Am. J. Pathol. 156, 1073-1083.
Hu, W.S., and Pathak, V.K. (2000). Design of retroviral vectors and helper cells for gene therapy. Pharmacol. Rev. 52, 493-511.
Inohara, H., Akahani, S., and Raz, A. (1998). Galectin-3 stimulates cell proliferation. Exp. Cell Res. 245, 294-302.
Iwakuma, T., Cui, Y., and Chang, L.J. (1999). Self-inactivating lentiviral vectors with U3 and U5 modifications. Virology 261, 120-132.
Joo, H.G., Goedegebuure, P.S., Sadanaga, N., Nagoshi, M., von Bernstorff, W., and Eberlein, T.J. (2001). Expression and function of galectin-3, a beta-galactoside-binding protein in activated T lymphocytes. J. Leukoc. Biol. 69, 555-564.
Jovanovic, D.V., Di Battista, J.A., Martel-Pelletier, J., Jolicoeur, F.C., He, Y., Zhang, M., Mineau, F., and Pelletier, J.P. (1998). IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. J. Immunol. 160, 3513-3521.
Karlsson, A., Follin, P., Leffler, H., and Dahlgren, C. (1998). Galectin-3 activates the NADPH-oxidase in exudated but not peripheral blood neutrophils. Blood 91, 3430-3438.
Lecellier, C.H., and Voinnet, O. (2004). RNA silencing: no mercy for viruses? Immunol. Rev. 198, 285-303.
Liu, F.T., Albrandt, K., Mendel, E., Kulczycki, A., Jr., and Orida, N.K. (1985). Identification of an IgE-binding protein by molecular cloning. Proc. Natl. Acad. Sci. U S A 82, 4100-4104.
Liu, F.T., Hsu, D.K., Zuberi, R.I., Kuwabara, I., Chi, E.Y., and Henderson, W.R., Jr. (1995). Expression and function of galectin-3, a beta-galactoside-binding lectin, in human monocytes and macrophages. Am. J. Pathol. 147, 1016-1028.
Liu, F.T., and Orida, N. (1984). Synthesis of surface immunoglobulin E receptor in Xenopus oocytes by translation of mRNA from rat basophilic leukemia cells. J. Biol. Chem. 259, 10649-10652.
Martel-Pelletier, J., Welsch, D.J., and Pelletier, J.P. (2001). Metalloproteases and inhibitors in arthritic diseases. Best Pract. Res. Clin. Rheumatol. 15, 805-829.
Mittal, V. (2004). Improving the efficiency of RNA interference in mammals. Nat. Rev. Genet. 5, 355-365.
Miyagishi, M., and Taira, K. (2002). U6 promoter-driven siRNAs with four uridine 3' overhangs efficiently suppress targeted gene expression in mammalian cells. Nat. Biotechnol. 20, 497-500.
Moiseeva, E.P., Javed, Q., Spring, E.L., and de Bono, D.P. (2000). Galectin 1 is involved in vascular smooth muscle cell proliferation. Cardiovasc. Res. 45, 493-502.
Moiseeva, E.P., Williams, B., Goodall, A.H., and Samani, N.J. (2003). Galectin-1 interacts with beta-1 subunit of integrin. Biochem. Biophys. Res. Commun. 310, 1010-1016.
Moreland, L.W., Baumgartner, S.W., Schiff, M.H., Tindall, E.A., Fleischmann, R.M., Weaver, A.L., Ettlinger, R.E., Cohen, S., Koopman, W.J., Mohler, K., et al. (1997). Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N. Engl. J. Med. 337, 141-147.
Moutsatsos, I.K., Wade, M., Schindler, M., and Wang, J.L. (1987). Endogenous lectins from cultured cells: nuclear localization of carbohydrate-binding protein 35 in proliferating 3T3 fibroblasts. Proc. Natl. Acad. Sci. U S A 84, 6452-6456.
Nangia-Makker, P., Honjo, Y., Sarvis, R., Akahani, S., Hogan, V., Pienta, K.J., and Raz, A. (2000). Galectin-3 induces endothelial cell morphogenesis and angiogenesis. Am. J. Pathol. 156, 899-909.
Nasu, K., Kohsaka, H., Nonomura, Y., Terada, Y., Ito, H., Hirokawa, K., and Miyasaka, N. (2000). Adenoviral transfer of cyclin-dependent kinase inhibitor genes suppresses collagen-induced arthritis in mice. J. Immunol. 165, 7246-7252.
Neidhart, M., Zaucke, F., von Knoch, R., Jungel, A., Michel, B.A., Gay, R.E., and Gay, S. (2005). Galectin-3 is induced in rheumatoid arthritis synovial fibroblasts after adhesion to cartilage oligomeric matrix protein. Ann. Rheum. Dis. 64, 419-424.
Niida, S., Amizuka, N., Hara, F., Ozawa, H., and Kodama, H. (1994). Expression of Mac-2 antigen in the preosteoclast and osteoclast identified in the op/op mouse injected with macrophage colony-stimulating factor. J. Bone Miner. Res. 9, 873-881.
Offner, H., Celnik, B., Bringman, T.S., Casentini-Borocz, D., Nedwin, G.E., and Vandenbark, A.A. (1990). Recombinant human beta-galactoside binding lectin suppresses clinical and histological signs of experimental autoimmune encephalomyelitis. J. Neuroimmunol. 28, 177-184.
Ohshima, S., Kuchen, S., Seemayer, C.A., Kyburz, D., Hirt, A., Klinzing, S., Michel, B.A., Gay, R.E., Liu, F.T., Gay, S., et al. (2003). Galectin 3 and its binding protein in rheumatoid arthritis. Arthritis Rheum. 48, 2788-2795.
Perillo, N.L., Marcus, M.E., and Baum, L.G. (1998). Galectins: versatile modulators of cell adhesion, cell proliferation, and cell death. J. Mol. Med. 76, 402-412.
Perillo, N.L., Pace, K.E., Seilhamer, J.J., and Baum, L.G. (1995). Apoptosis of T cells mediated by galectin-1. Nature 378, 736-739.
Perillo, N.L., Uittenbogaart, C.H., Nguyen, J.T., and Baum, L.G. (1997). Galectin-1, an endogenous lectin produced by thymic epithelial cells, induces apoptosis of human thymocytes. J. Exp. Med. 185, 1851-1858.
Perone, M.J., Larregina, A.T., Shufesky, W.J., Papworth, G.D., Sullivan, M.L., Zahorchak, A.F., Stolz, D.B., Baum, L.G., Watkins, S.C., Thomson, A.W., et al. (2006). Transgenic galectin-1 induces maturation of dendritic cells that elicit contrasting responses in naive and activated T cells. J. Immunol. 176, 7207-7220.
Rabinovich, G.A., Ariel, A., Hershkoviz, R., Hirabayashi, J., Kasai, K.I., and Lider, O. (1999a). Specific inhibition of T-cell adhesion to extracellular matrix and proinflammatory cytokine secretion by human recombinant galectin-1. Immunology 97, 100-106.
Rabinovich, G.A., Daly, G., Dreja, H., Tailor, H., Riera, C.M., Hirabayashi, J., and Chernajovsky, Y. (1999b). Recombinant galectin-1 and its genetic delivery suppress collagen-induced arthritis via T cell apoptosis. J. Exp. Med. 190, 385-398.
Rabinovich, G.A., Iglesias, M.M., Modesti, N.M., Castagna, L.F., Wolfenstein-Todel, C., Riera, C.M., and Sotomayor, C.E. (1998). Activated rat macrophages produce a galectin-1-like protein that induces apoptosis of T cells: biochemical and functional characterization. J. Immunol. 160, 4831-4840.
Rabinovich, G.A., Ramhorst, R.E., Rubinstein, N., Corigliano, A., Daroqui, M.C., Kier-Joffe, E.B., and Fainboim, L. (2002). Induction of allogenic T-cell hyporesponsiveness by galectin-1-mediated apoptotic and non-apoptotic mechanisms. Cell Death. Differ. 9, 661-670.
Redlich, K., Hayer, S., Ricci, R., David, J.P., Tohidast-Akrad, M., Kollias, G., Steiner, G., Smolen, J.S., Wagner, E.F., and Schett, G. (2002). Osteoclasts are essential for TNF-alpha-mediated joint destruction. J. Clin. Invest. 110, 1419-1427.
Robbins, P.D., Evans, C.H., and Chernajovsky, Y. (2003). Gene therapy for arthritis. Gene Ther. 10, 902-911.
Roff, C.F., and Wang, J.L. (1983). Endogenous lectins from cultured cells. Isolation and characterization of carbohydrate-binding proteins from 3T3 fibroblasts. J. Biol. Chem. 258, 10657-10663.
Rubinson, D.A., Dillon, C.P., Kwiatkowski, A.V., Sievers, C., Yang, L., Kopinja, J., Rooney, D.L., Ihrig, M.M., McManus, M.T., Gertler, F.B., et al. (2003). A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nat. Genet. 33, 401-406.
Saada, A., Reichert, F., and Rotshenker, S. (1996). Granulocyte macrophage colony stimulating factor produced in lesioned peripheral nerves induces the up-regulation of cell surface expression of MAC-2 by macrophages and Schwann cells. J. Cell Biol. 133, 159-167.
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.
Santucci, L., Fiorucci, S., Cammilleri, F., Servillo, G., Federici, B., and Morelli, A. (2000). Galectin-1 exerts immunomodulatory and protective effects on concanavalin A-induced hepatitis in mice. Hepatology. 31, 399-406.
Santucci, L., Fiorucci, S., Rubinstein, N., Mencarelli, A., Palazzetti, B., Federici, B., Rabinovich, G.A., and Morelli, A. (2003). Galectin-1 suppresses experimental colitis in mice. Gastroenterology 124, 1381-1394.
Shou, J., Bull, C.M., Li, L., Qian, H.R., Wei, T., Luo, S., Perkins, D., Solenberg, P.J., Tan, S.L., Chen, X.Y., et al. (2006). Identification of blood biomarkers of rheumatoid arthritis by transcript profiling of peripheral blood mononuclear cells from the rat collagen-induced arthritis model. Arthritis Res. Ther. 8, R28.
Steiner, G., Tohidast-Akrad, M., Witzmann, G., Vesely, M., Studnicka-Benke, A., Gal, A., Kunaver, M., Zenz, P., and Smolen, J.S. (1999). Cytokine production by synovial T cells in rheumatoid arthritis. Rheumatology (Oxford) 38, 202-213.
Stevenson, M. (2004). Therapeutic potential of RNA interference. N. Engl. J. Med. 351, 1772-1777.
Stock, M., Schafer, H., Stricker, S., Gross, G., Mundlos, S., and Otto, F. (2003). Expression of galectin-3 in skeletal tissues is controlled by Runx2. J. Biol. Chem. 278, 17360-17367.
Stout, R.D. (1993). Macrophage activation by T cells: cognate and non-cognate signals. Curr. Opin. Immunol. 5, 398-403.
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.
Teitelbaum, S.L. (2000). Bone resorption by osteoclasts. Science 289, 1504-1508.
Thijssen, V.L., Postel, R., Brandwijk, R.J., Dings, R.P., Nesmelova, I., Satijn, S., Verhofstad, N., Nakabeppu, Y., Baum, L.G., Bakkers, J., et al. (2006). Galectin-1 is essential in tumor angiogenesis and is a target for antiangiogenesis therapy. Proc. Natl. Acad. Sci. U S A 103, 15975-15980.
Thomas, C.E., Ehrhardt, A., and Kay, M.A. (2003). Progress and problems with the use of viral vectors for gene therapy. Nat. Rev. Genet. 4, 346-358.
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.
Truong, M.J., Gruart, V., Kusnierz, J.P., Papin, J.P., Loiseau, S., Capron, A., and Capron, M. (1993a). Human neutrophils express immunoglobulin E (IgE)-binding proteins (Mac-2/epsilon BP) of the S-type lectin family: role in IgE-dependent activation. J. Exp. Med. 177, 243-248.
Truong, M.J., Gruart, V., Liu, F.T., Prin, L., Capron, A., and Capron, M. (1993b). IgE-binding molecules (Mac-2/epsilon BP) expressed by human eosinophils. Implication in IgE-dependent eosinophil cytotoxicity. Eur. J. Immunol. 23, 3230-3235.
van den Brule, F.A., Buicu, C., Baldet, M., Sobel, M.E., Cooper, D.N., Marschal, P., and Castronovo, V. (1995). Galectin-1 modulates human melanoma cell adhesion to laminin. Biochem. Biophys. Res. Commun. 209, 760-767.
van der Leij, J., van den Berg, A., Blokzijl, T., Harms, G., van Goor, H., Zwiers, P., van Weeghel, R., Poppema, S., and Visser, L. (2004). Dimeric galectin-1 induces IL-10 production in T-lymphocytes: an important tool in the regulation of the immune response. J. Pathol. 204, 511-518.
Wadhwa, R., Kaul, S.C., Miyagishi, M., and Taira, K. (2004). Know-how of RNA interference and its applications in research and therapy. Mutat. Res. 567, 71-84.
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.
Wells, V., and Mallucci, L. (1991). Identification of an autocrine negative growth factor: mouse beta-galactoside-binding protein is a cytostatic factor and cell growth regulator. Cell 64, 91-97.
Wiznerowicz, M., and Trono, D. (2003). Conditional suppression of cellular genes: lentivirus vector-mediated drug-inducible RNA interference. J. Virol. 77, 8957-8961.
Woo, H.J., Shaw, L.M., Messier, J.M., and Mercurio, A.M. (1990). The major non-integrin laminin binding protein of macrophages is identical to carbohydrate binding protein 35 (Mac-2). J. Biol. Chem. 265, 7097-7099.
Yang, R.Y., Hsu, D.K., and Liu, F.T. (1996). Expression of galectin-3 modulates T-cell growth and apoptosis. Proc. Natl. Acad. Sci. U S A 93, 6737-6742.
Yoo, T.J., Kim, S.Y., Stuart, J.M., Floyd, R.A., Olson, G.A., Cremer, M.A., and Kang, A.H. (1988). Induction of arthritis in monkeys by immunization with type II collagen. J. Exp. Med. 168, 777-782.
Yu, F., Finley, R.L., Jr., Raz, A., and Kim, H.R. (2002). Galectin-3 translocates to the perinuclear membranes and inhibits cytochrome c release from the mitochondria. A role for synexin in galectin-3 translocation. J. Biol. Chem. 277, 15819-15827.
Zufferey, R., Dull, T., Mandel, R.J., Bukovsky, A., Quiroz, D., Naldini, L., and Trono, D. (1998). Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J. Virol. 72, 9873-9880.
Zufferey, R., Nagy, D., Mandel, R.J., Naldini, L., and Trono, D. (1997). Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo. Nat. Biotechnol. 15, 871-875.
Zuniga, E., Rabinovich, G.A., Iglesias, M.M., and Gruppi, A. (2001). Regulated expression of galectin-1 during B-cell activation and implications for T-cell apoptosis. J. Leukoc. Biol. 70, 73-79.