Abstract
Gene therapy represents a new form of medical intervention that relies on direct transfer of genetic materials into patients. Although initially envisioned as a treatment for genetic diseases, gene therapy is currently being explored for a wide range of acquired disorders including cancer, cardiovascular diseases, arthritis, and neurodegenerative disorders. Since most acquired diseases are not caused by single gene mutations, the choice of therapeutic genes is crucial for the success of the gene therapy. In this review, we discuss the progresses that have been made and problems that remain to be resolved in using Fas (CD95, Apo-1) ligand gene for the treatment of acquired disorders. Fas ligand is a member of the tumor necrosis factor family that can induce both apoptosis and activation of various cells. While Fas ligand gene transfer indeed eliminates cancer cells and inflammatory cells through apoptosis, it also kills normal cells and initiates inflammation in certain tissues. Thus, new strategies that can modify the apoptotic or proinflammatory activities of the FasL will help to fully realize the potential of the FasL gene therapy.
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REFERENCES
Trauth BC, Klas C, Peters AM, Matzku S, Moller P, Falk W, Debatin KM, Krammer PH: Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science 245:301, 1989
Nagata S, Golstein P: The Fas death factor. Science 267:1449, 1995
Nagata S: Apoptosis by death factor. Cell 88:355, 1997
Nagata S, Suda T: Fas and Fas ligand: lpr and gld mutations. Immunol Today 16:39, 1995
Arase H, Arase N, Saito T: Fas-mediated cytotoxicity by freshly isolated natural killer cells. J Exp Med 181:1235, 1995
Suda T, Okazaki T, Naito Y, Yokota T, Arai N, Ozaki S, Nakao K, Nagata S: Expression of the Fas ligand in cells of T cell lineage. J Immunol 154:3806, 1995
Nagata S: Fas and FasL: A death factor and its receptor. Adv Immunol 57:129, 1996
Ramsdell F, Seaman MS, Miller RE, Tough TW, Alderson MR, Lynch DH: gld/gld mice are unable to express a functional ligand for Fas. Eur J Immunol 24:928, 1994
Takahashi T, Tanaka M, Brannan CI, Jenkins NA, Copeland NG, Suda T, Nagata S: Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell 76:969, 1994
Abbas AK: Die and let live: Eliminating dangerous lymphocytes. Cell 84:655, 1996
Hahne M, Rimoldi D, Schroter M, Romero P, Schreier M, French LE, Schneider P, Bornand T, Fontana A, Lienard D, Cerottini J, Tschopp J: Melanoma cell expression of Fas(Apo-1/CD95) ligand: Implications for tumor immune escape. Science 274:1363, 1996
Arai H, Chan SY, Bishop DK, Nabel GJ: Inhibition of the alloantibody response by CD95 ligand. Nature Med 3:843, 1997
Seino K, Kayagaki N, Okumura K, Yagita H: Antitumor effect of locally produced CD95 ligand. Nat Med 3:165, 1997
Galle PR, Hofmann WJ, Walczak H, Schaller H, Otto G, Stremmel W, Krammer PH, Runkel L: Involvement of the CD95 (Apo-1/Fas) receptor and ligand in liver damage. J Exp Med 182:1223, 1995
Boudet F, Lecoeur H, Gougeon ML: Apoptosis associated with ex vivo down-regulation of Bcl-2 and up-regulation of Fas in potential cytotoxic CD81 T lymphocytes during HIV infection. J Immunol 156:2282, 1996
De Maria R, Boirivant M, Cifone MG, Roncaioli P, Hahne M, Tschopp J, Pallone F, Santoni A, Testi R: Functional expression of Fas and Fas ligand on human gut lamina propria T lymphocytes. A potential role for the acidic sphingomyelinase pathway in normal immunoregulation. J Clin Invest 97:316, 1996
Peter ME, Kischkel FC, Scheuerpflug CG, Medema JP, Debatin KM, Krammer PH: Resistance of cultured peripheral T cells towards activation-induced cell death involves a lack of recruitment of FLICE (MACH/caspase 8) to the CD95 death-inducing signaling complex. Eur J Immunol 27:1207, 1997
Cifone MG, Roncaioli P, De Maria R, Camarda G, Santoni A, Ruberti G, Testi: Multiple pathways originate at the Fas/APO-1 (CD95) receptor: Sequential involvement of phosphatidylcholinespecific phospholipase C and acidic sphingomyelinase in the propagation of the apoptotic signal. EMBO J 14:5859, 1995
Martin SJ, Green DR: Protease activation during apoptosis: Death by a thousand cuts? Cell 82:349, 1995
Testi R: Sphingomyelin breakdown and cell fate. Trends Biochem Sci 21:468, 1996
Chan FK, Chun HJ, Zheng L, Siegel RM, Bui KL, Lenardo MJ: A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science 288:2351, 2000
Chinnaiyan AM, O'Rourke K, Tewari M, Dixit VM: FADD, a novel death domain-containing protein, interact with the death domain of Fas and initiates apoptosis. Cell 81:505, 1995
Zhang J, Cado D, Chen A, Kabra NH, Winoto A: Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature 392:296, 1998
Boldin MP, Goncharov TM, Goltsev YV, Wallach D: Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/ APO-1-and TNF receptor-induced cell death. Cell 85:803, 1996
Muzio M, Stockwell BR, Stennicke HR, Salvesen GS, Dixit VM: An induced proximity model for caspase-8 activation. J Biol Chem 273:2926, 1998
Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter ME: Cytotoxicity-dependent APO-1 (Fas/ CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J 14:5579, 1995
Yang X, Chang HY, Baltimore D: Autoproteolytic activation of pro-caspases by oligomerization. Mol Cell 1:319, 1998
Enari M, Talanian RV, Wong WW, Nagata S: Sequential activation of ICE-like and CPP32-like proteases during Fas-mediated apoptosis. Nature 380:723, 1996
Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME, Dixit VM: FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85:817, 1996
Villa P, Kaufmann SH, Earnshaw WC: Caspases and caspase inhibitors. Trends Biochem Sci 22:388, 1997
Yang X, Khosravi-Far R, Chang HY, Baltimore D: Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell 89:1067, 1997
Thome M, Schneider P, Hofmann K, Fickenscher H, Meinl E, Neipel F, Mattmann C, Burns K, Bodmer JL, Schroter M, Scaffidi C, Krammer PH, Peter ME, Tschopp J: Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386:517, 1997
Wallach D: Apoptosis. Placing death under control. Nature 388:125, 1997
Colombo MP, Forni G: Cytokine gene transfer in tumor inhibition and tumor therapy: Where are we now? Immunol Today 15:48, 1994
Arai H, Gordon D, Nabel EG, Nabel GJ: Gene transfer of Fas ligand induces tumor regression in vivo. Proc Natl Acad Sci USA 94:13862, 1997
Bellgrau D, Gold D, Selawry H, Moore J, Franzusoff A, Duke RC: A role for CD95 ligand in preventing graft rejection. Nature 377:630, 1995
Griffith TS, Brunner T, Fletcher SM, Green DR, Ferguson TA: Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 270:1189, 1995
Lau HT, Yu M, Fontana A, Stoeckert CJ: Prevention of islet allograft rejection with engineered myoblasts expressing FasL in mice. Science 273:109, 1996
Chen JJ, Sun Y, Nabel GJ: Regulation of the proinflammatory effects of Fas ligand (CD95L). Science 282:1714, 1998
Liles WC, Kiener PA, Ledbetter JA, Aruffo A, Klebanoff SJ: Differential expression of Fas (CD95) and Fas ligand on normal human phagocytes: Implications for the regulation of apoptosis in neutrophils. J Exp Med 184:429, 1996
Arnold B, Schonrich G, Hammerling GJ: Multiple levels of peripheral tolerance. Immunol Today 14:12, 1993
Kabelitz D, Janssen O: Antigen-induced death of T-Lymphocytes. Front Biosci 2:d61, 1997
Wang J, Nonomura N, Ichimaru N, Azuma H, Hatori M, Kokado Y, Matsumiya K, Miki T, Takahara S, Okuyama A: Expression of Fas and Fas ligand in renal grafts with acute and chronic rejection in the rat model. J Interferon Cytokine Res 17:369, 1997
Krams SM, Egawa H, Quinn MB, Villanueva JC, Garcia-Kennedy R, Martinez OM: Apoptosis as a mechanism of cell death in liver allograft rejection. Transplantation 59:621, 1995
Fayyazi A, Schlemminger R, Gieseler R, Peters JH, Radzun HJ: Apoptosis in the small intestinal allograft of the rat. Transplantation 63:947, 1997
Szabolcs M, Michler RE, Yang X, Aji W, Roy D, Athan E, Sciacca RR, Minanov OP, Cannon PJ: Apoptosis of cardiac myocytes during cardiac allograft rejection. Relation to induction of nitric oxide synthase. Circulation 94:1665, 1996
Bergese SD, Klenotic SM, Wakely ME, Sedmak DD, Orosz CG: Apoptosis in murine cardiac grafts. Transplantation 63:320, 1997
Sharma VK, Bologa RM, Li B, Xu GP, Lagman M, Hiscock W, Mouradian J, Wang J, Serur D, Rao VK, Suthanthiran M: Molecular executors of cell death-differential 71 intrarenal expression of Fas ligand, Fas, Granzyme B, and perforin during acute and/or chronic rejection of human renal allografts. Transplantation 62:1860, 1996
Larsen CP, Alexander DZ, Hendrix R, Ritchie SC, Pearson TC: Fas-mediated cytotoxicity. An immunoeffector or immunoregulatory pathway in T cell-mediated immune responses? Transplantation 60:221, 1995
Jollow KC, Sundstrom JB, Gravanis MB, Kanter K, Herskowitz A, Ansari AA: Apoptosis of mononuclear cell infiltrates in cardiac allograft biopsy specimens questions studies of biopsy-cultured cells. Transplantation 63:1482, 1997
Qian S, Lu L, Fu F, Li Y, Li W, Starzl TE, Fung JJ, Thomson AW: Apoptosis within spontaneously accepted mouse liver allografts: Evidence for deletion of cytotoxic T cells and implications for tolerance induction. J Immunol 158:4654, 1997
Allison J, Georgiou HM, Strasser A, Vaux DL: Transgenic expression of CD 95 ligand on islet beta cells induces a granulocytic infiltration but does not confer immune privilege upon islet allografts. Proc Natl Acad Sci USA 94:3943, 1997
Kang SM, Schneider DB, Lin Z, Hanahan D, Dichek DA, Stock PG, Baekkeskov S: Fas ligand expression in islets of Langerhans does not confer immune privilege and instead targets them for rapid destruction. Nat Med 3:738, 1997
Stuart PM, Griffith TS, Usui N, Pepose J, Yu X, Ferguson TA: CD95 ligand (FasL)-induced apoptosis is necessary for corneal allograft survival. J Clin Invest 99:396, 1997
Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S: Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356:314, 1992
Drappa J, Vaishnaw AK, Sullivan KE, Chu JL, Elkon KB: Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity. N Engl J Med 335:1643, 1996
Fisher GH, Rosenberg FJ, Straus SE, Dale JK, Middleton LA, Lin AY, Strober W, Lenardo MJ, Puck JM: Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 81:935, 1995
Griffith TS, Yu X, Herndon JM, Green DR, Ferguson TA: CD95-induced apoptosis of lymphocytes in an immune privileged site induces immunological tolerance. Immunity 5:7, 1996
Tisch R, McDevitt H: Insulin-dependent diabetes mellitus. Cell 85:291, 1996
Itoh N, Imagawa A, Hanafusa T, Waguri M, Yamamoto K, Iwahashi H, Moriwaki M, Nakajima H, Miyagawa J, Namba M, Makino S, Nagata S, Kono N, Matsuzawa Y: Requirement of Fas for the development of autoimmune diabetes in nonobese diabetic mice. J Exp Med 186:613, 1997
Bauer J, Ruuls SR, Huitinga I, Dijkstra CD: The role of macrophage subpopulations in autoimmune disease of the central nervous system. Histochem J 28:83, 1996
Martin R, McFarland HF, McFarlin DE: Immunological aspects of demyelinating diseases. Annu Rev Immunol 10:153, 1992
Sabelko KA, Kelly KA, Nahm MH, Cross AH, Russell JH: Fas and Fas ligand enhance the pathogenesis of experimental allergic encephalomyelitis, but are not essential for immune privilege in the central nervous system. J Immunol 159:3096, 1997
Waldner H, Sobel RA, Howard E, Kuchroo VK: Fas-and FasLdeficient mice are resistant to induction of autoimmune encephalomyelitis. J Immunol 159:3100, 1997
Liu TS, Hillard B, Samoilova EB, Chen Y: Differential roles of Fas ligand in spontaneous and actively induced autoimmune encephalomyelitis. Clin Immunol 95:203, 2000
Suvannavejh GC, Dal Canto MC, Matis LA, Miller SD: Fasmediated apoptosis in clinical remissions of relapsing experimental autoimmune encephalomyelitis. J Clin Invest 105:223, 2000
D'souza SD, Bonetti B, Balasingam V, Cashman NR, Barker PA, Troutt AB, Raine CS, Antel JP: Multiple sclerosis: Fas signaling in oligodendrocyte cell death. J Exp Med 184:2361, 1996
Cantwell MJ, Hua T, Zvaifler NJ, Kipps TJ: Deficient Fas ligand expression by synovial lymphocytes from patients with rheumatoid arthritis. Arthritis Rheum 40:1644, 1997
Fujisawa K, Asahara H, Okamoto K, Aono H, Hasunuma T, Kobata T, Iwakura Y, Yonehara S, Sumida T, Nishioka K: Therapeutic effect of the anti-Fas antibody on arthritis in HTLV-1 tax transgenic mice. J Clin Invest 98:271, 1996
Zhang H, Yang Y, Horton JL, Samoilova EB, Judge TA, Turka LA, Wilson JM, Chen Y: Amelioration of collagen-induced arthritis by CD95 (Apo-1/Fas)-ligand gene transfer. J Clin Invest 100:1951, 1997
Chervonsky AV, Wang Y, Wong FS, Visintin I, Flavell RA, Janeway CA, Matis LA: The role of Fas in autoimmune diabetes. Cell 89:17, 1997
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Lamhamedi-Cherradi, SE., Chen, Y. Fas (CD95, Apo-1) Ligand Gene Transfer. J Clin Immunol 21, 24–29 (2001). https://doi.org/10.1023/A:1006784830473
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DOI: https://doi.org/10.1023/A:1006784830473