Abstract
Gene transfer using a recombinant adenovirus is a powerful tool for research and clinical applications, but its cytotoxicity and immune response limit its use, especially when repeated application of the vector is necessary. This study investigated the effects of dexamethasone (DEX)-induced immunosuppression on the outcome of adenovirus gene transfer in guinea pig inner ears. Animals received DEX for 29 days. Their inner ear was inoculated with 5 µl of adenovirus vector twice, on days 5 and 26. Auditory brainstem response was measured on days 1, 8 and 29. The animals were sacrificed on day 29, and reporter gene expression was evaluated. In control animals that received no DEX, postinoculation threshold shifts and lesions in the organ of Corti were observed and reporter gene expression was absent. In contrast, DEX-treated ears were largely protected, and transduction of inner ear cells was readily apparent. These data demonstrate that immunosuppressive treatment can reduce the negative consequences of repeated adenovirus-mediated gene therapy.
References
1.
Ardehali H, Volmar K, Roberts C, Forman M, Becker LC: Fatal disseminated adenoviral infection in a renal transplant patient. Transplantation 2001;71:998–999.
2.
Benihoud K, Yeh P, Perricaudet M: Adenovirus vectors for gene delivery. Curr Opin Biotechnol 1999;10:440–447.
3.
Boumpas DT, Paliogianni F, Anastassiou ED, Balow JE: Glucocorticosteroid action on the immune system: Molecular and cellular aspects. Clin Exp Rheumatol 1991;9:413–423.
4.
Bouvet M, Fang B, Ekmekcioglu S, Ji L, Bucana CD, Hamada K, Grimm EA, Roth JA: Suppression of the immune response to an adenovirus vector and enhancement of intratumoral transgene expression by low-dose etoposide. Gene Ther 1998;5:189–195.
5.
Cichon G, Strauss M: Transient immunosuppression with 15-deoxyspergualin prolongs reporter gene expression and reduces humoral immune response after adenoviral gene transfer. Gene Ther 1998;5:85–90.
6.
Darmstadt GL, Keithley EM, Harris JP: Effects of cyclophosphamide on the pathogenesis of cytomegalovirus-induced labyrinthitis. Ann Otol Rhinol Laryngol 1990;99:960–968.
7.
Dazert S, Battaglia A, Ryan AF: Transfection of neonatal rat cochlear cells in vitro with an adenovirus vector. Int J Dev Neurosci 1997;15:595–600.
8.
Derby ML, Sena-Esteves M, Breakefield XO, Corey DP: Gene transfer into the mammalian inner ear using HSV-1 and vaccinia virus vectors. Hear Res 1999;134:1–8.
9.
Gillis S, Crabtree GR, Smith KA: Glucocorticoid-induced inhibition of T cell growth factor production. I. The effect on mitogen-induced lymphocyte proliferation. J Immunol 1979;123:1624–1631.
10.
Harris JP: Immunology of the inner ear: Response of the inner ear to antigen challenge. Otolaryngol Head Neck Surg 1983;91:18–32.
11.
Jooss K, Turka LA, Wilson JM: Blunting of immune responses to adenoviral vectors in mouse liver and lung with CTLA4Ig. Gene Ther 1998;5:309–319.
12.
Kanzaki J: Immune-mediated sensorineural hearing loss. Acta Otolaryngol Suppl 1994;514:70–72.
13.
Kaplan JM, Smith AE: Transient immunosuppression with deoxyspergualin improves longevity of transgene expression and ability to readminister adenoviral vector to the mouse lung. Hum Gene Ther 1997;8:1095–1104.
14.
Kitajima T, Ariizumi K, Bergstresser PR, Takashima A: A novel mechanism of glucocorticoid-induced immune suppression: The inhibiton of T-cell-mediated terminal maturation of a murine dendritic cell line. J Clin Invest 1996;98:142–147.
15.
Kozarsky KF, McKinley DR, Austin LL, Raper SE, Stratford-Perricaudet LD, Wilson JM: In vivo correction of low density lipoprotein receptor deficiency in the Watanabe heritable hyperlipidemic rabbit with recombinant adenoviruses. J Biol Chem 1994;269:13695–13702.
16.
Kuriyama S, Tominaga K, Kikukawa M, Tsujimoto T, Nakatani T, Tsujinoue H, Okuda H, Nagao S, Mitoro A, Yoshiji H, Fukui H: Transient cyclophosphamide treatment before intraportal readministration of an adenoviral vector can induce re-expression of the original gene construct in rat liver. Gene Ther 1999;6:749–757.
17.
Lalwani AK, Mhatre AN: Cochlear gene therapy. Adv Otorhinolaryngol 2000;56:275–278.
18.
Lalwani A, Walsh B, Reilly P, Carvalho G, Zolotukhin S, Muzyczka N, Mhatre A: Long-term in vivo cochlear transgene expression mediated by recombinant adeno-associated virus. Gene Ther 1998;5:277–281.
19.
Lei D, Lehmann M, Shellito JE, Nelson S, Siegling A, Volk HD, Kolls JK: Nondepleting anti-CD4 antibody treatment prolongs lung-directed E1-deleted adenovirus-mediated gene expression in rats. Hum Gene Ther 1996;7:2273–2279.
20.
Luebke AE, Steiger JD, Hodges BL, Amalfitano A: A modified adenovirus can transfect cochlear hair cells in vivo without compromising cochlear function. Gene Ther 2001;8:789–794.
21.
Ma C, Billings P, Harris JP, Keithley EM: Characterization of an experimentally induced inner ear immune response. Laryngoscope 2000;110:451–456.
22.
Mayo D, Armstrong JA, Ho M: Activation of latent murine cytomegalovirus infection: Cocultivation, cell transfer, and the effect of immunosuppression. J Infect Dis 1978;138:890–896.
23.
Munck A, Guyre PM, Holbrook NJ: Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev 1984;5:25–44.
24.
Nabel GJ: From rhyme to reason. Nature 1998;392:3–4.
25.
Nabel GJ: Development of optimized vectors for gene therapy. Proc Natl Acad Sci USA 1999;96:324–326.
26.
Raphael Y, Frisancho JC, Roessler BJ: Adenoviral-mediated gene transfer into guinea pig cochlear cells in vivo. Neurosci Lett 1996;207:137–141.
27.
Rosenberg SA, Blaese RM, Brenner MK, Deisseroth AB, Ledley FD, Lotze MT, Wilson JM, Nabel GJ, Cornetta K, Economou JS, Freeman SM, Riddell SR, Oldfield E, Gansbacher B, Dunbar C, Walker RE, Schuening FG, Roth JA, Crystal RG, Welsh MJ, Culver K, Heslop HE, Simons J, Wilmott RW, Tiberghien P, et al: Human gene marker/therapy clinical protocols. Hum Gene Ther 1996;7:2287–2313.
28.
Russo-Marie F: Macrophages and the glucocorticoids. J Neuroimmunol 1992;40:281–286.
29.
Scaria A, St George JA, Gregory RJ, Noelle RJ, Wadsworth SC, Smith AE, Kaplan JM: Antibody to CD40 ligand inhibits both humoral and cellular immune responses to adenoviral vectors and facilitates repeated administration to mouse airway. Gene Ther 1997;4:611–617.
30.
Smith TA, Mehaffey MG, Kayda DB, Saunders JM, Yei S, Trapnell BC, McClelland A, Kaleko M: Adenovirus mediated expression of therapeutic plasma levels of human factor IX in mice. Nat Genet 1993;5:397–402.
31.
Smith TA, White BD, Gardner JM, Kaleko M, McClelland A: Transient immunosuppression permits successful repetitive intravenous administration of an adenovirus vector. Gene Ther 1996;3:496–502.
32.
Staecker H, Gabaizadeh R, Federoff H, Van de Water TR: Brain-derived neurotrophic factor gene therapy prevents spiral ganglion degeneration after hair cell loss. Otolaryngol Head Neck Surg 1998;119:7–13.
33.
Stam WB, Van Oosterhout AJ, Nijkamp FP: Pharmacologic modulation of Th1- and Th2-associated lymphokine production. Life Sci 1993;53:1921–1934.
34.
Stöver T, Yagi M, Raphael Y: Cochlear gene transfer: Round window versus cochleostomy inoculation. Hear Res 1999;136:124–130.
35.
Stöver T, Yagi M, Raphael Y: Transduction of the contralateral ear after adenovirus-mediated cochlear gene transfer. Gene Ther 2000;7:377–383.
36.
Suzuki M, Yagi M, Brown JN, Miller AL, Miller JM, Raphael Y: Effect of transgenic GDNF expression on gentamicin-induced cochlear and vestibular toxicity. Gene Ther 2000;7:1046–1054.
37.
Tomiyama S, Harris JP: Elevation of inner ear antibody levels following direct antigen challenge of the endolymphatic sac. Acta Otolaryngol 1989;107:202–209.
38.
Tortorella D, Gewurz BE, Furman MH, Schust DJ, Ploegh HL: Viral subversion of the immune system. Annu Rev Immunol 2000;18:861–926.
39.
Vilquin JT, Guerette B, Kinoshita I, Roy B, Goulet M, Gravel C, Roy R, Tremblay JP: FK506 immunosuppression to control the immune reactions triggered by first-generation adenovirus-mediated gene transfer. Hum Gene Ther 1995;6:1391–1401.
40.
Whitlon DS, Szakaly R, Greiner MA: Cryoembedding and sectioning of cochleas for immunocytochemistry and in situ hybridization. Brain Res Brain Res Protoc 2001;6:159–166.
41.
Woolf NK, Harris JP: Cochlear pathophysiology associated with inner ear immune responses. Acta Otolaryngol 1986;102:353–364.
42.
Yagi M, Magal E, Sheng Z, Ang KA, Raphael Y: Hair cell protection from aminoglycoside ototoxicity by adenovirus-mediated overexpression of glial cell line-derived neurotrophic factor. Hum Gene Ther 1999;10:813–823.
43.
Yagi M, Kanzaki S, Kawamoto K, Shin B, Shah PP, Magal E, Sheng J, Raphael Y: Spiral ganglion neurons are protected from degeneration by GDNF gene therapy. JARO 2000;1:315–325.
44.
Yang Y, Jooss KU, Su Q, Ertl HC, Wilson JM: Immune responses to viral antigens versus transgene product in the elimination of recombinant adenovirus-infected hepatocytes in vivo. Gene Ther 1996a;3:137–144.
45.
Yang Y, Su Q, Grewal IS, Schilz R, Flavell RA, Wilson JM: Transient subversion of CD40 ligand function diminishes immune responses to adenovirus vectors in mouse liver and lung tissues. J Virol 1996a;70:6370–6377.
46.
Yei S, Mittereder N, Tang K, O’Sullivan C, Trapnell BC: Adenovirus-mediated gene transfer for cystic fibrosis: Quantitative evaluation of repeated in vivo vector administration to the lung. Gene Ther 1994;1:192–200.
47.
Zsengeller ZK, Wert SE, Hull WM, Hu X, Yei S, Trapnell BC, Whitsett JA: Persistence of replication-deficient adenovirus-mediated gene transfer in lungs of immune-deficient (nu/nu) mice. Hum Gene Ther 1995;6:457–467.
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2003
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