Abstract
Gene therapy of inherited hepatic disease relies on sustained expression of the therapeutic transgene. In many instances, such expression will require immune tolerization to the non-self therapeutic transgene product. We previously demonstrated that a cytotoxic immune response eliminated hepatocytes after in vivo transduction using recombinant retroviral vectors. In the present study we investigated whether prior gene transfer to the retina, which is suspected to induce immune tolerance, could alleviate the immune response occurring after retrovirus mediated gene transfer to the liver. Retinal cells were transduced using adeno-associated viral vectors harbouring a β-galactosidase transgene. Sixty days later, regenerating hepatocytes were transduced after partial hepatectomy using a recombinant retrovirus carrying the transgene. Three weeks later, anti β-galactosidase antibodies were present in all animals. Elimination of the transduced hepatocytes eventually occurred in all animals by 2 months after liver gene transfer, although sustained β-galactosidase expression was still present in the retina in 66% of the animals. We conclude that although the retina behaves as an immunoprivileged site, gene expression in the subretinal space is not sufficient to induce immune tolerance to a transgene product expressed in the liver.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Kitten O, Cosset FL, Ferry N (1997) Highly efficient retrovirus-mediated gene transfer into rat hepatocytes in vivo. Hum Gene Ther 8:1491–1494
Izembart A, Aguado E, Gauthier O, Aubert D, Moullier P, Ferry N (1999) In vivo retrovirus-mediated gene transfer to the liver of dogs results in transient expression and induction of a cytotoxic immune response. Hum Gene Ther 10:2917–2925
Aubert D, Menoret S, Chiari E, Pichard V, Durand S, Tesson L, Moullier P, Anegon I, Ferry N (2002) Cytotoxic immune response blunts long-term transgene expression after efficient retroviral-mediated hepatic gene transfer in rat. Mol Ther 5:388–396
Ponder KP, Melniczek JR, Xu L, Weil MA, O’Malley TM, O’Donnell PA, Knox VW, Aguirre GD, Mazrier H, Ellinwood NM, Sleeper M, Maguire AM, Volk SW, Mango RL, Zweigle J, Wolfe JH, Haskins ME (2002) Therapeutic neonatal hepatic gene therapy in mucopolysaccharidosis VII dogs. Proc Natl Acad Sci USA 99:13102–13107
Ilan Y, Jona VK, Sengupta K, Davidson A, Horwitz MS, Roy-Chowdhury N, Roy-Chowdhury J (1997) Transient immunosuppression with FK506 permits long-term expression of therapeutic genes introduced into the liver using recombinant adenoviruses in the rat. Hepatology 26:949–956
Jooss K, Yang Y, Wilson JM (1996) Cyclophosphamide diminishes inflammation and prolongs transgene expression following delivery of adenoviral vectors to mouse liver and lung. Hum Gene Ther 7:1555–1566
Thummala NR, Ghosh SS, Lee SW, Reddy B, Davidson A, Horwitz MS, Chowdhury JR, Chowdhury NR (2002) A non-immunogenic adenoviral vector, coexpressing CTLA4Ig and bilirubin-uridine-diphosphoglucuronateglucuronosyltransferase permits long-term, repeatable transgene expression in the Gunn rat model of Crigler-Najjar syndrome. Gene Ther 9:981–990
Kay MA, Meuse L, Gown AM, Linsley P, Hollenbaugh D, Aruffo A, Ochs HD, Wilson CB (1997) Transient immunomodulation with anti-CD40 ligand antibody and CTLA4Ig enhances persistence and secondary adenovirus-mediated gene transfer into mouse liver. Proc Natl Acad Sci USA 94:4686–4691
Yang YP, Su Q, Grewal IS, Schilz R, Flavell RA, Wilson JM (1996) Transient subversion of CD40 ligand function diminishes immune responses to adenovirus vectors in mouse liver and lung tissues. J Virol 70:6370–6377
Ilan Y, Attavar P, Takahashi M, Davidson A, Horwitz MS, Guida J, Chowdhury NR, Chowdhury JR (1996) Induction of central tolerance by intrathymic inoculation of adenoviral antigens into the host thymus permits long-term gene therapy in Gunn rats. J Clin Invest 98:2640–2647
Ilan Y, Prakash R, Davidson A, Jona Droguett G, Horwitz MS, Chowdhury NR, Chowdhury JR (1997) Oral tolerization to adenoviral antigens permits long-term gene expression using recombinant adenoviral vectors. J Clin Invest 99:1098–1106
Heim DA, Hanazono Y, Giri N, Wu T, Childs R, Sellers SE, Muul L, Agricola BA, Metzger ME, Donahue RE, Tisdale JF, Dunbar CE (2000) Introduction of a xenogeneic gene via hematopoietic stem cells leads to specific tolerance in a rhesus monkey model. Mol Ther 1:533–544
Donahue RE, Wersto RP, Allay JA, Agricola BA, Metzger ME, Nienhuis AW, Persons DA, Sorrentino BP (2000) High levels of lymphoid expression of enhanced green fluorescent protein in nonhuman primates transplanted with cytokine-mobilized peripheral blood CD34(+) cells. Blood 95:445–452
Rosenzweig M, MacVittie TJ, Harper D, Hempel D, Glickman RL, Johnson RP, Farese AM, Whiting-Theobald N, Linton GF, Yamasaki G, Jordan CT, Malech HL (1999) Efficient and durable gene marking of hematopoietic progenitor cells in nonhuman primates after nonablative conditioning. Blood 94:2271–2286
Anand V, Duffy B, Yang Z, Dejneka NS, Maguire AM, Bennett J (2002) A deviant immune response to viral proteins and transgene product is generated on subretinal administration of adenovirus and adeno-associated virus. Mol Ther 5:125–132
Salvetti A, Oreve S, Chadeuf G, Favre D, Cherel Y, Champion-Arnaud P, David-Ameline J, Moullier P (1998) Factors influencing recombinant adeno-associated virus production. Hum Gene Ther 9:695–706
Cosset FL, Takeuchi Y, Battini JL, Weiss RA, Collins MKL (1995) High-titer packaging cells producing recombinant retroviruses resistant to human serum. J Virol 69:7430–7436
Duisit G, Conrath H, Saleun S, Folliot S, Provost N, Cosset FL, Sandrin V, Moullier P, Rolling F (2002) Five recombinant simian immunodeficiency virus pseudotypes lead to exclusive transduction of retinal pigmented epithelium in rat. Mol Ther 6:446–454
Higgins GM, Anderson RM (1931) Experimental pathology of the liver I. Restoration of the liver of the white rat following partial surgical removal. Arch Pathol 12:186–202
Ali RR, Reichel MB, De Alwis M, Kanuga N, Kinnon C, Levinsky RJ, Hunt DM, Bhattacharya SS, Thrasher AJ (1998) Adeno-associated virus gene transfer to mouse retina. Hum Gene Ther 9:81–86
Bennett J, Maguire AM, Cideciyan AV, Schnell M, Glover E, Anand V, Aleman TS, Chirmule N, Gupta AR, Huang Y, Gao GP, Nyberg WC, Tazelaar J, Hughes J, Wilson JM, Jacobson SG (1999) Stable transgene expression in rod photoreceptors after recombinant adeno-associated virus-mediated gene transfer to monkey retina. Proc Natl Acad Sci USA 96:9920–9925
Ali RR, Reichel MB, Thrasher AJ, Levinsky RJ, Kinnon C, Kanuga N, Hunt DM, Bhattacharya SS (1996) Gene transfer into the mouse retina mediated by an adeno-associated viral vector. Hum Mol Genet 5:591–594
Podevin G, Otta E, Nguyen JM, Pichard V, Aubert D, Moullier P, Ferry N (2004) Factors influencing immune response after in vivo retrovirus-mediated gene transfer to the liver. J Gene Med 6:16–21
Isenmann S, Engel S, Kugler S, Gravel C, Weller M, Bahr M (2001) Intravitreal adenoviral gene transfer evokes an immune response in the retina that is directed against the heterologous lacZ transgene product but does not limit transgene expression. Brain Res 892:229–240
Folliot S, Briot D, Conrath H, Provost N, Cherel Y, Moullier P, Rolling F (2003) Sustained tetracycline-regulated transgene expression in vivo in rat retinal ganglion cells using a single type 2 adeno-associated viral vector. J Gene Med 5:493–501
Weber M, Rabinowitz J, Provost N, Conrath H, Folliot S, Briot D, Cherel Y, Chenuaud P, Samulski J, Moullier P, Rolling F (2003) Recombinant adeno-associated virus serotype 4 mediates unique and exclusive long-term transduction of retinal pigmented epithelium in rat, dog, and nonhuman primate after subretinal delivery. Mol Ther 7:774–781
Sarukhan A, Soudais C, Danos O, Jooss K (2001) Factors influencing cross-presentation of non-self antigens expressed from recombinant adeno-associated virus vectors. J Gene Med 3:260–270
Aubert D, Pichard V, Durand S, Moullier P, Ferry N (2003) Cytotoxic immune response after retroviral-mediated hepatic gene transfer in rat does not preclude expression from adeno-associated virus 1 transduced muscles. Hum Gene Ther 14:473–481
Gregerson DS, Torseth JW, McPherson SW, Roberts JP, Shinohara T, Zack DJ (1999) Retinal expression of a neo-self antigen, beta-galactosidase, is not tolerogenic and creates a target for autoimmune uveoretinitis. J Immunol 163:1073–1080
McPherson SW, Roberts JP, Gregerson DS (1999) Systemic expression of rat soluble retinal antigen induces resistance to experimental autoimmune uveoretinitis. J Immunol 163:4269–4276
Acknowledgements
This work was supported by grants from the Association Française contre les Myopathies. We thank the vector core facility of the University Hospital of Nantes for the preparation of AAV vectors.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bellodi-Privato, M., Le Meur, G., Aubert, D. et al. AAV gene transfer to the retina does not protect retrovirally transduced hepatocytes from the immune response. J Mol Med 82, 403–410 (2004). https://doi.org/10.1007/s00109-004-0537-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00109-004-0537-0