Abstract
The transfer of genes encoding immunomodulatory agents into allografts holds promise as an inductive therapy in transplantation (reviewed in refs. 1–3). This approach is clinically applicable, since vascularized transplants are routinely perfused at the time of organ harvest and therefore may be transfected by perfusion. However, many fundamental aspects of this technology must be addressed before it may be optimally applied to clinical transplantation. For example, it has been suggested that immunosuppressive gene therapy may provide advantages over conventional immunosuppression (1–3). Notably, gene transfer should allow for the persistent, local release of the agent within the microenvironment of the graft, thereby negating the deleterious side effects of systemic immunosuppression. Although this feature of immunosuppressive gene transfer is attractive, it has not been validated. Indeed, adenovirus mediated transfer of CTLA4Ig in liver allografts results in readily detectable levels of the transgene product in the sera (4). Hence, local secretion of the transgene product may result in systemic immunosuppression and increased susceptibility to infections and neoplasia. This fundamental aspect of immunosuppressive gene therapy has not been fully addressed and should be rigorously investigated.
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References
Knechtle, S. J. (1996) Gene therapy and transplantation—a brief review. Transplant. Proc. 28(suppl 1), 19–23.
Bromberg, J. S., DeBruyne, L. A., Sung, R. S., and Qin, L. (2000) Gene transfer to facilitate transplantation, in Gene Therapy in Inflammatory Diseases (Evans, C. H. and Robbins, P. D., eds.), Birkhauser Verlag, Basel, pp. 163–204.
Giannoukakis, N., Thomson, A. W., and Robbins, P. D. (1999) Gene therapy in transplantation. Gene Ther. 6, 1499–1511.
Olthoff, K. M., Judge, T. A., Gelman, A. E., et al. (1998) Adenovirus-mediated gene transfer into cold-preserved liver allografts: Survival pattern and unresponsiveness following transduction with CTLA4Ig. Nat. Med. 4, 194–200.
Blaese, R. M., Culver, K. W., Miller, A. D., et al. (1995) T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years. Science 270, 475–480.
Riddell, S. R., Elliot, M., Lewinsohn, D. A., et al. (1996) T-cell mediated rejection of gene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected patients. Nat. Med. 2, 216–223.
Tripathy, S. K., Black, H. B., Goldwasser, E., and Leiden J. M. (1996) Immune responses to transgene-encoded proteins limit the stability of gene expression after injection of replication-defective adenovirus vectors. Nat. Med. 2, 545–550.
Kay, M. A., Landen, C. N., Rothenberg, S. R., et al. (1994) In vivo hepatic gene therapy: complete albeit transient correction of factor IX deficiency in hemophilia B dogs. Proc. Natl. Acad. Sci. USA 91, 2353–2357.
Connelly, S., Mount, J., Mauser, A., et al. (1996) Complete short-term correction of canine hemophilia A by in vivo gene therapy. Blood 88, 3846–3853.
Kozarsky, K. F., McKinley, D. R., Austin, L. L., Raper, S. E., Raper, Stratford-Perricaudet, L. D., and Wilson, J. M. (1994) In vivo correction of low density lipoprotein receptor deficiency in the Watanabe heritable hyperlipidemic rabbit with recombinant adenoviruses. J. Biol. Chem. 269, 13,695–13,702.
Yang, Y., Li, Q., Ertl, H. C. J., and Wilson, J. M. (1995) Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses. J. Virol. 69, 2004–2015.
Yang, Y., Jooss, K. U., Su, Q., Ertl, H. C. J., and Wilson, J. M. (1996) Immune responses to viral antigens versus transgene product in the elimination of recombinant adenovirus-infected hepatocytes in vivo. Gene Ther. 3, 137–44.
Vilquin, J.-T., Guerette, B., Kinoshita, I., et al. (1995) FK506 immunosuppression to control the immune reactions triggered by first-generation adenovirus-mediated gene transfer. Hum. Gene Ther. 6, 1391–1401.
Lee, M. G., Abina, M. A., Haddada, H., and Perricaudet, M. (1995) The constitutive expression of the immunomodulatory gp 19k protein in E1-, E3-adenoviral vectors strongly reduces the host cytotoxic T cell response against the vector. Gene Ther. 2, 256–262.
Ilan, Y., Droguett, G., Chowdhury, N. R., et al. (1997) Insertion of the adenoviral E3 region into a recombinant viral vector prevents antiviral humoral and cellular immune responses and permits long-term gene expression. Proc. Natl. Acad. Sci. USA 94, 2587–2592.
McCoy, R. D., Davidson, B. L., Roessler, B. J., Huffnagle, B. B., and Simon, R. H. (1995) Expression of human interleukin-1 receptor antagonist in mouse lungs using a recombinant adenovirus: effects on vector-induced inflammation. Gene Ther. 2, 437–442.
Qin, L., Ding, Y., Pahud, D. R., Robson, N. D., Shaked, A., and Bromberg, J. S. (1997) Adenovirus-mediated gene transfer of viral IL-10 inhibits the immune response to both alloantigen and adenoviral antigen. Hum. Gene Ther. 8, 1365–1374.
Chan, S. Y., Louie, M. C., Piccotti, J. R., et al. (1998) Genetic vaccination-induced immune responsiveness to the HIV protein Rev: emergence of the IL-2 producing helper T lymphocyte. Hum. Gene Ther. 9, 2187–2196.
Chan, S. Y., Goodman, R. E., Szmuszkovicz, J. R., et al. (2000) DNA-liposome versus adenoviral mediated gene transfer of TGFβ1 in vascularized cardiac allografts: Differential sensitivity of CD4+ and CD8+ T cells to TGFβ1. Transplantion 70, 1292–1301.
Kay, M. A., Glorioso, J. C., and Naldini, L. (2001) Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics. Nat. Med. 7, 33–39.
Trono, D. (2000) Lentiviral vectors: turning a deadly foe into a therapeutic agent. Gene Ther. 7, 20–23.
Monahan, P. E. and Samulski, R. J. (2000) AAV vectors: is clinical success on the horizon? Gene Ther. 7, 24–30.
Russell, D. W. and Kay, M. K. (1999) Adeno-associated virus vectors and hematology. Blood 94, 864–874.
Wilson, J. M. (1996) Adenoviruses as gene-delivery vehicles. N. Engl. J. Med. 334, 1185–1187.
Chan, S. Y., Li, K., Piccotti, J. R., et al. (1999) Tissue specific consequences of the anti-adenoviral immune response: Implications for cardiac transplants. Nat. Med. 5, 1143–1149.
Gao, X. and Huang, L. (1995) Cationic liposome-mediated gene transfer. Gene Ther. 2, 710–722.
Crystal, R. G. (1995) The gene as the drug. Nat. Med. 1, 15–17.
Li, S. and Huang, L. (2000) Nonviral gene therapy: promises and challenges. Gene Ther. 7, 31–34.
Ardehali, A., Fyfe, A., Laks, H., Drinkwater, D. C., Qiao, J.-H., and Lusis, A. (1995) Direct gene transfer into donor hearts at the time of harvest. J. Thorac. Cardiovasc, Surg. 109, 716–720.
Fyfe, A. I., Ardehali, A., Laks, H., Drinkwater, D. C., and Lusis, A. J. (1995) Biologic modification of the immune response in mouse cardiac isografts using gene transfer. J. Heart Lung Transplant. 14, S165–S170.
Dalesandro, J., Akimoto, H., Gorman, C. M., et al. (1996) Gene therapy for donor hearts: ex vivo liposome-mediated transfection. J. Thorac. Cardiovasc. Surg. 111, 416–422.
DeBruyne, L. A., Li, K., Chan, S. Y., Qin, L., Bishop, D. K., and Bromberg, J. S. (1998) Cationic lipid-mediated gene transfer of viral IL-10 prolongs graft survival in a vascularized cardiac allograft model. Gene Ther. 5, 1079–1087.
Stephan, D. J., Yang, A.-Y., San, H, et al. (1996) A new cationic liposome DNA complex enhances efficiency of arterial gene transfer in vivo. Human Gene Ther. 7, 1803–1812.
Corry, R. J., Winn, H. J., and Russell, P. S. (1973) Primarily vascularized allografts of hearts in mice: the role of H-2D, H-2K, and Non-H-2 antigens in rejection. Transplantation 16, 343.
Bishop, D. K., Shelby, J., and Eichwald, E. J. (1992) Mobilization of T lymphocytes following cardiac transplantation: evidence that CD4 positive cells are required for cytotoxic T lymphocyte activation, inflammatory endothelial development, graft infiltration, and acute allograft rejection. Transplantation 53, 849–857.
Chan, S. Y., DeBruyne, L. A., Goodman, R. E., Eichwald, E. J., and Bishop, D. K. (1995) In vivo depletion of CD8 positive T cells results in Th2 cytokine production and alternate mechanisms of allograft rejection. Transplantation 59, 1155–1161.
Piccotti, J. R., Chan, S. Y., Goodman, R. E., Magram, J., Eichwald, E. J., and Bishop, D. K. (1996) IL-12 antagonism induces Th2 responses, yet exacerbates mouse cardiac allograft rejection: evidence against a dominant protective role for Th2 cytokines in alloimmunity. J. Immunol. 157, 1951–1157.
Piccotti, J. R., Li, K., Chan, S. Y. et al. (1998) Alloantigen-reactive Th1 helper development in IL-12 deficient mice. J. Immunol. 160, 1132–1138.
Piccotti, J. R., Li, K., Chan, S. Y., Eichwald E. J., and D.K., Bishop. (1999) Cytokine regulation of chronic cardiac allograft rejection: evidence against a role for Th1 in the disease process. Transplantation 67, 1548–1555.
Bishop, D. K., Chan, S. Y., Eichwald, E. J., and Orosz, C. G. (2001) Immunobiology of allograft rejection in the absence of interferon-gamma: CD8+ effector cells develop independent of CD4+ cells and CD40–CD40L interactions. J. Immunol. 166, 3248–3255.
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Lu, G., Bishop, D.K. (2003). Theoretical and Technical Considerations for Gene Transfer into Vascularized Cardiac Transplants. In: Metzger, J.M. (eds) Cardiac Cell and Gene Transfer. Methods in Molecular Biology, vol 219. Springer, Totowa, NJ. https://doi.org/10.1385/1-59259-350-X:135
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DOI: https://doi.org/10.1385/1-59259-350-X:135
Publisher Name: Springer, Totowa, NJ
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