Investigation of gene therapy of denovirus in immune suppression

Abstract

The aim of this paper is to investigate the safety of reconstructed adenovirus in immunosuppressive therapeutics and to explore the role of ciclosporin A in antagonizing the elimination of the vector. Several rats were given retroperitoneal injection of purified ADV-TK in order to obtain models. After 14 days’ treatment of ciclosporin A, samples of different periods were obtained, then stained with hematoxylin-eosin (HE) to detect inflammation reactions. Immunohistochemistry was used to examine the expression of adenovirus in organs. The results are as follows: (1) In HE stained sections of the organs, some transitory and reversible inflammation was detected. (2) In immunohistochemistry assay, reconstructed adenovirus decreased gradually as time went by in the control group, while it did not happen in the experimental group in which the adenovirus showed a relative increase compared with their counterparts (P < 0.05). (3) The distributions of adenovirus in the liver, spleen and lung were higher than those in the other organs detected. Reconstructed adenovirus as a vector is definitely safe in immunosuppressive therapeutics, and ciclosporin A, to some extent, is able to consequently inhibit the immune response of the rats and prolong the existing period of adenovirus.

References

1. Cao M M . Research progress of gene therapy. GuowaiYixue (Zhongliu Xue Fen Ce), 2004, 31(1): 22–25 (in Chinese)
2. O'Riordan C R, Song A . PEGylated adenovirus fortargeted gene therapy. Methods Mol Biol, 2008, 434: 133–160. doi:10.1007/978-1-60327-248-3_9
3. Luo J, Xia Q, Zhang R, Lv C, Zhang W, Wang Y, Cui Q, Liu L, Cai R, Qian C . Treatment of cancer with a novel dual-targetedconditionally replicative adenovirus armed with mda-7/IL-24 gene. Clin Cancer Res, 2008, 14(8): 2450–2457. doi:10.1158/1078-0432.CCR-07-4596
4. Zamir G, Gelman A, Olthoff K M, Debonera F, Aldeguer X, Shaked A . Patterns of transgene expression and viral clearancefrom the transplanted liver following ex vivo adenovirus-mediatedgene transfer. J Hepatol, 2004, 41(5): 714–720. doi:10.1016/j.jhep.2004.07.008
5. Hu Y, He Y, Srivenuqopal K S, Fan S, Jiang Y . In vitro antitumor cytotoxic T lymphocyteresponse induced by dendritic cells transduced with DeltaNp73alpharecombinant adenovirus. Oncol Rep, 2007, 18(5): 1085–1091
6. Bessis N, GarciaCozar F J, Boissier M C . Immune responses to gene therapy vectors: influence onvector function and effector mechanisms. Gene Ther, 2004 (Suppl 1): 10–17
7. Bouvet M, Fang B, Ekmekcioglu S, Ji L, Bucana C D, Hamada K, Grimm E A, Roth J A . Suppression of immune response to an adenovirus vectorand enhancement of intratumoral transgene expression by low-dose etoposide. Gene Ther, 1998, 5(2): 189–195. doi:10.1038/sj.gt.3300564
8. Lu Y P, Wang S X, Zhou J F . Construction and identification of Adenovirus - herpessimplex virus thymidine kinase gene therapy vector. Tongji Yike Daxue Xuebao, 1999, 28(3): 198–203 (in Chinese)
9. Kovarik J M, Villamil F, Otero A, Levy G, Llynch S, Cillo U, fischer L, Nashan B, Pollard S, De Carlis L . Cyclosporine pharmacokineticsand blood pressure responses after conversion to once-daily dosingin maintenance liver transplant patients. Clin Transplant, 2008, 22(1): 68–75
10. Peng Z,Yu Q, Bao L . The application of gene therapy in China. IDrugs, 2008, 11(5): 346–350
11. Banerjee D . Americanassociation for cancer research-89th annual meeting. Cancer gene therapy. IDrugs, 1998, 1(1): 42–44
12. Wu H, Curiel D T . Fiber-modified adenovirusesfor targeted gene therapy. Methods MolBiol, 2008, 434: 113–132. doi:10.1007/978-1-60327-248-3_8
13. Cassivi S D, Liu M, Boehler A, Pierre A, Tanswell A K, O'Brodovich H, Mullen J B, Slutsky A S, Keshavjee S H . Transplant immunosuppression increases and prolongs transgene expressionfollowing adenoviral-mediated transfection of rat lungs. J Heart Lung Transplant, 2000, 19(10): 984–994. doi:10.1016/S1053-2498(00)00166-2
14. Kaiser S, Toborek M . Liposome-mediated high-efficiencytransfection of human endothelial cells. J Vasc Res, 2001, 38(2): 133–143. doi:10.1159/000051040
15. Gao P, Shan Y X, Yang D R . Construction of the recombinant adenovirus vector bearingdual-survivin shRNA. Zhonghua Nan Ke Xue, 2008, 14(4): 324–327 (in Chinese)
16. Thomas C E, Abordo-Adesida E, Maleniak T C, Stone D, Gerdes C A, Lowenstein P R . Gene transfer into rat brain using adenoviral vectors. Curr Protoc Neurosci, 2001, 4(4): 24
17. Worgall S, Wolff G, FalckPedersen E, Crystal R G . Innate immune mechanisms dominate elimination of adenoviral vectorsfollowing in vivo administration. Hum Gene Ther, 1997, 8(1): 37–44. doi:10.1089/hum.1997.8.1-37
18. Schagen F H, Ossevoort M, Toes R E, Hoeben R C . Immune responsesagainst adenoviral vectors and their transgene products: a reviewof strategies for evasion. Crit Rev OncolHematol, 2004, 50(1): 51–70. doi:10.1016/S1040-8428(03)00172-0
19. Kawahara T, Murakami S, Noiri Y . Effects of cyclosporin-A-induced immunosuppression onperiapical lesions in rats. Dent Res, 2004, 83(9): 683–687
20. Suh K S, Yi N J . Liver transplantation forhepatocellular carcinoma. Korean J Hepatol, 2006, 12(4): 493–506
21. Wang D C, Zhang T L, Song S B, Yuan J, Xiu D R, Yang X X . A report of 28 cases of 3-year follow-up after liver transplantationfor advanced hepatocellular carcinoma. World J Gastroenterol, 2004, 10(14): 2134–2135