Evaluation of therapeutic potency of human papillomavirus-16 E7 DNA vaccine alone and with interleukin-18 as a genetic adjuvant
DOI:
https://doi.org/10.15448/1980-6108.2018.3.30555Palavras-chave:
imunidade celular, papiloma vírus humano, proteínas oncogênicas, interleucina-18.Resumo
***Avaliação da potência terapêutica da vacina de DNA do papilomavírus humano-16 E7 isolada e com interleucina-18 como adjuvante genético***
OBJETIVOS: Apesar da existência de vacinas preventivas eficazes contra o papilomavírus humano (HPV), são necessárias vacinas terapêuticas que desencadeiem respostas imunes mediadas por células para tratar infecções e malignidades estabelecidas. O objetivo deste estudo foi avaliar a potência terapêutica da vacina de ácido desoxirribonucleico (DNA) HPV-16 E7 isolada e com interleucina (IL)-18.
MÉTODOS: Expressões in vitro de IL-18 foram realizadas em células renais embrionárias humanas 293 e confirmadas por Western blotting. A vacina de DNA foi disponibilizada em um estudo anterior. Um total de 45 camundongos fêmeas C57BL/6 divididos em cinco grupos (vacina de DNA, vacina de DNA adjuvada com IL-18, pcDNA3.1 e solução salina tamponada com fosfato) e foram inoculados com linhagem murina-1 de carcinoma relacionado ao HPV, expressando antígenos E6 / E7 do HPV-16. Os animais foram então imunizados por via subcutânea duas vezes no intervalo de sete dias. A imunidade antitumoral e antígeno-celular específica foi avaliada pela proliferação de linfócitos (ensaio de brometo de 3- [4,5-dimetiltiazol-2-il] -2,5-difeniltetrazólio: MTT), ensaio de liberação de lactato desidrogenase, ensaio de IL-4 e ensaio de interferon-gama [IFN-γ]. O tamanho do tumor foi seguido por 62 dias.
RESULTADOS: O ensaio MTT, que mede a proliferação de linfócitos em resposta ao antígeno específico, aumentou nos grupos de coadministração e de vacina de DNA em comparação aos grupos controle e adjuvante genético (p <0,001). Os camundongos imunizados com a coadministração geraram significativamente mais IFN-γ e IL-4 do que os outros camundongos imunizados (p<0,001). A redução do tamanho do tumor nos grupos de coadministração e de vacina de DNA foi significativamente mais acentuada do que nos grupos controle e adjuvante genético (p<0,001), mas não houve nenhuma diferença estatisticamente significativa entre os grupos vacina de DNA e coadministração (p=0,15).
CONCLUSÕES: A IL-18 como adjuvante genético e a vacina de DNA E7 aumentaram as respostas imunes em sistemas modelo de camundongos contra o câncer cervical. No entanto, o uso de IL-18 como adjuvante genético com a vacina de DNA E7 não teve efeito sinérgico significativo nas respostas imunes in vivo.
Downloads
Referências
Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013 [cited 2018 Jan 31]. Available from: http://globocan.iarc.fr
Zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer. 2002;2(5):342-50. https://doi.org/10.1038/nrc798
Kadaja M, Silla T, Ustav E, Ustav M. Papillomavirus DNA replication from initiation to genomic instability. Virol. 2009;384(2):360-8. https://doi.org/10.1016/j.virol.2008.11.032
Finzer P, Aguilar-Lemarroy A, Rösl F. The role of human papillomavirus oncoproteins E6 and E7 in apoptosis. Cancer lett. 2002;188(1):15-24. https://doi.org/10.1016/S0304-3835(02)00431-7
Toussaint-Smith E, Donner DB, Roman A. Expression of human papillomavirus type 16 E6 and E7 oncoproteins in primary foreskin keratinocytes is sufficient to alter the expression of angiogenic factors. Oncogene. 2004;23(17):2988-95. https://doi.org/10.1038/sj.onc.1207442
Todorovic B, Hung K, Massimi P, Avvakumov N, Dick FA, Shaw GS, Banks L, Mymryk JS. Conserved region 3 of human papillomavirus 16 E7 contributes to deregulation of the retinoblastoma tumor suppressor. J virol. 2012;86(24):13313-23. https://doi.org/10.1128/JVI.01637-12
Fabbi M, Carbotti G, Ferrini S. Context-dependent role of IL-18 in cancer biology and counter-regulation by IL-18BP. J Leukoc Biol. 2015;97(4):665-75. https://doi.org/10.1189/jlb.5RU0714-360RR
Jin H, Li Y, Ma Z, Zhang F, Xie Q, Gu D, Wang B. Effect of chemical adjuvants on DNA vaccination. Vaccine. 2004;22(21):2925-35. https://doi.org/10.1016/j.vaccine.2003.12.026
Liu MA. DNA vaccines: an historical perspective and view to the future. Immunol Rev. 2011;239(1):62-84. https://doi.org/10.1111/j.1600-065X.2010.00980.x
Gableh F, Saeidi M, Hemati S, Hamdi K, Soleimanjahi H, Gorji A, Ghaemi A. Combination of the toll like receptor agonist and alpha-Galactosylceramide as an efficient adjuvant for cancer vaccine. J Biomed Sci. 2016;23(1):16-27. https://doi.org/10.1186/s12929-016-0238-3
Sajadian A, Tabarraei A, Soleimanjahi H, Fotouhi F, Gorji A, Ghaemi A. Comparing the effect of Toll-like receptor agonist adjuvants on the efficiency of a DNA vaccine. Arch Virol. 2014;159(8):1951-60. https://doi.org/10.1007/s00705-014-2024-4
Wang Q, Yu H, Ju D, He L, Pan J, Xia D, Zhang L, Cao X. Intratumoral IL-18 gene transfer improves therapeutic efficacy of antibody-targeted superantigen in established murine melanoma. Gene Ther. 2001;8(7):542-50. https://doi.org/10.1038/sj.gt.3301428
Akamatsu S, Arai N, Hanaya T, Arai S, Tanimoto T, Fujii M, Kohno K, Micallef MJ, Ikeda M, Kurimoto M. Antitumor activity of interleukin-18 against the murine T-cell leukemia/lymphoma EL-4 in syngeneic mice. J Immunother. 2002;25:S28-S34. https://doi.org/10.1097/00002371-200203001-00005
Osaki T, Péron J-M, Cai Q, Okamura H, Robbins PD, Kurimoto M, Lotze MT, Tahara H. IFN-γ-inducing factor/IL-18 administration mediates IFN-γ-and IL-12-independent antitumor effects. J Immunol. 1998;160(4):1742-9.
Zhang Y, Li Y, Ma Y, Liu S, She Y, Zhao P, Jing M, Han T, Yan C, Wu Z, Gao J, Ye L. Dual effects of interleukin-18: inhibiting hepatitis B virus replication in HepG2. 2.15 cells and promoting hepatoma cells metastasis. Am J Physiol Gastrointest Liver Physiol. 2011;301(3):G565-G73. https://doi.org/10.1152/ajpgi.00058.2011
Coughlin CM, Salhany KE, Wysocka M, Aruga E, Kurzawa H, Chang AE, Hunter CA, Fox JC, Trinchieri G, Lee WM. Interleukin-12 and interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis. J Clin Invest. 1998;101(6):1441-52. https://doi.org/10.1172/JCI1555
Ghaemi A, Soleimanjahi H, Gill P, Hassan Z, Jahromi SRM, Roohvand F. Recombinant λ-phage nanobioparticles for tumor therapy in mice models. Genet Vaccines Ther. 2010;8(1):3-10. https://doi.org/10.1186/1479-0556-8-3
Tahamtan A, Ghaemi A, Gorji A, Kalhor HR, Sajadian A, Tabarraei A, Moradi A, Atyabi F, Kelishadi M. Antitumor effect of therapeutic HPV DNA vaccines with chitosan-based nanodelivery systems. J Biomed Sci. 2014;21(1):69-79. https://doi.org/10.1186/s12929-014-0069-z
Fazeli M, Soleimanjahi H, Ghaemi A, Farzanepour M, Amanzadeh A, Hashemi SR. Efficacy of HPV-16 E7 based vaccine in a TC-1 tumoric animal model of cervical cancer. Cell J. 2011;12(4):483-8.
Gableh F, Saeidi M, Hemati S, Hamdi K, Soleimanjahi H, Gorji A, Ghaemi A. Combination of the toll like receptor agonist and α-Galactosylceramide as an efficient adjuvant for cancer vaccine. J Biomed Sci. 2016;23(1):16-27. https://doi.org/10.1186/s12929-016-0238-3
Garnett MC. Gene-delivery systems using cationic polymers. Crit Rev Ther Drug Carrier Syst. 1999;16(2):147-207. https://doi.org/10.1615/CritRevTherDrugCarrierSyst.v16.i2.10
Tindle R, Frazer I. Immune response to human papillomaviruses and the prospects for human papillomavirus-specific immunisation. Human pathogenic papillomaviruses. New York: Springer; 1994.
Šmahel M, Šíma P, Ludvíková V, Vonka V. Modified HPV16 E7 genes as DNA vaccine against E7-containing oncogenic cells. Virol. 2001;281(2):231-8. https://doi.org/10.1006/viro.2000.0794
Bahrami AA, Ghaemi A, Tabarraei A, Sajadian A, Gorji A, Soleimanjahi H. DNA vaccine encoding HPV-16 E7 with mutation in LYCYE pRb-binding motif induces potent anti-tumor responses in mice. J Virol Methods. 2014;206:12-18. https://doi.org/10.1016/j.jviromet.2014.05.013
Fazeli M, Soleimanjahi H, Dadashzadeh S. Further stimulation of cellular immune responses through association of HPV-16 E6, E7 and L1 genes in order to produce more effective therapeutic DNA vaccines in cervical cancer model. Iran J Cancer Prev. 2015;8(1):18.
Soleimanjahi H, Razavinikoo H, Fotouhi F, Ardebili A. Antitumor Response to a Codon-Optimized HPV-16 E7/HSP70 Fusion Antigen DNA Vaccine. Iran J Immunol. 2017;14(3):180-91.
Kaser A, Kaser S, Kaneider NC, Enrich B, Wiedermann CJ, Tilg H. Interleukin-18 attracts plasmacytoid dendritic cells (DC2s) and promotes Th1 induction by DC2s through IL-18 receptor expression. Blood. 2004;103(2):648-55. https://doi.org/10.1182/blood-2002-07-2322
Lee SJ, Cho YS, Cho MC, Shim JH, Lee KA, Ko KK, Choe YK, Park SN, Hoshino T, Kim S, Dinarello CA, Yoon DY. Both E6 and E7 oncoproteins of human papillomavirus 16 inhibit IL-18-induced IFN-γ production in human peripheral blood mononuclear and NK cells. J Immunol. 2001;167(1):497-504. https://doi.org/10.4049/jimmunol.167.1.497
Zhu M, Xu X, Liu H, Liu X, Wang S, Dong F, Yang B, Song G. Enhancement of DNA vaccine potency against herpes simplex virus 1 by co-administration of an interleukin-18 expression plasmid as a genetic adjuvant. J Med Microbiol. 2003;52(3):223-8. https://doi.org/10.1099/jmm.0.04998-0
Cho YS, Kang JW, Cho M, Cho CW, Lee S, Choe YK, Kim YM, Choi IP, Park SN, Kim SH, Dinarello CA, Yoon DY. Down modulation of IL‐18 expression by human papillomavirus type 16 E6 oncogene via binding to IL‐18. FEBS Lett. 2001;501(2-3):139-45. https://doi.org/10.1016/S0014-5793(01)02652-7
Kang YH, Lee KA, Yang Y, Kim HS, Kim HJ, Park NS, Paik SG, Yoon DY. The apoptotic effect of intercalating agents on HPV-negative cervical cancer C-33A cells. Amino Acides. 2007;33(1):105-12. https://doi.org/10.1007/s00726-006-0417-8
Robertson MJ, Mier JW, Logan T, Atkins M, Koon H, Koch KM, Kathman S, Pandite LN, Oei C, Kirby LC, Jewell RC, Bell WN, Thurmond LM, Weisenbach J, Roberts S, Dar MM. Clinical and biological effects of recombinant human interleukin-18 administered by intravenous infusion to patients with advanced cancer. Clin Cancer Res. 2006;12(14):4265-73. https://doi.org/10.1158/1078-0432.CCR-06-0121
Tarhini AA, Millward M, Mainwaring P, Kefford R, Logan T, Pavlick A, Kathman SJ, Laubscher KH, Dar MM. A phase 2, randomized study of SB‐485232, rhIL‐18, in patients with previously untreated metastatic melanoma. Cancer. 2009;115(4):859-68. https://doi.org/10.1002/cncr.24100
Nakahira M, Ahn H-J, Park W-R, Gao P, Tomura M, Park C-S, et al. Synergy of IL-12 and IL-18 for IFN-γ gene expression: IL-12-induced STAT4 contributes to IFN-γ promoter activation by up-regulating the binding activity of IL-18-induced activator protein 1. The Journal of Immunology. 2002;168(3):1146-53. https://doi.org/10.4049/jimmunol.168.3.1146
Tominaga K, Yoshimoto T, Torigoe K, Kurimoto M, Matsui K, Hada T, et al. IL-12 synergizes with IL-18 or IL-1β for IFN-γ production from human T cells. International immunology. 2000;12(2):151-60. https://doi.org/10.1093/intimm/12.2.151
Downloads
Publicado
Como Citar
Edição
Seção
Licença
Copyright (c) 2018 Scientia Medica
Este trabalho está licenciado sob uma licença Creative Commons Attribution 4.0 International License.
Direitos Autorais
A submissão de originais para a Scientia Medica implica na transferência, pelos autores, dos direitos de publicação. Os direitos autorais para os artigos publicados nesta revista são do autor, com direitos da revista sobre a primeira publicação. Os autores somente poderão utilizar os mesmos resultados em outras publicações indicando claramente a Scientia Medica como o meio da publicação original.
Licença Creative Commons
Exceto onde especificado diferentemente, aplicam-se à matéria publicada neste periódico os termos de uma licença Creative Commons Atribuição 4.0 Internacional, que permite o uso irrestrito, a distribuição e a reprodução em qualquer meio desde que a publicação original seja corretamente citada.
