Doctoral Thesis
DOI
https://doi.org/10.11606/T.42.2016.tde-23022016-094214
Document
Author
Full name
Bruna Felicio Milazzotto Maldonado Porchia
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2015
Supervisor
Committee
Ferreira, Luis Carlos de Souza (President)
Bargieri, Bruna Cunha de Alencar
Basso, Alexandre Salgado
Pierulivo, Enrique Mario Boccardo
Rigato, Paula Ordonhez
Title in Portuguese
Imunoterapia e imunomodulação envolvendo a glicoproteína D (gD) do HSV-1 em formulações vacinais voltadas para o controle de tumores associados ao HPV-16.
Keywords in Portuguese
Cancer cervical
E7
gD
HPV-16
HSV-1
Imunoterapia
Abstract in Portuguese
O câncer cervical é considerado um grande problema de saúde pública e um dos maiores causadores de mortes relacionadas a tumores em mulheres. O principal objetivo desta tese foi aumentar a eficácia antitumoral terapêutica da proteína gDE7 por meio da associação de adjuvantes vacinais em formulações testadas em condições experimentais com a linhagem celular tumoral TC-1. A proteína gDE7 foi produzida a partir de uma linhagem de E. coli e associada a diferentes adjuvantes. A proteína gDE7 coadministrada ao poly(I:C) conferiu proteção antitumoral completa aos camundongos previamente desafiados e induziu ativação de linfócitos T CD8+ E7-específicos polifuncionais, citotóxicos e de fenótipo de memória efetora/efetor. Foi demonstrado que a proteína gDE7 ativa de forma específica a subpopulação de células dendríticas especializada na apresentação cruzada de antígenos para linfócitos T CD8+, tanto em camundongos como em seres humanos. Esses resultados abrem perspectivas para o emprego da proteína gD como plataforma vacinal para o controle de tumores induzidos pelo HPV-16.
Title in English
Immunotherapy and immunomodulation involving glycoprotein D (gD) of HSV-1 in vaccine formulations directed to HPV-16-associated tumors control.
Keywords in English
Cervical câncer
E7
gD
HPV-16
HSV-1
Immunotherapy
Abstract in English
Cervical cancer is considered a major public health problem and one of the leading causes of cancer death in women. The main goal of this thesis was the improvement of a therapeutic antitumor vaccine based on gDE7 protein in formulations admixed with adjuvants under experimental conditions with the tumor cell line TC-1. The gDE7 protein was expressed and purified from E. coli, and then tested in combination with different vaccine adjuvants. The gDE7 protein admixed with poly(I:C) conferred complete therapeutic antitumor protection to mice previously challenged with TC-1 cells and induced polyfunctional, cytotoxic E7-specific CD8+ T cells with effector/effector memory phenotype. It was also demonstrated that the gDE7 protein activated a specialized dendritic cell subset involved in specific antigen cross-presentation to CD8+ T cells, both in mice and humans. These results open perspectives for the use of the gD protein use as a vaccine platform for the control of HPV-16-induced tumors.
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Publishing Date
2016-02-24