Avaliação da modulação da resposta imune induzida por vacina contra tuberculose: rBCG-CMX
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFG |
Texto Completo: | http://repositorio.bc.ufg.br/tede/handle/tede/5550 |
Resumo: | In the first chapter of this thesis we demonstrate, in a review article, some of the successful strategies employed in the construction of Bacillus Calmette-Guérin (BCG) vaccines, among others being: overexpression of promising Mycobacterium tuberculosis (Mtb) immunodominant antigens already expressed by BCG introduction of Mtb immunodominant antigens not expressed by BCG, such as antigens in the regions of difference (RD) 1 thru 16; combination of overexpression and introduction of novel antigens to BCG; BCG modification to skew immune response toward TCD8+, as for example recombinant BCG (rBCG) expressing cytokines. In the second chapter, we demonstrate that the recombinant fusion protein CMX is capable of aggregating important immunogenic properties to vaccine vectors, by inducing an effective response for the control of Mtb infection in the mouse tuberculosis infection model. It is hypothesized that the introduction of the rCMX protein in the BCG vaccine could add immunological properties that are absent in BCG, thus leading to the induction of important cell populations for the control of Mtb infection. Our results demonstrate that the introduction of the rCMX in the BCG vaccine, resulting the recombinant BCG vaccine (rBCG-CMX) was an important factor for the observed Th1 and Th17 responses, as well as polyfunctional cells, that could be responsible for the reduced inflammatory lesions seen in the lungs of Mtb infected BALB/c mice, significantly reducing the bacillary load in comparison to in comparison to mice immunized with BCG Moreau vaccine. Lastly, in the third chapter of this thesis we propose that rCMX protein could be responsible for modulating the BCG vaccine to activate a more adequate and protective innate immunity. Our results show that the rBCG-CMX vaccine induces the activation of alveolar macrophages by means of expression of activation-associated molecules CD86 and CD206. The increase in the expression of those molecules are accompanied by the production of TGF-β e IL-1α which in turn could be responsible for the decreased necrosis and higher apoptosis induction promoted by rBCG-CMX vaccination. This phenomenon could be providing a higher cellular survival rate of the recombinant vaccine, leading to a better processing and presentation by MHC-II. As rCMX was shown to induce the production of IL-1α, IL-6 e TGF-β by a pathway that seems to involve the participation of TLR-4, we hypothesize that this recombinant protein could be modulating the BCG vaccine to induce a more appropriate and protectiveresponse for Mtb infection. |
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Junqueira-Kipnis, Ana Paulahttp://lattes.cnpq.br/1252262903952987Kipnis, Andréhttp://lattes.cnpq.br/4434965360286741Kipnis, Ana Paula JunqueiraSantana, Jaime Martins deLeite, Luciana Cezar CerqueiraStefani, Mariane Martins de AraújoCeles, Mara Rúbia Nuneshttp://lattes.cnpq.br/9373163292240939Costa, Adeliane Castro da2016-05-12T10:41:03Z2016-03-01COSTA, A. C. Avaliação da modulação da resposta imune induzida por vacina contra tuberculose: rBCG-CMX. 2016. 143 f. Tese (Doutorado em Medicina Tropical e Saúde Publica) - Universidade Federal de Goiás, Goiânia, 2016.http://repositorio.bc.ufg.br/tede/handle/tede/5550In the first chapter of this thesis we demonstrate, in a review article, some of the successful strategies employed in the construction of Bacillus Calmette-Guérin (BCG) vaccines, among others being: overexpression of promising Mycobacterium tuberculosis (Mtb) immunodominant antigens already expressed by BCG introduction of Mtb immunodominant antigens not expressed by BCG, such as antigens in the regions of difference (RD) 1 thru 16; combination of overexpression and introduction of novel antigens to BCG; BCG modification to skew immune response toward TCD8+, as for example recombinant BCG (rBCG) expressing cytokines. In the second chapter, we demonstrate that the recombinant fusion protein CMX is capable of aggregating important immunogenic properties to vaccine vectors, by inducing an effective response for the control of Mtb infection in the mouse tuberculosis infection model. It is hypothesized that the introduction of the rCMX protein in the BCG vaccine could add immunological properties that are absent in BCG, thus leading to the induction of important cell populations for the control of Mtb infection. Our results demonstrate that the introduction of the rCMX in the BCG vaccine, resulting the recombinant BCG vaccine (rBCG-CMX) was an important factor for the observed Th1 and Th17 responses, as well as polyfunctional cells, that could be responsible for the reduced inflammatory lesions seen in the lungs of Mtb infected BALB/c mice, significantly reducing the bacillary load in comparison to in comparison to mice immunized with BCG Moreau vaccine. Lastly, in the third chapter of this thesis we propose that rCMX protein could be responsible for modulating the BCG vaccine to activate a more adequate and protective innate immunity. Our results show that the rBCG-CMX vaccine induces the activation of alveolar macrophages by means of expression of activation-associated molecules CD86 and CD206. The increase in the expression of those molecules are accompanied by the production of TGF-β e IL-1α which in turn could be responsible for the decreased necrosis and higher apoptosis induction promoted by rBCG-CMX vaccination. This phenomenon could be providing a higher cellular survival rate of the recombinant vaccine, leading to a better processing and presentation by MHC-II. As rCMX was shown to induce the production of IL-1α, IL-6 e TGF-β by a pathway that seems to involve the participation of TLR-4, we hypothesize that this recombinant protein could be modulating the BCG vaccine to induce a more appropriate and protectiveresponse for Mtb infection.A Tuberculose (Tb) é uma doença infecto contagiosa, causada pelo Mycobacterium tuberculosis (Mtb). Apesar de ser uma doença antiga, a Tb continua sendo um dos principais problemas de saúde pública. A Organização Mundial de Saúde acredita que cerca de um terço da população mundial está infectado com Mtb, gerando milhões de mortes por ano. Uma das medidas que podem melhorar a prevenção e bloquear a transmissão do Mtb é o desenvolvimento de novas vacinas que previnam o estabelecimento e a progressão da TB em humanos. Embora exista a vacina BCG que é eficiente contra formas graves de TB na infância, existe a necessidade do desenvolvimento de novas vacinas para controlar a disseminação da TB, que sejam mais eficientes e seguras que a BCG. Com este intuito, o objetivo deste trabalho é avaliar a proteção e a modulação da resposta imune induzida por BCG recombinante expressando espítopos imunodominantes Ag85C, MPT-51 e HspX do Mycobacterium tuberculosis induzida em modelo murino. Nossos resultados demonstram que a inserção da proteína CMX na vacina BCG recombinante (rBCG-CMX) foi um fator determinante para indução de resposta Th1 e Th17, além de células polifuncionais que possivelmente foram responsáveis pela redução das lesões inflamatórias no pulmão de camundongos BALB/c, reduzindo significantemente a carga bacilar em comparação com imunização com BCG Moreau. Além disso mostramos neste trabalho que a proteína rCMX é capaz de modular a vacina BCG e ativar a imunidade inata para a indução de uma melhor resposta protetora. Nossos resultados demonstram que a vacina rBCG-CMX induz ativação de macrófagos pulmonares por meio da expressão de moléculas de ativação CD86 e CD206. O aumento da expressão dessas moléculas é acompanhada por produção de TGF-β e IL-1α, sendo prováveis responsáveis pela menor indução de necrose e maior indução de apoptose pela vacina rBCG-CMX. Este fenômeno pode estar proporcionando a esta vacina maior capacidade de sobrevivência celular, colaborando para um melhor processamento e apresentação por MHC-II. Devido a proteína rCMX ser capaz de induzir produção de IL-1α, IL-6 e TGF-β por uma via que parece haver a participação de TLR-4. In vivo demonstramos que a vacina rBCG-CMX depende de TLR-2 e TLR-4 para induzir respostas Th1 e Th17, após imunização de camundongos com esta vacina. Neste trabalho hipotetizamos que a proteína CMX pode modular a resposta imune inata e adaptativa, por uma via em que há a participação do TLR-4. Esta pode ser a via pela qual a CMX, quando expressa por BCG favorece uma boa resposta protetora em animais desafiados com Mtb.Submitted by Cláudia Bueno (claudiamoura18@gmail.com) on 2016-05-11T20:41:59Z No. of bitstreams: 2 Tese - Adeliane Castro da Costa - 2016.pdf: 6997901 bytes, checksum: a6d453a5d3acafaed991fe945aa59330 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5)Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2016-05-12T10:41:03Z (GMT) No. of bitstreams: 2 Tese - Adeliane Castro da Costa - 2016.pdf: 6997901 bytes, checksum: a6d453a5d3acafaed991fe945aa59330 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5)Made available in DSpace on 2016-05-12T10:41:03Z (GMT). No. of bitstreams: 2 Tese - Adeliane Castro da Costa - 2016.pdf: 6997901 bytes, checksum: a6d453a5d3acafaed991fe945aa59330 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2016-03-01Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPqapplication/pdfporUniversidade Federal de GoiásPrograma de Pós-graduação em Medicina Tropical e Saúde Publica (IPTSP)UFGBrasilInstituto de Patologia Tropical e Saúde Pública - IPTSP (RG)http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessTuberculoseVacinasBCGrBCG-CMXTuberculosisVaccineBCGrBCG-CMXCIENCIAS BIOLOGICAS::IMUNOLOGIAAvaliação da modulação da resposta imune induzida por vacina contra tuberculose: rBCG-CMXEvaluation of the immune response modulation induced by vaccine against tuberculosis: rBCG-CMXinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesis6085308344741430434600600600600-77690114445645562885989919188376747614-2555911436985713659reponame:Repositório Institucional da UFGinstname:Universidade Federal de Goiás (UFG)instacron:UFGLICENSElicense.txtlicense.txttext/plain; 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dc.title.por.fl_str_mv |
Avaliação da modulação da resposta imune induzida por vacina contra tuberculose: rBCG-CMX |
dc.title.alternative.eng.fl_str_mv |
Evaluation of the immune response modulation induced by vaccine against tuberculosis: rBCG-CMX |
title |
Avaliação da modulação da resposta imune induzida por vacina contra tuberculose: rBCG-CMX |
spellingShingle |
Avaliação da modulação da resposta imune induzida por vacina contra tuberculose: rBCG-CMX Costa, Adeliane Castro da Tuberculose Vacinas BCG rBCG-CMX Tuberculosis Vaccine BCG rBCG-CMX CIENCIAS BIOLOGICAS::IMUNOLOGIA |
title_short |
Avaliação da modulação da resposta imune induzida por vacina contra tuberculose: rBCG-CMX |
title_full |
Avaliação da modulação da resposta imune induzida por vacina contra tuberculose: rBCG-CMX |
title_fullStr |
Avaliação da modulação da resposta imune induzida por vacina contra tuberculose: rBCG-CMX |
title_full_unstemmed |
Avaliação da modulação da resposta imune induzida por vacina contra tuberculose: rBCG-CMX |
title_sort |
Avaliação da modulação da resposta imune induzida por vacina contra tuberculose: rBCG-CMX |
author |
Costa, Adeliane Castro da |
author_facet |
Costa, Adeliane Castro da |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Junqueira-Kipnis, Ana Paula |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/1252262903952987 |
dc.contributor.advisor-co1.fl_str_mv |
Kipnis, André |
dc.contributor.advisor-co1Lattes.fl_str_mv |
http://lattes.cnpq.br/4434965360286741 |
dc.contributor.referee1.fl_str_mv |
Kipnis, Ana Paula Junqueira |
dc.contributor.referee2.fl_str_mv |
Santana, Jaime Martins de |
dc.contributor.referee3.fl_str_mv |
Leite, Luciana Cezar Cerqueira |
dc.contributor.referee4.fl_str_mv |
Stefani, Mariane Martins de Araújo |
dc.contributor.referee5.fl_str_mv |
Celes, Mara Rúbia Nunes |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/9373163292240939 |
dc.contributor.author.fl_str_mv |
Costa, Adeliane Castro da |
contributor_str_mv |
Junqueira-Kipnis, Ana Paula Kipnis, André Kipnis, Ana Paula Junqueira Santana, Jaime Martins de Leite, Luciana Cezar Cerqueira Stefani, Mariane Martins de Araújo Celes, Mara Rúbia Nunes |
dc.subject.por.fl_str_mv |
Tuberculose Vacinas BCG rBCG-CMX |
topic |
Tuberculose Vacinas BCG rBCG-CMX Tuberculosis Vaccine BCG rBCG-CMX CIENCIAS BIOLOGICAS::IMUNOLOGIA |
dc.subject.eng.fl_str_mv |
Tuberculosis Vaccine BCG rBCG-CMX |
dc.subject.cnpq.fl_str_mv |
CIENCIAS BIOLOGICAS::IMUNOLOGIA |
description |
In the first chapter of this thesis we demonstrate, in a review article, some of the successful strategies employed in the construction of Bacillus Calmette-Guérin (BCG) vaccines, among others being: overexpression of promising Mycobacterium tuberculosis (Mtb) immunodominant antigens already expressed by BCG introduction of Mtb immunodominant antigens not expressed by BCG, such as antigens in the regions of difference (RD) 1 thru 16; combination of overexpression and introduction of novel antigens to BCG; BCG modification to skew immune response toward TCD8+, as for example recombinant BCG (rBCG) expressing cytokines. In the second chapter, we demonstrate that the recombinant fusion protein CMX is capable of aggregating important immunogenic properties to vaccine vectors, by inducing an effective response for the control of Mtb infection in the mouse tuberculosis infection model. It is hypothesized that the introduction of the rCMX protein in the BCG vaccine could add immunological properties that are absent in BCG, thus leading to the induction of important cell populations for the control of Mtb infection. Our results demonstrate that the introduction of the rCMX in the BCG vaccine, resulting the recombinant BCG vaccine (rBCG-CMX) was an important factor for the observed Th1 and Th17 responses, as well as polyfunctional cells, that could be responsible for the reduced inflammatory lesions seen in the lungs of Mtb infected BALB/c mice, significantly reducing the bacillary load in comparison to in comparison to mice immunized with BCG Moreau vaccine. Lastly, in the third chapter of this thesis we propose that rCMX protein could be responsible for modulating the BCG vaccine to activate a more adequate and protective innate immunity. Our results show that the rBCG-CMX vaccine induces the activation of alveolar macrophages by means of expression of activation-associated molecules CD86 and CD206. The increase in the expression of those molecules are accompanied by the production of TGF-β e IL-1α which in turn could be responsible for the decreased necrosis and higher apoptosis induction promoted by rBCG-CMX vaccination. This phenomenon could be providing a higher cellular survival rate of the recombinant vaccine, leading to a better processing and presentation by MHC-II. As rCMX was shown to induce the production of IL-1α, IL-6 e TGF-β by a pathway that seems to involve the participation of TLR-4, we hypothesize that this recombinant protein could be modulating the BCG vaccine to induce a more appropriate and protectiveresponse for Mtb infection. |
publishDate |
2016 |
dc.date.accessioned.fl_str_mv |
2016-05-12T10:41:03Z |
dc.date.issued.fl_str_mv |
2016-03-01 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
COSTA, A. C. Avaliação da modulação da resposta imune induzida por vacina contra tuberculose: rBCG-CMX. 2016. 143 f. Tese (Doutorado em Medicina Tropical e Saúde Publica) - Universidade Federal de Goiás, Goiânia, 2016. |
dc.identifier.uri.fl_str_mv |
http://repositorio.bc.ufg.br/tede/handle/tede/5550 |
identifier_str_mv |
COSTA, A. C. Avaliação da modulação da resposta imune induzida por vacina contra tuberculose: rBCG-CMX. 2016. 143 f. Tese (Doutorado em Medicina Tropical e Saúde Publica) - Universidade Federal de Goiás, Goiânia, 2016. |
url |
http://repositorio.bc.ufg.br/tede/handle/tede/5550 |
dc.language.iso.fl_str_mv |
por |
language |
por |
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6085308344741430434 |
dc.relation.confidence.fl_str_mv |
600 600 600 600 |
dc.relation.department.fl_str_mv |
-7769011444564556288 |
dc.relation.cnpq.fl_str_mv |
5989919188376747614 |
dc.relation.sponsorship.fl_str_mv |
-2555911436985713659 |
dc.rights.driver.fl_str_mv |
http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
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http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Goiás |
dc.publisher.program.fl_str_mv |
Programa de Pós-graduação em Medicina Tropical e Saúde Publica (IPTSP) |
dc.publisher.initials.fl_str_mv |
UFG |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Instituto de Patologia Tropical e Saúde Pública - IPTSP (RG) |
publisher.none.fl_str_mv |
Universidade Federal de Goiás |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UFG instname:Universidade Federal de Goiás (UFG) instacron:UFG |
instname_str |
Universidade Federal de Goiás (UFG) |
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UFG |
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UFG |
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Repositório Institucional da UFG |
bitstream.url.fl_str_mv |
http://repositorio.bc.ufg.br/tede/bitstreams/78c5b61c-99bf-42c4-aa45-9063f94c45c1/download http://repositorio.bc.ufg.br/tede/bitstreams/b48acfb4-139f-49f4-87dd-9e7a70cc9c25/download http://repositorio.bc.ufg.br/tede/bitstreams/01b95212-8153-4128-b97a-2e7534816cb3/download http://repositorio.bc.ufg.br/tede/bitstreams/8b3edc70-a58c-4fb4-a781-537a51ef75a5/download http://repositorio.bc.ufg.br/tede/bitstreams/78c51218-0379-452a-ac98-24b5086a9d72/download |
bitstream.checksum.fl_str_mv |
bd3efa91386c1718a7f26a329fdcb468 4afdbb8c545fd630ea7db775da747b2f ef48816a10f2d45f2e2fee2f478e2faf 9da0b6dfac957114c6a7714714b86306 a6d453a5d3acafaed991fe945aa59330 |
bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 MD5 MD5 MD5 |
repository.name.fl_str_mv |
Repositório Institucional da UFG - Universidade Federal de Goiás (UFG) |
repository.mail.fl_str_mv |
tasesdissertacoes.bc@ufg.br |
_version_ |
1798044336419504128 |