Made available in DSpace on 2015-04-14T14:51:21Z (GMT). No. of bitstreams: 1
442974.pdf: 1168003 bytes, checksum: 61a64ae8027da7ef2e5ef378d8f25eb3 (MD5)
Previous issue date: 2011-07-05 / Breast cancer is an important cause of morbidity and mortality in Brazil and worldwide. New therapeutic strategies have been proposed and one of them is the use of cell therapy with dendritic cells (DCs), however, the literature regarding the real benefit of this approach shows great variability and inability to produce a lasting immunity. In this paper we made a detailed characterization of monocyte-derived dendritic cells (MoDCs) of patients with breast cancer and monocytes that originated them. A lower yield of MoDCs was obtained from patients when compared to age matched healthy controls. Patient MoDCs exhibited decreased expressions of maturation and activation markers. Furthermore, cultures of MoDCs of patients had significantly elevated levels of spontaneous production of IL-6, which is consistent with a pro-tumor phenotype. These differences in molecule expression and cytokine production led us to postulate that the signaling pathways and / or the expression of toll like receptors (TLRs) could be altered. A decrease of TLR9 and TLR2 and an increase in the expression of NFkBp50 was found in MoDCs of patients without stimulation. After stimulation with LPS and CPG the patients did not upregulate expression of MyD88, suggesting a downregulation of the signaling pathways activated by these molecular patterns. The number of monocytes was also were decreased in patients, showing a reduced expression of GM-CSF receptors compared to monocytes of healthy controls. Cytokine production by monocytes from cancer patients was also altered, with an increased production of IL-6, IL-4 and IL-10. TLR2 and TLR9 expression was downregulated in monocytes of patients. Together these data show that monocytes are already altered in patients with cancer, and that will influence the phenotype of DCs differentiated from them. Tumor burden seems to induce a tolerogenic and pro-tumoral phenotype in patients?cells. This finding is important for the development of DC-based cancer immunotherapy. / A neoplasia mam?ria ? uma causa importante de morbidade e mortalidade no Brasil e no mundo. Novas estrat?gias terap?uticas vem sendo propostas e uma delas ? a utiliza??o de terapia celular com c?lulas dendr?ticas (DCs), entretanto, os dados da literatura em rela??o ao real benef?cio desta abordagem apresentam grande variabilidade e inabilidade em produzir uma imunidade duradoura. No presente trabalho fizemos uma caracteriza??o detalhada das c?lulas dendr?ticas derivadas de mon?citos (MoDCs) das pacientes com c?ncer de mama e dos mon?citos que as originaram. As MoDCs das pacientes s?o obtidas com um menor rendimento quando comparadas a controles saud?veis pareados por idade, e exibem uma diminui??o nos marcadores de matura??o e ativa??o. Al?m disso, as culturas de MoDCs das pacientes apresentaram altos n?veis de IL-6, o que ? compat?vel com um fen?tipo pr?-tumoral. Essas diferen?as na produ??o de citocinas nos levou a postular que as vias de sinaliza??o e/ou a express?o de toll like receptors (TLRs) poderiam estar alteradas. Observamos uma diminui??o de TLR9 e TLR2 e um aumento na express?o de NFkBp50 nas MoDCs das pacientes, sem est?mulo. Ap?s est?mulo com LPS e CPG as pacientes n?o aumentaram a express?o de MyD88, sugerindo uma diminui??o Ada via de sinaliza??o da resposta a esses padr?es moleculares. Quando analisamos os mon?citos, eles tamb?m estavam diminu?dos nas pacientes, e apresentavam uma express?o de receptores para GM-CSF inferior a dos controles saud?veis. A produ??o de citocinas pelos mon?citos das pacientes com c?ncer tamb?m estava alterada com uma produ??o aumentada de IL-6, IL-4 e IL-10. A frequ?ncia de TLR9 e TLR2 estava diminu?da nos mon?citos das pacientes. Esses dados conjuntamente demonstram que os mon?citos j? est?o alterados nas pacientes com c?ncer, assim como as DCs diferenciadas a partir deles. O crescimento tumoral parece induzir um fen?tipo de toler?ncia nestas c?lulas. Esse dado ? de fundamental import?ncia para o desenvolvimento de imunoterapia baseada em DCs.
| Identifer | oai:union.ndltd.org:IBICT/oai:tede2.pucrs.br:tede/5448 |
| Date | 05 July 2011 |
| Creators | Torronteguy, Carolina Antas |
| Contributors | Bonorino, Cristina |
| Publisher | Pontif?cia Universidade Cat?lica do Rio Grande do Sul, Programa de P?s-Gradua??o em Biologia Celular e Molecular, PUCRS, BR, Faculdade de Bioci?ncias |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/doctoralThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da PUC_RS, instname:Pontifícia Universidade Católica do Rio Grande do Sul, instacron:PUC_RS |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 8198246930096637360, 600, 600, 36528317262667714 |
Page generated in 0.0024 seconds