Análise da síntese de IL-12 em linfócitos T CD4+ e correlação com fatores de transcrição em pacientes com câncer avançado

Detalhes bibliográficos
Autor(a) principal: VIEIRA, Jéssica Ferreira
Data de Publicação: 2017
Tipo de documento: Dissertação
Idioma: por
Título da fonte: Biblioteca Digital de Teses e Dissertações da UFTM
Texto Completo: http://bdtd.uftm.edu.br/handle/tede/831
Resumo: No contexto tumoral, o sistema imunológico desempenha papeis que podem prevenir o desenvolvimento ou a progressão tumoral. Assim, a produção de citocinas, principalmente por linfócitos T CD4+, representa um fenômeno crucial na resposta imune, uma vez que variações nesta regulação podem resultar em uma resposta inadequada. Anteriormente, esse grupo de pesquisa demonstrou que linfócitos T CD4+ de pacientes com estádios avançados de câncer expressavam interleucina-12, o mesmo se aplicando a camundongos induzidos a câncer de mama com DMBA (7, 12 – Dimetilbenzantraceno). Então, o objetivo do presente estudo foi avaliar a síntese de IL-12 em linfócitos T CD4+ do sangue periférico de pacientes com câncer, correlacionando com a expressão dos fatores de transcrição T-bet, GATA-3, RORγt e FoxP3, utilizando citometria de fluxo e abordagens moleculares. As células T CD3+CD4+IL-12+ foram isoladas a partir do sangue periférico obtido de pacientes com câncer, utilizando técnica de citometria de fluxo com princípio de cell sorting (triagem de células) e submetidas a análise do perfil transcricional. Os resultados demonstram uma porcentagem significativamente maior de linfócitos T CD3+CD4+IL-12+ no sangue periférico de pacientes com câncer (p<0,0001). E estas expressam o fator de transcrição RORγt, podendo ainda algumas coexpressarem o fator T-bet. Ainda foi observado que algum fator (s) sérico (s) presente no soro dos pacientes com câncer são capazes ainda de induzir a diferenciação de linfócitos T CD3+CD4+IL-12+, sendo notável o aumento na porcentagem destas células em culturas estimuladas com o soro (p=0,0020). Entretanto novas investigações são necessárias, para compreender esse fenótipo de linfócito.
id UFTM_678eab2980b4958fde3d9cf244fcd4a3
oai_identifier_str oai:bdtd.uftm.edu.br:tede/831
network_acronym_str UFTM
network_name_str Biblioteca Digital de Teses e Dissertações da UFTM
repository_id_str
spelling Análise da síntese de IL-12 em linfócitos T CD4+ e correlação com fatores de transcrição em pacientes com câncer avançadoLinfócitos T auxiliares.Interleucina 12.RORγt.T-bet.Resposta antitumoral.Peripheral helper T lymphocytes.Interleukin-12.RORγt.T-bet.Antitumor response.Imunologia CelularNo contexto tumoral, o sistema imunológico desempenha papeis que podem prevenir o desenvolvimento ou a progressão tumoral. Assim, a produção de citocinas, principalmente por linfócitos T CD4+, representa um fenômeno crucial na resposta imune, uma vez que variações nesta regulação podem resultar em uma resposta inadequada. Anteriormente, esse grupo de pesquisa demonstrou que linfócitos T CD4+ de pacientes com estádios avançados de câncer expressavam interleucina-12, o mesmo se aplicando a camundongos induzidos a câncer de mama com DMBA (7, 12 – Dimetilbenzantraceno). Então, o objetivo do presente estudo foi avaliar a síntese de IL-12 em linfócitos T CD4+ do sangue periférico de pacientes com câncer, correlacionando com a expressão dos fatores de transcrição T-bet, GATA-3, RORγt e FoxP3, utilizando citometria de fluxo e abordagens moleculares. As células T CD3+CD4+IL-12+ foram isoladas a partir do sangue periférico obtido de pacientes com câncer, utilizando técnica de citometria de fluxo com princípio de cell sorting (triagem de células) e submetidas a análise do perfil transcricional. Os resultados demonstram uma porcentagem significativamente maior de linfócitos T CD3+CD4+IL-12+ no sangue periférico de pacientes com câncer (p<0,0001). E estas expressam o fator de transcrição RORγt, podendo ainda algumas coexpressarem o fator T-bet. Ainda foi observado que algum fator (s) sérico (s) presente no soro dos pacientes com câncer são capazes ainda de induzir a diferenciação de linfócitos T CD3+CD4+IL-12+, sendo notável o aumento na porcentagem destas células em culturas estimuladas com o soro (p=0,0020). Entretanto novas investigações são necessárias, para compreender esse fenótipo de linfócito.In the tumor context, the immune system plays roles that can prevent development or progression of tumor. Thus, the production of cytokines by CD4+ T lymphocytes represents a crucial phenomenon in the immune response, because the variations in this regulation may result in an inadequate response. Previously, our research group demonstrated that CD4+ T lymphocytes from advanced cancer patients expressed interleukin-12 and the same was applied to mice induced breast cancer with DMBA (7,12-Dimethylbenzanthracene). The aim of the present study was to evaluate the synthesis of IL-12 in CD4+ T lymphocytes from the peripheral blood of cancer patients, correlating with the expression of T-bet, GATA-3, RORγt and FoxP3 transcription factors. The CD3+CD4+IL-12+ T cells were isolated from the peripheral blood obtained from cancer patients, using flow cytometry technique with cell sorting principle and submitted to transcriptional profile analysis. The results demonstrate a significantly higher percentage of CD3+CD4+IL-12+ T lymphocytes in the peripheral blood of cancer patients (p <0.0001). In addition, these express the transcription factor RORγt, and some may coexpress the T-bet factor. It has been observed that some serum factor (s) present in the serum of cancer patients are still capable of inducing the differentiation of CD3+CD4+IL-12+ T lymphocytes, being remarkable the increase in the percentage of these cells in stimulated cultures with serum (p = 0.0020). However new investigations are needed to understand this lymphocyte phenotype.Fundação de Amparo à Pesquisa do Estado de Minas GeraisUniversidade Federal do Triângulo MineiroConselho Nacional de Desenvolvimento Científico e TecnológicoFundação de Amparo e Pesquisa de UberabaUniversidade Federal do Triângulo MineiroInstituto de Ciências da Saúde - ICS::Programa de Pós-Graduação em Ciências da SaúdeBrasilUFTMPrograma de Pós-Graduação em Ciências da SaúdeMICHELIN, Márcia Antoniazi11828808865http://lattes.cnpq.br/2599409028588669MURTA, Eddie Fernando Cândido47668032649http://lattes.cnpq.br/5724192420139830VIEIRA, Jéssica Ferreira2019-08-26T14:34:22Z2017-06-19info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfapplication/pdfVIEIRA, Jéssica Ferreira. Análise da síntese de IL-12 em linfócitos T CD4+ e correlação com fatores de transcrição em pacientes com câncer avançado. 2017. 65f . Dissertação (Mestrado em Ciências da Saúde) - Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal do Triângulo Mineiro, Uberaba, 2017 .http://bdtd.uftm.edu.br/handle/tede/831porABBAS, A. K.; LICHTMAN, A. H. H.; PILLAI, S. Imunologia celular e molecular. Elsevier Brasil, 2015. ALMEIDA, J. R. C. et al. Marcadores tumorais: revisão de literatura. Revista Brasileira de Cancerologia, v. 53, n. 3, p. 305-316, 2007. ARRUDA, J. T. et al. Proteína p53 e o câncer: Controvérsias e esperanças. Estudos, v. 35, p.123-141, 2008. BAILEY, S. R. et al. Th17 cells in cancer: the ultimate identity crisis. Frontiers in immunology, v. 5, p. 276, 2014. BOUDREAU, J. E. et al. Engineering dendritic cells to enhance cancer immunotherapy. Molecular Therapy, v. 19, n. 5, p. 841-853, 2011. BRUSTLE, A. et al. The development of inflammatory TH-17 cells requires interferonregulatory factor 4. Nature immunology, v. 8, n. 9, p. 958-966, 2007. BURNET, F. M. The concept of immunological surveillance. Progress in Experimental Tumor Research, v.13, p 1-27. 1970. CAVALLO, F. et al. Antitumor efficacy of adenocarcinoma cells engineered to produce interleukin 12 (IL-12) or other cytokines compared with exogenous IL-12. Journal of the National Cancer Institute, v. 89, n. 14, p. 1049-1058, 1997. CIOFANI, M. et al. A validated regulatory network for Th17 cell specification. Cell, v. 151, n. 2, p. 289-303, 2012. COLOMBO, M. P.; TRINCHIERI, G. Interleukin-12 in anti-tumor immunity and immunotherapy. Cytokine e growth factor reviews, v. 13, n. 2, p. 155-168, 2002. COSMI, L. et al. Human interleukin 17–producing cells originate from a CD161+ CD4+ T cell precursor. The Journal of Experimental Medicine, v. 205, n. 8, p. 1903-1916, 2008. COUSSENS, L. M.; WERB, Z. Inflammation and cancer. Nature, v. 420, n. 6917, p. 860- 867, 2002. CRUVINEL, W. M. et al. Immune system - Part I: fundamentals of innate immunity with emphasis on molecular and cellular mechanisms of inflammatory response. Revista Brasileira de Reumatologia, v. 50, n. 4, p. 434-447, 2010. CUA, D. J.; KASTELEIN, R. A. TGF-β, a 'double agent' in the imune pathology war. Nature immunology, v. 7, n. 6, p. 557-559, 2006. DE VISSER, K. E.; EICHTEN, A.; COUSSENS, L. M. Paradoxical roles of the immune system during cancer development. Nature reviews cancer, v. 6, n. 1, p. 24-37, 2006. DING, J. et al. Tumor Associated Macrophage × Cancer Cell Hybrids 781 May Acquire Cancer Stem Cell Properties in Breast Cancer. PLoS ONE, 782 v. 7, n. 7, p. e41942, 2012. DONG, C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nature Reviews Immunology, v. 8, n. 5, p. 337-348, 2008. DOUGAN, M.; DRANOFF, G. Immunetherapy for cancer. Annual Review of Immunology. v. 27, p. 83-117, 2009. ELYAMAN, W. et al. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proceedings of the National Academy of Sciences, v. 106, n. 31, p. 12885-12890, 2009. FREYTAG, S. O.; ZHANG, Y.; SIDDIQUI, F. Preclinical toxicology of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy for prostate cancer. Molecular Therapy-Oncolytics, v. 2, p. 15006, 2015. GABRILOVICH, D. Mechanisms and functional significance of tumor-induced dendritic-cell defects. NatureReviewsImmunology. v. 4, n. 12, p. 941-952, 2004. GARCIA PAZ, F. G. et al. The relationship between the antitumor effector of the IL-12 gene therapy and the expression of Th1 cytokines in an HPV-16 positive murine tumor model. Mediators of inflammation, v. 2014, p.1-9, 2014. GUEMBAROVSKI, R. L.; CÓLUS, I. M. S. Câncer: uma doença genética. Revista SBG, v. 3, n. 1, p. 4-7, 2009. HUNG, K. et al. The central role of CD4+ T cells in the antitumor immune response. The Journal of experimental medicine, v. 188, n. 12, p. 2357-2368, 1998. HUSSAIN, S. P.; HARRIS, C. C. Molecular epidemiology and carcinogenesis: endogenous and exogenous carcinogens. Mutation Research/Reviews in Mutation Research, v. 462, n. 2, p. 311-322, 2000. HWANG, E. et al. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science, v. 307, n. 5708, p. 430-433, 2005. IGNEY, F. H.; KRAMMER, P. H. Immune escape of tumors: apoptosis resistance and tumor counterattack. Journal of leukocyte biology, v. 71, n. 6, p. 907-920, 2002. INCA – INSTITUTO NACIONAL DE CÂNCER (Brasil). Ministério da Saúde. Coordenação de Prevenção e Vigilância de Câncer. Estimativas 2016: Incidência de Câncer no Brasil. Disponível em: <http://www.inca.gov.br/estimativa/2014/tabelaestados.asp?UF=BR >. Acesso em 23/12/2016. INOUE, D.P; AMAR, A; CERVANTES, O. Markers in larynxcancer. Revista brasileira de cirurgia de cabeça e pescoço, v. 34, n. 1, p. 7-14, 2005. INTERNATIONAL AGENCY FOR RESEARCH ON CANCER et al. GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. 2012. IVANOV, I. I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell, v. 126, n. 6, p. 1121-1133, 2006. JOHUNG, K.; GOODWIN, E. C.; DIMAIO, D. Human papillomavirus E7 repression in cervical carcinoma cells initiates a transcriptional cascade driven by the retinoblastoma family, resulting in senescence. Journal of virology, v. 81, n. 5, p. 2102-2116, 2007. JONES, L. L. et al. Distinct subunit pairing criteria within the heterodimeric IL-12 cytokine family. Molecular immunology, v. 51, n. 2, p. 234-244, 2012. JONES, L. L.; VIGNALI, D. A. A. Molecular interactionswithinthe IL-6/IL-12 cytokine/receptor superfamily. Immunologicresearch, v. 51, n. 1, p. 5-14, 2011. JOSEFOWICZ, S. Z.; RUDENSKY, A. Control of regulatory T cell lineage commitment and maintenance. Immunity, v. 30, n. 5, p. 616-625, 2009. KAPLAN, D. et al. Demonstration of an interferon gamma -dependent tumor surveillance system in immunocompetent mice. The Proceedings of the National Academy of Sciences, v. 95, n. 13, p. 7556-7561, 1998. KASTELEIN, R. A.; HUNTER, C. A.; CUA, D. J. Discovery and biologyof IL-23 and IL-27: relatedbutfunctionallydistinctregulatorsofinflammation. AnnualReviewofImmunology, v. 25, p. 221-242, 2007. KERKAR, S. P. et al. Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts. Cancer research, v. 70, n. 17, p. 6725-6734, 2010. KIDD, P. Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Alternative Medicine Review, v. 8, n. 3, p. 223-246, 2003. KORN, T. et al. IL-17 and Th17 Cells. Annual review of immunology, v. 27, p. 485-517, 2009. KUKA, M.; MUNITIC, I.; ASHWELL, J. D. Identification and characterization of polyclonal αβ T cells with dendritic cell properties. Nature communications, v. 3, p. 1223, 2012. KUMAR, V.; ASTER, J. C.; ABBAS, A. Robbins & Cotran Patologia-Bases Patológicas das Doenças. Elsevier Brasil, 2015. LANGENKAMP, A. et al. Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells. Nature immunology, v. 1, n. 4, p. 311-316, 2000. LASEK, W.; ZAGOŻDŻON, R.; JAKOBISIAK, M. Interleukin 12: still a promising candidate for tumor immunotherapy?. Cancer Immunology Immunotherapy, v. 63, n. 5, p. 419-435, 2014. LAZAREVIC, V.; GLIMCHER, L. H.; LORD, G. M. T-bet: a bridge between innate and adaptive immunity. Nature Reviews Immunology, v. 13, n. 11, p. 777-789, 2013. LEE, Y. K. et al. Late development alplasticity in the T helper 17 lineage. Immunity, v. 30, n. 1, p. 92-107, 2009. LEHRNBECHER, T. et al. Changes in host defense induced by malignancies and antineoplastic treatment: implication for immunotherapeutic strategies. The Lancet Oncology. v. 9, n. 3, p. 269-278, 2008. LI, H.; ROSTAMI, A. IL-9: basic biology, signaling pathways in CD4+ T cells and implications for autoimmunity. Journal of Neuroimmune Pharmacology, v. 5, n. 2, p. 198- 209, 2010. LIN, Z. et al. The Expression Levels of Transcription Factors T-bet, GATA-3, RORγt and FOXP3 in Peripheral Blood Lymphocyte (PBL) of Patients with Liver Cancer and their Significance. International Journal of Medical Sciences, v. 12, n. 1, p. 7, 2015. LOEB, L. A.; HARRIS, C. C. Advances in chemical carcinogenesis: a historical review and prospective. Cancer research, v. 68, n. 17, p. 6863-6872, 2008. LOOSE, D.; VAN DE WIELE, C. The immune system and cancer. Cancer Biotherapy and Radiopharmaceuticals, v. 24, n. 3, p. 369-376, 2009. LUPARDUS, P. J.; GARCIA, K. C. The structure of interleukin-23 reveals the molecular basis of p40 subunit sharing with interleukin-12. Journal of molecular biology, v. 382, n. 4, p. 931-941, 2008. MICHELIN, M. A. et al. Interleukin-12 in patients with cancer is synthesized by peripheral helper T lymphocytes. Oncology letters, v. 10, n. 3, p. 1523-1526, 2015. MICHELIN, M. A. et al. Peripheral helper lymphocytes produce interleukin 12 in cancer patients. Clinical Medicine Insights Oncology, v. 7, p. 75, 2013. MIOSSEC, P.; KORN, T.; KUCHROO, V. K. Interleukin-17 and type 17 helper T cells. New England Journal of Medicine, v. 361, n. 9, p. 888-898, 2009. MISSON, D. R. et al. Cytokine serum levels in patients with cervical intraepithelial neoplasia grade II–III treated with intralesional interferon-α 2b. Tumori, v. 97, n. 5, p. 578-84, 2011. MOSMANN, T. R. et al. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. The Journal of Immunology, v. 136, n. 7, p. 2348-2357, 1986. MOSMANN, T. R.; COFFMAN, R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annual review of immunology, v. 7, n. 1, p. 145-173, 1989. MUKASA, R. et al. Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage. Immunity, v. 32, n. 5, p. 616-627, 2010. MULLEN, A. C. et al. Hlx is induced by and genetically interacts withTbettopromoteheritable TH1 gene induction. Nature immunology, v. 3, n. 7, p. 652-658, 2002. ONUCHIC, A. C.; CHAMMAS, R. Câncer e o microambiente tumoral. Revista Médica, v. 89, n. 1, p. 21-31, 2010. OPPMANN, B. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity, v. 13, n. 5, p. 715-725, 2000. PAN, M. et al. Mutation of the IFNAR-1 receptor binding site of human IFN-alpha2 generates type I IFN competitive antagonists. Biochemistry. v. 47(46), p. 12018-12027, 2008. PEGHINI, B. C. et al. Local cytokine profiles of patients with cervical intraepithelial and invasive neoplasia. Human immunology, v. 73, n. 9, p. 920-926, 2012. PELUZIO, M. C.G. et al. The suppressor proteins in malignant neoplasia - Knowing their role. Revista Brasileira de Nutrição Clínica, v. 21, n. 3, p 233-238, 2006. RADFORD, K. J.; TULLETT, K. M.; LAHOUD, M. H. Dendritic cells and cancer immunotherapy. Current opinion in immunology, v. 27, n. DC, p. 26–32, abr. 2014. RATAJEWSKI, M. et al. Upstream stimulating factors regulate the expression. Of RORγT in human lymphocytes. The Journal of Immunology, v. 189, n. 6, p. 3034-3042, 2012. RODRIGUES, C. M. et al. The role of T lymphocytes in cancer patients undergoing immunotherapy with autologous dendritic cells. Clinical Medicine Insights Oncology, v. 5, p. 107, 2011. RODRIGUEZ-GALAN, M. et al. Coexpression of IL-18 strongly attenuates IL-12-induced systemic toxicity through a rapid induction of IL-10 without affecting its antitumor capacity. The Journal of Immunology, v. 183, n. 1, p. 740-748, 2009. ROTH, W. et al. Soluble decoy receptor 3 is expressed by malignant gliomas and suppresses CD95 ligand-induced apoptosis and chemotaxis. Cancer Research. v. 61, p. 2759–2765, 2001. SCHAROVSKY, O. G. et al. From immune surveillance to tumor-immune escape: the story of an enemy with multiple strategies of resistance and counterattack. Inmunología, v. 25, n. 2, p. 101-14, 2006. SEGURA, E. et al. Human inflammatory dendritic cells induce Th17 cell differentiation. Immunity, v. 38, n. 2, p. 336–48, 21 fev. 2013. SERAFINI, P. et al. High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells. Cancer research, v. 64, n. 17, p. 6337-6343, 2004. SHI, Y.; EVANS, J.E.; ROCK, K.L. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature. v.425, p. 516-521, 2003. SHIH, H. A. et al. BRCA1 and BRCA2 mutations in breast cancer families with multiple primary cancers. Clinicalcancerresearch, v. 6, n. 11, p. 4259-4264, 2000. SILVA, A. E.; SERAKIDES, R.; CASSALI, G. D. Carcinogênese hormonal e neoplasias hormônio-dependentes. Revista Ciências Rural, Santa Maria, v. 2, n. 34, p.625-633, 2004. SNIJDERS, A. et al. Regulation of bioactive IL-12 production in lipopolysaccharidestimulated human monocytesis determined by the expression ofthe p35 subunit. The Journal of Immunology, v. 156, n. 3, p. 1207-1212, 1996. SOMBROEK, C. C. et al. Prostanoids play a major role in the primary tumor-induced inhibition of dendritic cell differentiation. The Journal of Immunology. v. 168, n. 9, 4333- 4343, 2002. STEINMAN, L. A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell–mediated tissue damage. Nature medicine, v. 13, n. 1, p. 139-145, 2007. STEINMAN, R. M.; BANCHEREAU, J. Taking dendritic cells into medicine. Nature, v. 449, n. 7161, p. 419–26, 27 set. 2007. TATSUMI, T. et al. Intratumoral delivery of dendritic cells engineered to secrete both interleukin (IL)-12 and IL-18 effectively treats local and distant disease in association with broadly reactive Tc1-type immunity. Cancer research, v. 63, n. 19, p. 6378-6386, 2003. TLSTY, T. D.; COUSSENS, L. M. Tumor stroma and regulation of cancer development. AnnualReviewPathologyMechanismsofDisease, v. 1, p. 119-150, 2006. TORRENZINI, T.; ATHANAZIO, D. A. Imunovigilância e imunoedição de neoplasias: implicações clínicas e potencial terapêutico. Revista Brasileira de Cancerologia, v. 54, n. 1, p. 63-77, 2008. TRICHOPOULOS, D.; LI, F. P.; HUNTER, D. J. What causes cancer? Scientific American, v. 275, n. 3, p. 80-84, 1996. TRINCHIERI, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nature Reviews Immunology, v. 3, n. 2, p. 133-146, 2003. VIGNALI, D. A. A; KUCHROO, V. K. IL-12 family cytokines: immunological playmakers. Nature immunology, v. 13, n. 8, p. 722-728, 2012. WANG, Y. et al. The transcription factors T-bet and Runx are required for the ontogeny of pathogenic interferon-γ-producing T helper 17 cells. Immunity, v. 40, n. 3, p. 355-366, 2014. WANG, X. et al. Changes of Th17/Treg cell and related cytokines in pancreatic cancer patients. International journal of clinical and experimental pathology, v. 8, n. 5, p. 5702, 2015. WEINBERG, R. A. How cancer arises: an explosion of research in uncovering the longhidden molecular underpinnings of cancer and suggesting new therapies. Scientific American, v. 275, n. 3, p. 62-71, 1996. WESA A. et al. Polarized type-1 cells (DC1) producing high levels of IL-12 family members rescue patient Th1-type anti-melanoma CD4+ T cell responses in vitro. Journal of Immunotherapy, v. 30, n. 1, p. 75–82, 2007. WING, K.; FEHERVARI, Z.; SAKAGUCHI, S. Emerging possibilities in the development and function of regulatory T cells. International immunology, v. 18, n. 7, p. 991-1000, 2006. WORLD HEALTH ORGANIZATION. World health statistics 2008. Geneva , 2008. Cap.1, p. 21 (1:112). YANG, X. O. et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. Journal of Biological Chemistry, v. 282, n. 13, p. 9358-9363, 2007. YANG, X. O. et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ. Immunity, v. 28, n. 1, p. 29-39, 2008. ZHANG, F.; MENG, G.; STROBER, W. Interactions among the transcription factors Runx1, RORγt and Foxp3 regulate the differentiation of interleukin 17–producing T cells. Nature immunology, v. 9, n. 11, p. 1297-1306, 2008. ZHENG, S. Regulatory T cellsvs Th17: differentiation of Th17 versus Treg, are the mutually exclusive. American Journal of Clinical and Experimental Immunology, v. 2, n. 1, p. 94- 106, 2013. ZHENG, Y. et al. Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature, v. 445, n. 7128, p. 648-651, 2007. ZHU, J. et al. The transcription factor T-bet is induced by multiple pathways and prevents an endogenous Th2 cell program during Th1 cell responses. Immunity, v. 37, n. 4, p. 660-673, 2012. ZHU, J.; PAUL, W. E. CD4 T cells: fates, functions, and faults. Blood, v. 112, n. 5, p. 1557- 1569, 2008.http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UFTMinstname:Universidade Federal do Triangulo Mineiro (UFTM)instacron:UFTM2019-09-02T17:07:47Zoai:bdtd.uftm.edu.br:tede/831Biblioteca Digital de Teses e Dissertaçõeshttp://bdtd.uftm.edu.br/PUBhttp://bdtd.uftm.edu.br/oai/requestbdtd@uftm.edu.br||bdtd@uftm.edu.bropendoar:2019-09-02T17:07:47Biblioteca Digital de Teses e Dissertações da UFTM - Universidade Federal do Triangulo Mineiro (UFTM)false
dc.title.none.fl_str_mv Análise da síntese de IL-12 em linfócitos T CD4+ e correlação com fatores de transcrição em pacientes com câncer avançado
title Análise da síntese de IL-12 em linfócitos T CD4+ e correlação com fatores de transcrição em pacientes com câncer avançado
spellingShingle Análise da síntese de IL-12 em linfócitos T CD4+ e correlação com fatores de transcrição em pacientes com câncer avançado
VIEIRA, Jéssica Ferreira
Linfócitos T auxiliares.
Interleucina 12.
RORγt.
T-bet.
Resposta antitumoral.
Peripheral helper T lymphocytes.
Interleukin-12.
RORγt.
T-bet.
Antitumor response.
Imunologia Celular
title_short Análise da síntese de IL-12 em linfócitos T CD4+ e correlação com fatores de transcrição em pacientes com câncer avançado
title_full Análise da síntese de IL-12 em linfócitos T CD4+ e correlação com fatores de transcrição em pacientes com câncer avançado
title_fullStr Análise da síntese de IL-12 em linfócitos T CD4+ e correlação com fatores de transcrição em pacientes com câncer avançado
title_full_unstemmed Análise da síntese de IL-12 em linfócitos T CD4+ e correlação com fatores de transcrição em pacientes com câncer avançado
title_sort Análise da síntese de IL-12 em linfócitos T CD4+ e correlação com fatores de transcrição em pacientes com câncer avançado
author VIEIRA, Jéssica Ferreira
author_facet VIEIRA, Jéssica Ferreira
author_role author
dc.contributor.none.fl_str_mv MICHELIN, Márcia Antoniazi
11828808865
http://lattes.cnpq.br/2599409028588669
MURTA, Eddie Fernando Cândido
47668032649
http://lattes.cnpq.br/5724192420139830
dc.contributor.author.fl_str_mv VIEIRA, Jéssica Ferreira
dc.subject.por.fl_str_mv Linfócitos T auxiliares.
Interleucina 12.
RORγt.
T-bet.
Resposta antitumoral.
Peripheral helper T lymphocytes.
Interleukin-12.
RORγt.
T-bet.
Antitumor response.
Imunologia Celular
topic Linfócitos T auxiliares.
Interleucina 12.
RORγt.
T-bet.
Resposta antitumoral.
Peripheral helper T lymphocytes.
Interleukin-12.
RORγt.
T-bet.
Antitumor response.
Imunologia Celular
description No contexto tumoral, o sistema imunológico desempenha papeis que podem prevenir o desenvolvimento ou a progressão tumoral. Assim, a produção de citocinas, principalmente por linfócitos T CD4+, representa um fenômeno crucial na resposta imune, uma vez que variações nesta regulação podem resultar em uma resposta inadequada. Anteriormente, esse grupo de pesquisa demonstrou que linfócitos T CD4+ de pacientes com estádios avançados de câncer expressavam interleucina-12, o mesmo se aplicando a camundongos induzidos a câncer de mama com DMBA (7, 12 – Dimetilbenzantraceno). Então, o objetivo do presente estudo foi avaliar a síntese de IL-12 em linfócitos T CD4+ do sangue periférico de pacientes com câncer, correlacionando com a expressão dos fatores de transcrição T-bet, GATA-3, RORγt e FoxP3, utilizando citometria de fluxo e abordagens moleculares. As células T CD3+CD4+IL-12+ foram isoladas a partir do sangue periférico obtido de pacientes com câncer, utilizando técnica de citometria de fluxo com princípio de cell sorting (triagem de células) e submetidas a análise do perfil transcricional. Os resultados demonstram uma porcentagem significativamente maior de linfócitos T CD3+CD4+IL-12+ no sangue periférico de pacientes com câncer (p<0,0001). E estas expressam o fator de transcrição RORγt, podendo ainda algumas coexpressarem o fator T-bet. Ainda foi observado que algum fator (s) sérico (s) presente no soro dos pacientes com câncer são capazes ainda de induzir a diferenciação de linfócitos T CD3+CD4+IL-12+, sendo notável o aumento na porcentagem destas células em culturas estimuladas com o soro (p=0,0020). Entretanto novas investigações são necessárias, para compreender esse fenótipo de linfócito.
publishDate 2017
dc.date.none.fl_str_mv 2017-06-19
2019-08-26T14:34:22Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/masterThesis
format masterThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv VIEIRA, Jéssica Ferreira. Análise da síntese de IL-12 em linfócitos T CD4+ e correlação com fatores de transcrição em pacientes com câncer avançado. 2017. 65f . Dissertação (Mestrado em Ciências da Saúde) - Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal do Triângulo Mineiro, Uberaba, 2017 .
http://bdtd.uftm.edu.br/handle/tede/831
identifier_str_mv VIEIRA, Jéssica Ferreira. Análise da síntese de IL-12 em linfócitos T CD4+ e correlação com fatores de transcrição em pacientes com câncer avançado. 2017. 65f . Dissertação (Mestrado em Ciências da Saúde) - Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal do Triângulo Mineiro, Uberaba, 2017 .
url http://bdtd.uftm.edu.br/handle/tede/831
dc.language.iso.fl_str_mv por
language por
dc.relation.none.fl_str_mv ABBAS, A. K.; LICHTMAN, A. H. H.; PILLAI, S. Imunologia celular e molecular. Elsevier Brasil, 2015. ALMEIDA, J. R. C. et al. Marcadores tumorais: revisão de literatura. Revista Brasileira de Cancerologia, v. 53, n. 3, p. 305-316, 2007. ARRUDA, J. T. et al. Proteína p53 e o câncer: Controvérsias e esperanças. Estudos, v. 35, p.123-141, 2008. BAILEY, S. R. et al. Th17 cells in cancer: the ultimate identity crisis. Frontiers in immunology, v. 5, p. 276, 2014. BOUDREAU, J. E. et al. Engineering dendritic cells to enhance cancer immunotherapy. Molecular Therapy, v. 19, n. 5, p. 841-853, 2011. BRUSTLE, A. et al. The development of inflammatory TH-17 cells requires interferonregulatory factor 4. Nature immunology, v. 8, n. 9, p. 958-966, 2007. BURNET, F. M. The concept of immunological surveillance. Progress in Experimental Tumor Research, v.13, p 1-27. 1970. CAVALLO, F. et al. Antitumor efficacy of adenocarcinoma cells engineered to produce interleukin 12 (IL-12) or other cytokines compared with exogenous IL-12. Journal of the National Cancer Institute, v. 89, n. 14, p. 1049-1058, 1997. CIOFANI, M. et al. A validated regulatory network for Th17 cell specification. Cell, v. 151, n. 2, p. 289-303, 2012. COLOMBO, M. P.; TRINCHIERI, G. Interleukin-12 in anti-tumor immunity and immunotherapy. Cytokine e growth factor reviews, v. 13, n. 2, p. 155-168, 2002. COSMI, L. et al. Human interleukin 17–producing cells originate from a CD161+ CD4+ T cell precursor. The Journal of Experimental Medicine, v. 205, n. 8, p. 1903-1916, 2008. COUSSENS, L. M.; WERB, Z. Inflammation and cancer. Nature, v. 420, n. 6917, p. 860- 867, 2002. CRUVINEL, W. M. et al. Immune system - Part I: fundamentals of innate immunity with emphasis on molecular and cellular mechanisms of inflammatory response. Revista Brasileira de Reumatologia, v. 50, n. 4, p. 434-447, 2010. CUA, D. J.; KASTELEIN, R. A. TGF-β, a 'double agent' in the imune pathology war. Nature immunology, v. 7, n. 6, p. 557-559, 2006. DE VISSER, K. E.; EICHTEN, A.; COUSSENS, L. M. Paradoxical roles of the immune system during cancer development. Nature reviews cancer, v. 6, n. 1, p. 24-37, 2006. DING, J. et al. Tumor Associated Macrophage × Cancer Cell Hybrids 781 May Acquire Cancer Stem Cell Properties in Breast Cancer. PLoS ONE, 782 v. 7, n. 7, p. e41942, 2012. DONG, C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nature Reviews Immunology, v. 8, n. 5, p. 337-348, 2008. DOUGAN, M.; DRANOFF, G. Immunetherapy for cancer. Annual Review of Immunology. v. 27, p. 83-117, 2009. ELYAMAN, W. et al. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proceedings of the National Academy of Sciences, v. 106, n. 31, p. 12885-12890, 2009. FREYTAG, S. O.; ZHANG, Y.; SIDDIQUI, F. Preclinical toxicology of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy for prostate cancer. Molecular Therapy-Oncolytics, v. 2, p. 15006, 2015. GABRILOVICH, D. Mechanisms and functional significance of tumor-induced dendritic-cell defects. NatureReviewsImmunology. v. 4, n. 12, p. 941-952, 2004. GARCIA PAZ, F. G. et al. The relationship between the antitumor effector of the IL-12 gene therapy and the expression of Th1 cytokines in an HPV-16 positive murine tumor model. Mediators of inflammation, v. 2014, p.1-9, 2014. GUEMBAROVSKI, R. L.; CÓLUS, I. M. S. Câncer: uma doença genética. Revista SBG, v. 3, n. 1, p. 4-7, 2009. HUNG, K. et al. The central role of CD4+ T cells in the antitumor immune response. The Journal of experimental medicine, v. 188, n. 12, p. 2357-2368, 1998. HUSSAIN, S. P.; HARRIS, C. C. Molecular epidemiology and carcinogenesis: endogenous and exogenous carcinogens. Mutation Research/Reviews in Mutation Research, v. 462, n. 2, p. 311-322, 2000. HWANG, E. et al. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science, v. 307, n. 5708, p. 430-433, 2005. IGNEY, F. H.; KRAMMER, P. H. Immune escape of tumors: apoptosis resistance and tumor counterattack. Journal of leukocyte biology, v. 71, n. 6, p. 907-920, 2002. INCA – INSTITUTO NACIONAL DE CÂNCER (Brasil). Ministério da Saúde. Coordenação de Prevenção e Vigilância de Câncer. Estimativas 2016: Incidência de Câncer no Brasil. Disponível em: <http://www.inca.gov.br/estimativa/2014/tabelaestados.asp?UF=BR >. Acesso em 23/12/2016. INOUE, D.P; AMAR, A; CERVANTES, O. Markers in larynxcancer. Revista brasileira de cirurgia de cabeça e pescoço, v. 34, n. 1, p. 7-14, 2005. INTERNATIONAL AGENCY FOR RESEARCH ON CANCER et al. GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. 2012. IVANOV, I. I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell, v. 126, n. 6, p. 1121-1133, 2006. JOHUNG, K.; GOODWIN, E. C.; DIMAIO, D. Human papillomavirus E7 repression in cervical carcinoma cells initiates a transcriptional cascade driven by the retinoblastoma family, resulting in senescence. Journal of virology, v. 81, n. 5, p. 2102-2116, 2007. JONES, L. L. et al. Distinct subunit pairing criteria within the heterodimeric IL-12 cytokine family. Molecular immunology, v. 51, n. 2, p. 234-244, 2012. JONES, L. L.; VIGNALI, D. A. A. Molecular interactionswithinthe IL-6/IL-12 cytokine/receptor superfamily. Immunologicresearch, v. 51, n. 1, p. 5-14, 2011. JOSEFOWICZ, S. Z.; RUDENSKY, A. Control of regulatory T cell lineage commitment and maintenance. Immunity, v. 30, n. 5, p. 616-625, 2009. KAPLAN, D. et al. Demonstration of an interferon gamma -dependent tumor surveillance system in immunocompetent mice. The Proceedings of the National Academy of Sciences, v. 95, n. 13, p. 7556-7561, 1998. KASTELEIN, R. A.; HUNTER, C. A.; CUA, D. J. Discovery and biologyof IL-23 and IL-27: relatedbutfunctionallydistinctregulatorsofinflammation. AnnualReviewofImmunology, v. 25, p. 221-242, 2007. KERKAR, S. P. et al. Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts. Cancer research, v. 70, n. 17, p. 6725-6734, 2010. KIDD, P. Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Alternative Medicine Review, v. 8, n. 3, p. 223-246, 2003. KORN, T. et al. IL-17 and Th17 Cells. Annual review of immunology, v. 27, p. 485-517, 2009. KUKA, M.; MUNITIC, I.; ASHWELL, J. D. Identification and characterization of polyclonal αβ T cells with dendritic cell properties. Nature communications, v. 3, p. 1223, 2012. KUMAR, V.; ASTER, J. C.; ABBAS, A. Robbins & Cotran Patologia-Bases Patológicas das Doenças. Elsevier Brasil, 2015. LANGENKAMP, A. et al. Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells. Nature immunology, v. 1, n. 4, p. 311-316, 2000. LASEK, W.; ZAGOŻDŻON, R.; JAKOBISIAK, M. Interleukin 12: still a promising candidate for tumor immunotherapy?. Cancer Immunology Immunotherapy, v. 63, n. 5, p. 419-435, 2014. LAZAREVIC, V.; GLIMCHER, L. H.; LORD, G. M. T-bet: a bridge between innate and adaptive immunity. Nature Reviews Immunology, v. 13, n. 11, p. 777-789, 2013. LEE, Y. K. et al. Late development alplasticity in the T helper 17 lineage. Immunity, v. 30, n. 1, p. 92-107, 2009. LEHRNBECHER, T. et al. Changes in host defense induced by malignancies and antineoplastic treatment: implication for immunotherapeutic strategies. The Lancet Oncology. v. 9, n. 3, p. 269-278, 2008. LI, H.; ROSTAMI, A. IL-9: basic biology, signaling pathways in CD4+ T cells and implications for autoimmunity. Journal of Neuroimmune Pharmacology, v. 5, n. 2, p. 198- 209, 2010. LIN, Z. et al. The Expression Levels of Transcription Factors T-bet, GATA-3, RORγt and FOXP3 in Peripheral Blood Lymphocyte (PBL) of Patients with Liver Cancer and their Significance. International Journal of Medical Sciences, v. 12, n. 1, p. 7, 2015. LOEB, L. A.; HARRIS, C. C. Advances in chemical carcinogenesis: a historical review and prospective. Cancer research, v. 68, n. 17, p. 6863-6872, 2008. LOOSE, D.; VAN DE WIELE, C. The immune system and cancer. Cancer Biotherapy and Radiopharmaceuticals, v. 24, n. 3, p. 369-376, 2009. LUPARDUS, P. J.; GARCIA, K. C. The structure of interleukin-23 reveals the molecular basis of p40 subunit sharing with interleukin-12. Journal of molecular biology, v. 382, n. 4, p. 931-941, 2008. MICHELIN, M. A. et al. Interleukin-12 in patients with cancer is synthesized by peripheral helper T lymphocytes. Oncology letters, v. 10, n. 3, p. 1523-1526, 2015. MICHELIN, M. A. et al. Peripheral helper lymphocytes produce interleukin 12 in cancer patients. Clinical Medicine Insights Oncology, v. 7, p. 75, 2013. MIOSSEC, P.; KORN, T.; KUCHROO, V. K. Interleukin-17 and type 17 helper T cells. New England Journal of Medicine, v. 361, n. 9, p. 888-898, 2009. MISSON, D. R. et al. Cytokine serum levels in patients with cervical intraepithelial neoplasia grade II–III treated with intralesional interferon-α 2b. Tumori, v. 97, n. 5, p. 578-84, 2011. MOSMANN, T. R. et al. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. The Journal of Immunology, v. 136, n. 7, p. 2348-2357, 1986. MOSMANN, T. R.; COFFMAN, R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annual review of immunology, v. 7, n. 1, p. 145-173, 1989. MUKASA, R. et al. Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage. Immunity, v. 32, n. 5, p. 616-627, 2010. MULLEN, A. C. et al. Hlx is induced by and genetically interacts withTbettopromoteheritable TH1 gene induction. Nature immunology, v. 3, n. 7, p. 652-658, 2002. ONUCHIC, A. C.; CHAMMAS, R. Câncer e o microambiente tumoral. Revista Médica, v. 89, n. 1, p. 21-31, 2010. OPPMANN, B. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity, v. 13, n. 5, p. 715-725, 2000. PAN, M. et al. Mutation of the IFNAR-1 receptor binding site of human IFN-alpha2 generates type I IFN competitive antagonists. Biochemistry. v. 47(46), p. 12018-12027, 2008. PEGHINI, B. C. et al. Local cytokine profiles of patients with cervical intraepithelial and invasive neoplasia. Human immunology, v. 73, n. 9, p. 920-926, 2012. PELUZIO, M. C.G. et al. The suppressor proteins in malignant neoplasia - Knowing their role. Revista Brasileira de Nutrição Clínica, v. 21, n. 3, p 233-238, 2006. RADFORD, K. J.; TULLETT, K. M.; LAHOUD, M. H. Dendritic cells and cancer immunotherapy. Current opinion in immunology, v. 27, n. DC, p. 26–32, abr. 2014. RATAJEWSKI, M. et al. Upstream stimulating factors regulate the expression. Of RORγT in human lymphocytes. The Journal of Immunology, v. 189, n. 6, p. 3034-3042, 2012. RODRIGUES, C. M. et al. The role of T lymphocytes in cancer patients undergoing immunotherapy with autologous dendritic cells. Clinical Medicine Insights Oncology, v. 5, p. 107, 2011. RODRIGUEZ-GALAN, M. et al. Coexpression of IL-18 strongly attenuates IL-12-induced systemic toxicity through a rapid induction of IL-10 without affecting its antitumor capacity. The Journal of Immunology, v. 183, n. 1, p. 740-748, 2009. ROTH, W. et al. Soluble decoy receptor 3 is expressed by malignant gliomas and suppresses CD95 ligand-induced apoptosis and chemotaxis. Cancer Research. v. 61, p. 2759–2765, 2001. SCHAROVSKY, O. G. et al. From immune surveillance to tumor-immune escape: the story of an enemy with multiple strategies of resistance and counterattack. Inmunología, v. 25, n. 2, p. 101-14, 2006. SEGURA, E. et al. Human inflammatory dendritic cells induce Th17 cell differentiation. Immunity, v. 38, n. 2, p. 336–48, 21 fev. 2013. SERAFINI, P. et al. High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells. Cancer research, v. 64, n. 17, p. 6337-6343, 2004. SHI, Y.; EVANS, J.E.; ROCK, K.L. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature. v.425, p. 516-521, 2003. SHIH, H. A. et al. BRCA1 and BRCA2 mutations in breast cancer families with multiple primary cancers. Clinicalcancerresearch, v. 6, n. 11, p. 4259-4264, 2000. SILVA, A. E.; SERAKIDES, R.; CASSALI, G. D. Carcinogênese hormonal e neoplasias hormônio-dependentes. Revista Ciências Rural, Santa Maria, v. 2, n. 34, p.625-633, 2004. SNIJDERS, A. et al. Regulation of bioactive IL-12 production in lipopolysaccharidestimulated human monocytesis determined by the expression ofthe p35 subunit. The Journal of Immunology, v. 156, n. 3, p. 1207-1212, 1996. SOMBROEK, C. C. et al. Prostanoids play a major role in the primary tumor-induced inhibition of dendritic cell differentiation. The Journal of Immunology. v. 168, n. 9, 4333- 4343, 2002. STEINMAN, L. A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell–mediated tissue damage. Nature medicine, v. 13, n. 1, p. 139-145, 2007. STEINMAN, R. M.; BANCHEREAU, J. Taking dendritic cells into medicine. Nature, v. 449, n. 7161, p. 419–26, 27 set. 2007. TATSUMI, T. et al. Intratumoral delivery of dendritic cells engineered to secrete both interleukin (IL)-12 and IL-18 effectively treats local and distant disease in association with broadly reactive Tc1-type immunity. Cancer research, v. 63, n. 19, p. 6378-6386, 2003. TLSTY, T. D.; COUSSENS, L. M. Tumor stroma and regulation of cancer development. AnnualReviewPathologyMechanismsofDisease, v. 1, p. 119-150, 2006. TORRENZINI, T.; ATHANAZIO, D. A. Imunovigilância e imunoedição de neoplasias: implicações clínicas e potencial terapêutico. Revista Brasileira de Cancerologia, v. 54, n. 1, p. 63-77, 2008. TRICHOPOULOS, D.; LI, F. P.; HUNTER, D. J. What causes cancer? Scientific American, v. 275, n. 3, p. 80-84, 1996. TRINCHIERI, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nature Reviews Immunology, v. 3, n. 2, p. 133-146, 2003. VIGNALI, D. A. A; KUCHROO, V. K. IL-12 family cytokines: immunological playmakers. Nature immunology, v. 13, n. 8, p. 722-728, 2012. WANG, Y. et al. The transcription factors T-bet and Runx are required for the ontogeny of pathogenic interferon-γ-producing T helper 17 cells. Immunity, v. 40, n. 3, p. 355-366, 2014. WANG, X. et al. Changes of Th17/Treg cell and related cytokines in pancreatic cancer patients. International journal of clinical and experimental pathology, v. 8, n. 5, p. 5702, 2015. WEINBERG, R. A. How cancer arises: an explosion of research in uncovering the longhidden molecular underpinnings of cancer and suggesting new therapies. Scientific American, v. 275, n. 3, p. 62-71, 1996. WESA A. et al. Polarized type-1 cells (DC1) producing high levels of IL-12 family members rescue patient Th1-type anti-melanoma CD4+ T cell responses in vitro. Journal of Immunotherapy, v. 30, n. 1, p. 75–82, 2007. WING, K.; FEHERVARI, Z.; SAKAGUCHI, S. Emerging possibilities in the development and function of regulatory T cells. International immunology, v. 18, n. 7, p. 991-1000, 2006. WORLD HEALTH ORGANIZATION. World health statistics 2008. Geneva , 2008. Cap.1, p. 21 (1:112). YANG, X. O. et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. Journal of Biological Chemistry, v. 282, n. 13, p. 9358-9363, 2007. YANG, X. O. et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ. Immunity, v. 28, n. 1, p. 29-39, 2008. ZHANG, F.; MENG, G.; STROBER, W. Interactions among the transcription factors Runx1, RORγt and Foxp3 regulate the differentiation of interleukin 17–producing T cells. Nature immunology, v. 9, n. 11, p. 1297-1306, 2008. ZHENG, S. Regulatory T cellsvs Th17: differentiation of Th17 versus Treg, are the mutually exclusive. American Journal of Clinical and Experimental Immunology, v. 2, n. 1, p. 94- 106, 2013. ZHENG, Y. et al. Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature, v. 445, n. 7128, p. 648-651, 2007. ZHU, J. et al. The transcription factor T-bet is induced by multiple pathways and prevents an endogenous Th2 cell program during Th1 cell responses. Immunity, v. 37, n. 4, p. 660-673, 2012. ZHU, J.; PAUL, W. E. CD4 T cells: fates, functions, and faults. Blood, v. 112, n. 5, p. 1557- 1569, 2008.
dc.rights.driver.fl_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Universidade Federal do Triângulo Mineiro
Instituto de Ciências da Saúde - ICS::Programa de Pós-Graduação em Ciências da Saúde
Brasil
UFTM
Programa de Pós-Graduação em Ciências da Saúde
publisher.none.fl_str_mv Universidade Federal do Triângulo Mineiro
Instituto de Ciências da Saúde - ICS::Programa de Pós-Graduação em Ciências da Saúde
Brasil
UFTM
Programa de Pós-Graduação em Ciências da Saúde
dc.source.none.fl_str_mv reponame:Biblioteca Digital de Teses e Dissertações da UFTM
instname:Universidade Federal do Triangulo Mineiro (UFTM)
instacron:UFTM
instname_str Universidade Federal do Triangulo Mineiro (UFTM)
instacron_str UFTM
institution UFTM
reponame_str Biblioteca Digital de Teses e Dissertações da UFTM
collection Biblioteca Digital de Teses e Dissertações da UFTM
repository.name.fl_str_mv Biblioteca Digital de Teses e Dissertações da UFTM - Universidade Federal do Triangulo Mineiro (UFTM)
repository.mail.fl_str_mv bdtd@uftm.edu.br||bdtd@uftm.edu.br
_version_ 1797221134271250432