Atividade das enzimas que degradam nucleotídeos e nucleosídeo da adenina em leucemia linfoblástica aguda B derivada
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Manancial - Repositório Digital da UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/18972 |
Resumo: | B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a neoplasm characterized by an anomalous clonal proliferation of B lymphoid precursor cells and predominance in pediatric patients. BCP-ALL promotes the deregulation of physiological and immunological processes. Among the immune processes modulators, ATP, ADP, AMP and adenosine stand out. The extracellular concentrations of these nucleotides are regulated by the ectoenzymes E- NTPDase (CD39), E-5'-NT (CD73), and ecto-adenosine deaminase (E-ADA). This study aimed to evaluate the activities of E-NTPDase and E-ADA in peripheral lymphocytes, measure the expression of CD39 and CD73 in peripheral blood, evaluate the activities of NTPDase, ADA and XO, the levels of soluble nucleotides and nucleosides of adenine and the cytokines in the serum, in order to evaluate the immune response in BCP-ALL patients. Thirty-two patients were evaluated at diagnosis (D0), 14 patients 15 days after the beginning of the treatment (D15), and 34 healthy individuals in the control group (C). The activities of ectonucleotidases and soluble enzymes NTPDase and ADA were determined on isolated peripheral lymphocytes and serum, respectively. Flow cytometry method was used to evaluate the expressions of CD39 and CD73 in lysed whole blood and the levels of cytokines in the serum. The nucleotides and nucleosides levels were evaluated in serum by HPLC method. Concerning to the activity on lymphocytes, E-NTPDase (ADP substrate) was reduced in D15 group, while E-ADA activity was increased on D0 and on D15 when compared to the control group. The activities of NTPDase (ATP and ADP substrate) and XO in serum were decreased on D0, whereas ADA activity was significantly increased on D0 compared to the control group. D15 group showed increase on NTPDase and XO activities compared to D0 group. CD39 and CD73 expression levels were distinct according to the cell maturation degree. On D0, lymphoblasts showed lower CD39 and higher CD73 expressions in relation to lymphocytes from the same group. Serum purine levels of inosine and xanthine were significantly increased, whereas of hypoxanthine was decreased on D0. The cytokines IL-6, IL-17 and IL-10 levels were significantly increased on D0 when compared to control group. The results showed an inflammatory status of BCP-ALL at diagnosis, and a possible modulation of the purinergic signaling system and of cytokines on neoplasic lymphocytes, which may influence in the immunosuppression status and the changes in the immune response, making the neoplasic cell proliferation possible. Complementary studies may identify individual patient characteristics in the purinergic signalling, to assist in the choice of a more specific therapy. |
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Atividade das enzimas que degradam nucleotídeos e nucleosídeo da adenina em leucemia linfoblástica aguda B derivadaAtividade das enzimas que degradam nucleotídeos e nucleosídeo da adenina em leucemia linfoblástica aguda B derivadaLLA-BNTPDaseADACD39CD73LinfócitosBCP-ALLE-NTPDaseE-ADALymphocytesCNPQ::CIENCIAS DA SAUDE::FARMACIAB-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a neoplasm characterized by an anomalous clonal proliferation of B lymphoid precursor cells and predominance in pediatric patients. BCP-ALL promotes the deregulation of physiological and immunological processes. Among the immune processes modulators, ATP, ADP, AMP and adenosine stand out. The extracellular concentrations of these nucleotides are regulated by the ectoenzymes E- NTPDase (CD39), E-5'-NT (CD73), and ecto-adenosine deaminase (E-ADA). This study aimed to evaluate the activities of E-NTPDase and E-ADA in peripheral lymphocytes, measure the expression of CD39 and CD73 in peripheral blood, evaluate the activities of NTPDase, ADA and XO, the levels of soluble nucleotides and nucleosides of adenine and the cytokines in the serum, in order to evaluate the immune response in BCP-ALL patients. Thirty-two patients were evaluated at diagnosis (D0), 14 patients 15 days after the beginning of the treatment (D15), and 34 healthy individuals in the control group (C). The activities of ectonucleotidases and soluble enzymes NTPDase and ADA were determined on isolated peripheral lymphocytes and serum, respectively. Flow cytometry method was used to evaluate the expressions of CD39 and CD73 in lysed whole blood and the levels of cytokines in the serum. The nucleotides and nucleosides levels were evaluated in serum by HPLC method. Concerning to the activity on lymphocytes, E-NTPDase (ADP substrate) was reduced in D15 group, while E-ADA activity was increased on D0 and on D15 when compared to the control group. The activities of NTPDase (ATP and ADP substrate) and XO in serum were decreased on D0, whereas ADA activity was significantly increased on D0 compared to the control group. D15 group showed increase on NTPDase and XO activities compared to D0 group. CD39 and CD73 expression levels were distinct according to the cell maturation degree. On D0, lymphoblasts showed lower CD39 and higher CD73 expressions in relation to lymphocytes from the same group. Serum purine levels of inosine and xanthine were significantly increased, whereas of hypoxanthine was decreased on D0. The cytokines IL-6, IL-17 and IL-10 levels were significantly increased on D0 when compared to control group. The results showed an inflammatory status of BCP-ALL at diagnosis, and a possible modulation of the purinergic signaling system and of cytokines on neoplasic lymphocytes, which may influence in the immunosuppression status and the changes in the immune response, making the neoplasic cell proliferation possible. Complementary studies may identify individual patient characteristics in the purinergic signalling, to assist in the choice of a more specific therapy.A leucemia linfoblástica aguda de precursores B (LLA-B derivada) é uma neoplasia caracterizada pela proliferação clonal anômala de células precursoras linfoides B e pela predominância em pacientes pediátricos. A patogênese da LLA-B promove a desregulação das vias de controle de processos fisiológicos e imunológicos. Dentre os mediadores da modulação dos processos imunes, destacam-se os nucleotídeos ATP, ADP, AMP e o nucleosídeo adenosina, cujas concentrações extracelulares são controladas pela atividade das ectoenzimas E-NTPDase (CD39), E-5’-nucleotidase (CD73), ecto-nucleotídeo pirofosfatase/fosfodiesterase (E-NPP) e ecto-adenosina desaminase (E-ADA). O objetivo deste estudo foi avaliar as atividades da E-NTPDase e E-ADA em linfócitos periféricos, quantificar a expressão de CD39 e CD73 em sangue periférico, determinar no soro as atividades da NTPDase, ADA e xantina oxidase (XO), a concentração de nucleotídeos e nucleosídeos da adenina e a concentração de citocinas, de forma a avaliar a resposta imune em pacientes com LLA-B. Avaliaram-se pacientes pediátricos portadores de LLA–B recém diagnosticados (D0), com 15 dias de tratamento (D15) e um grupo controle pediátrico. Trinta e dois pacientes D0, 14 pacientes D15 e 34 controles sadios (C) foram admitidos. As atividades das ectonucleotidases e das enzimas solúveis NTPDase e ADA foram determinadas em linfócitos periféricos isolados e no soro, respectivamente. Avaliaram-se as expressões de CD39 e CD73 em sangue total lisado e, citocinas no soro, por citometria de fluxo. Quantificaram-se nucleotídeos no soro por CLAE. Os resultados mostraram que, em linfócitos, a atividade da E-NTPDase (substrato ATP), não mostrou variação significativa entre os grupos, enquanto na E-NTPDase (substrato ADP) houve redução no grupo D15 e, na E-ADA, houve aumento em D0 e D15. No soro, as atividades da NTPDase e XO mostraram redução significativa no grupo D0, enquanto a ADA mostrou-se elevada. No grupo D15 houve aumento nas atividades de NTPDase e XO na comparação com o grupo D0. A expressão de CD39 estava reduzida e a de CD73, aumentada, nos blastos do grupo DO, quando comparados aos linfócitos do grupo D0. As dosagens séricas de citocinas diferiram significativamente entre os grupos D0 e controle para IL-6, IL-17 e IL-10. Mostraram-se elevados os níveis dos nucleosídeos adenosina, inosina e xantina, enquanto a hipoxantina estava reduzida. Os resultados refletem um estado inflamatório da BCP-ALL ao diagnóstico e uma possível modulação do sistema purinérgico e das citocinas em linfócitos neoplásicos, influindo no estado de imunossupressão e de alteração na resposta imune, e possibilitando a proliferação de células neoplásicas. Estudos complementares poderiam identificar características individuais da sinalização purinérgica nos pacientes com LLA-B como forma de contribuir na escolha de uma terapêutica mais específica.Universidade Federal de Santa MariaBrasilFarmacologiaUFSMPrograma de Pós-Graduação em Ciências FarmacêuticasCentro de Ciências da SaúdeLeal, Daniela Bitencourt Rosahttp://lattes.cnpq.br/3639683273462361Moreira, Cleci Menezeshttp://lattes.cnpq.br/5805841991374556Silva, José Edson Paz dahttp://lattes.cnpq.br/1177504021154172Bagatini, Margarete Dulcehttp://lattes.cnpq.br/1677000967927092Chitolina, Maria Rosahttp://lattes.cnpq.br/4401319386725357Oliveira, Liliane Zimmermann de2019-11-19T18:15:47Z2019-11-19T18:15:47Z2017-09-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttp://repositorio.ufsm.br/handle/1/18972porAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessreponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSM2022-08-09T12:36:52Zoai:repositorio.ufsm.br:1/18972Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufsm.br/ONGhttps://repositorio.ufsm.br/oai/requestatendimento.sib@ufsm.br||tedebc@gmail.comopendoar:2022-08-09T12:36:52Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.none.fl_str_mv |
Atividade das enzimas que degradam nucleotídeos e nucleosídeo da adenina em leucemia linfoblástica aguda B derivada Atividade das enzimas que degradam nucleotídeos e nucleosídeo da adenina em leucemia linfoblástica aguda B derivada |
title |
Atividade das enzimas que degradam nucleotídeos e nucleosídeo da adenina em leucemia linfoblástica aguda B derivada |
spellingShingle |
Atividade das enzimas que degradam nucleotídeos e nucleosídeo da adenina em leucemia linfoblástica aguda B derivada Oliveira, Liliane Zimmermann de LLA-B NTPDase ADA CD39 CD73 Linfócitos BCP-ALL E-NTPDase E-ADA Lymphocytes CNPQ::CIENCIAS DA SAUDE::FARMACIA |
title_short |
Atividade das enzimas que degradam nucleotídeos e nucleosídeo da adenina em leucemia linfoblástica aguda B derivada |
title_full |
Atividade das enzimas que degradam nucleotídeos e nucleosídeo da adenina em leucemia linfoblástica aguda B derivada |
title_fullStr |
Atividade das enzimas que degradam nucleotídeos e nucleosídeo da adenina em leucemia linfoblástica aguda B derivada |
title_full_unstemmed |
Atividade das enzimas que degradam nucleotídeos e nucleosídeo da adenina em leucemia linfoblástica aguda B derivada |
title_sort |
Atividade das enzimas que degradam nucleotídeos e nucleosídeo da adenina em leucemia linfoblástica aguda B derivada |
author |
Oliveira, Liliane Zimmermann de |
author_facet |
Oliveira, Liliane Zimmermann de |
author_role |
author |
dc.contributor.none.fl_str_mv |
Leal, Daniela Bitencourt Rosa http://lattes.cnpq.br/3639683273462361 Moreira, Cleci Menezes http://lattes.cnpq.br/5805841991374556 Silva, José Edson Paz da http://lattes.cnpq.br/1177504021154172 Bagatini, Margarete Dulce http://lattes.cnpq.br/1677000967927092 Chitolina, Maria Rosa http://lattes.cnpq.br/4401319386725357 |
dc.contributor.author.fl_str_mv |
Oliveira, Liliane Zimmermann de |
dc.subject.por.fl_str_mv |
LLA-B NTPDase ADA CD39 CD73 Linfócitos BCP-ALL E-NTPDase E-ADA Lymphocytes CNPQ::CIENCIAS DA SAUDE::FARMACIA |
topic |
LLA-B NTPDase ADA CD39 CD73 Linfócitos BCP-ALL E-NTPDase E-ADA Lymphocytes CNPQ::CIENCIAS DA SAUDE::FARMACIA |
description |
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a neoplasm characterized by an anomalous clonal proliferation of B lymphoid precursor cells and predominance in pediatric patients. BCP-ALL promotes the deregulation of physiological and immunological processes. Among the immune processes modulators, ATP, ADP, AMP and adenosine stand out. The extracellular concentrations of these nucleotides are regulated by the ectoenzymes E- NTPDase (CD39), E-5'-NT (CD73), and ecto-adenosine deaminase (E-ADA). This study aimed to evaluate the activities of E-NTPDase and E-ADA in peripheral lymphocytes, measure the expression of CD39 and CD73 in peripheral blood, evaluate the activities of NTPDase, ADA and XO, the levels of soluble nucleotides and nucleosides of adenine and the cytokines in the serum, in order to evaluate the immune response in BCP-ALL patients. Thirty-two patients were evaluated at diagnosis (D0), 14 patients 15 days after the beginning of the treatment (D15), and 34 healthy individuals in the control group (C). The activities of ectonucleotidases and soluble enzymes NTPDase and ADA were determined on isolated peripheral lymphocytes and serum, respectively. Flow cytometry method was used to evaluate the expressions of CD39 and CD73 in lysed whole blood and the levels of cytokines in the serum. The nucleotides and nucleosides levels were evaluated in serum by HPLC method. Concerning to the activity on lymphocytes, E-NTPDase (ADP substrate) was reduced in D15 group, while E-ADA activity was increased on D0 and on D15 when compared to the control group. The activities of NTPDase (ATP and ADP substrate) and XO in serum were decreased on D0, whereas ADA activity was significantly increased on D0 compared to the control group. D15 group showed increase on NTPDase and XO activities compared to D0 group. CD39 and CD73 expression levels were distinct according to the cell maturation degree. On D0, lymphoblasts showed lower CD39 and higher CD73 expressions in relation to lymphocytes from the same group. Serum purine levels of inosine and xanthine were significantly increased, whereas of hypoxanthine was decreased on D0. The cytokines IL-6, IL-17 and IL-10 levels were significantly increased on D0 when compared to control group. The results showed an inflammatory status of BCP-ALL at diagnosis, and a possible modulation of the purinergic signaling system and of cytokines on neoplasic lymphocytes, which may influence in the immunosuppression status and the changes in the immune response, making the neoplasic cell proliferation possible. Complementary studies may identify individual patient characteristics in the purinergic signalling, to assist in the choice of a more specific therapy. |
publishDate |
2017 |
dc.date.none.fl_str_mv |
2017-09-01 2019-11-19T18:15:47Z 2019-11-19T18:15:47Z |
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.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/18972 |
url |
http://repositorio.ufsm.br/handle/1/18972 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International 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 Santa Maria Brasil Farmacologia UFSM Programa de Pós-Graduação em Ciências Farmacêuticas Centro de Ciências da Saúde |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Farmacologia UFSM Programa de Pós-Graduação em Ciências Farmacêuticas Centro de Ciências da Saúde |
dc.source.none.fl_str_mv |
reponame:Manancial - Repositório Digital da UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
instname_str |
Universidade Federal de Santa Maria (UFSM) |
instacron_str |
UFSM |
institution |
UFSM |
reponame_str |
Manancial - Repositório Digital da UFSM |
collection |
Manancial - Repositório Digital da UFSM |
repository.name.fl_str_mv |
Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM) |
repository.mail.fl_str_mv |
atendimento.sib@ufsm.br||tedebc@gmail.com |
_version_ |
1805922128279633920 |