Estudio celular de la inmunosenescencia en adultos mayores vacunados y en pacientes con cáncer de mama

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dc.contributor.advisorParra López, Carlos Alberto
dc.contributor.authorRodríguez Rodríguez, Ivon Johanna
dc.date.accessioned2021-08-25T21:20:45Z
dc.date.available2021-08-25T21:20:45Z
dc.date.issued2021-06-02
dc.descriptiongráficas, ilustraciones, tablasspa
dc.description.abstractIntroducción: La mejora continua de las condiciones de saneamiento básico ha aumentado la esperanza de vida de la población en la mayoría de los países, lo que se traduce en una mayor prevalencia de las enfermedades crónicas no transmisibles. El envejecimiento es un proceso heterogéneo de salud-enfermedad caracterizado por el deterioro progresivo de la capacidad funcional de las células que componen el organismo, incluidas las que componen el sistema inmune. Este deterioro de las células compromete la capacidad proliferativa, promueve la detención del ciclo celular, la expresión de marcadores asociados con la senescencia y el agotamiento, la producción de citocinas pro y antiinflamatorias y la acumulación de células senescentes. Además, el envejecimiento del sistema inmune (inmunosenesencia) se ha asociado con una menor capacidad de respuesta a la vacunación (parcialmente explicado por cambios en la frecuencia y fenotipo de los LT CD4+ foliculares helper (LTfh)) y una mayor susceptibilidad al cáncer, causado por inmunovigilancia deficiente del tumor. Materiales y Métodos: Para identificar el perfil de inmunosenescencia y su relación con una respuesta inmune deficiente a la vacunación y una mayor susceptibilidad al desarrollo de enfermedades como el cáncer, se analizó mediante citometría de flujo multiparamétrica el perfil fenotípico y funcional de diferentes subpoblaciones de leucocitos en sangre periférica de tres grupos de voluntarios: (i) adultos mayores sanos, (ii) adultos mayores sanos vacunados con toxoide tetánico y (iii) mujeres con cáncer de mama antes y después de la quimioterapia. Los datos recolectados se analizaron manualmente utilizando el software de análisis FlowJo y mediante algoritmos automatizados de reducción de dimensionalidad (t-SNE) y agrupamiento no supervisado (FlowSOM y CITRUS). Este protocolo fue aprobado por el comité de ética de la facultad de medicina de la Universidad Nacional de Colombia No. 008-063. .. Resultados: (i) Los adultos sanos exhiben un incremento de monocitos proinflamatorios con una disminución en la respuesta al estímulo inflamatorio, y un número mayor de poblaciones senescentes de células asesinas naturales y linfocitos T, (ii) Los adultos mayores tienen una menor expansión de LTfhc después de la vacunación contra toxoide tetánico que los jóvenes, y una menor expresión de Bcl-6, CXCR3 y CD40L, moléculas importantes para la diferenciación de LTfhc y su interacción en los centros germinales con linfocitos B y (iii) las pacientes con cáncer de mama prequimioterapia exhiben cambios en la frecuencia y el fenotipo de diferentes poblaciones de leucocitos con características de inmunosenescencia y agotamiento celular, que pueden estar afectando su capacidad de inmunovigilancia. Después de la quimioterapia neoadyuvante hay cambios asociados con inmunomodulación, pero también un incremento en marcadores de senescencia. Conclusiones: Encontramos cambios asociados con la inmunosenescencia que podrían aumentar la susceptibilidad de los adultos mayores a enfermedades crónicas no transmisibles, infecciones y cáncer, una menor capacidad de expansión de Tfh en adultos mayores como lo demuestra la respuesta de vacunación al toxoide tetánico. Y en pacientes con cáncer de mama, las características de inmunosenescencia de los leucocitos pueden estar asociadas con un mecanismo de escape del tumor. Además, la quimioterapia podría tener un papel ambiguo sobre los leucocitos, por un lado, generando cambios funcionales para favorecer la reactivación de la inmunovigilancia y, por otro, aumentando la senescencia en las células asesinas naturales y los Linfocitos T. (Texto tomado de la fuente)spa
dc.description.abstractIntroduction: The continuous improvement of sanitation conditions has increased the population's life expectancy (aging) and the higher prevalence of chronic non-communicable diseases in most countries. Aging is a heterogeneous health-disease process characterized by the progressive deterioration of the functional capacity of the cells that make up the body, including those that make up the immune system. This deterioration on cells compromise proliferative capacity, promote cell cycle arrest, the expression of markers associated with senescence and depletion, the production of pro-and anti-inflammatory cytokines, and the accumulation of senescent cells. In addition, aging of the immune system (Immunosenesence) has been associated with a lower capacity to respond to vaccination (partially explained by changes in the frequency and phenotype of CD4 + T follicular helper cells (LTfh)) and greater susceptibility to cancer, caused by poor immunosurveillance of the tumor. Materials and Methods: To identify the immunosenescence profile and its relationship with an inadequate immune response to vaccination and greater susceptibility to the development of diseases such as cancer, the phenotypic and functional profile of different subpopulations of leukocytes was analyzed using multiparametric flow cytometry in peripheral blood samples from three groups of volunteers: (i) healthy older adults, (ii) healthy older adults vaccinated with tetanus toxoid, and (iii) women with breast cancer before and after chemotherapy. The collected data were analyzed manually using FlowJo analysis software and automated algorithms for dimensionality reduction (t-SNE) and unsupervised clustering (FlowSOM and CITRUS). This protocol was approved by the ethics committee of Universidad Nacional de Colombia No. 008-063. Results: (i) Healthy older adults show an increase in pro-inflammatory monocytes with a decrease in response to the inflammatory stimulus and increased natural killer and T senescent cells number of senescent populations (ii) Older adults showed less expansion of TFH after vaccination against tetanus toxoid than young people, and a lower expression of Bcl-6, CXCR3, and CD40L, essential molecules for the differentiation of TFH and its interaction in the germinal centers with B lymphocytes and (iii) the patients with pre-chemotherapy breast cancer exhibits changes in the frequency and phenotype of different populations of leukocytes with characteristics of immunosenescence and cellular depletion, which may be affecting their immunosurveillance capacity. post-chemotherapy, there are changes associated with immunomodulation, but also an increase in senescence markers. Conclusions: We found changes associated with immunosenescence that could increase the susceptibility of older adults to chronic non-communicable diseases, infections, and cancer — a lower expansion capacity of TFH in older adults as shown by vaccination response to tetanus toxoid. And in patients with breast cancer, the immunosenescence characteristics of leukocytes may be associated with a tumor escape mechanism. Furthermore, chemotherapy could have an ambiguous role on leukocytes, on the one hand, generating functional changes to favor the reactivation of immunosurveillance and, on the other, increasing senescence in natural killer cells and T cells.eng
dc.description.degreelevelDoctoradospa
dc.description.degreenameDoctor en Ciencias Biomédicasspa
dc.description.degreenameDoctora en Ciencias Biomédicasspa
dc.description.methodsEste trabajo es una investigación biomédica con un diseño experimental comparativo. En este estudio, mediante muestras de sangre periférica de tres grupos de voluntarios se realizó el análisis de diferentes poblaciones de leucocitos con el propósito de mejorar el conocimiento acerca de las bases celulares de la inmunosenescencia y su relación con la respuesta a las vacunas y la susceptibilidad al cáncer de mama. Diseño experimental En el presente proyecto de investigación se utilizaron PBMCs aisladas de sangre periférica, mediante ensayos ex vivo e in vitro se evaluaron marcadores asociados con senescencia en distintas células del sistema inmune. Los grupos de estudio fueron: (i) jóvenes y adultos mayores (≥60 años) sanos, (ii) jóvenes y adultos mayores (≥65 años) sanos vacunados con toxoide tetánico y (iii) mujeres con cáncer de mama y contrapartes sanas. Universo de estudio y selección de la muestra poblacional Las instituciones donde se presentó el proyecto para la recolección de las muestras de estudio fueron: (i) Unisalud y Facultad de Medicina-UNAL (ii) Hospital Universitario Nacional de Colombia (HUN) y (iv) Instituto Nacional de Cancerología (INC). Después de la aprobación del protocolo de investigación en cada institución, las personas que aceptaron participar firmaron el consentimiento informado y donaron muestras de sangre periférica de 60 ml/toma en tubos heparinizados previa asepsia y antisepsia. Las muestras fueron procesadas en el laboratorio de Inmunología y Medicina traslacional de la Facultad de Medicina. Las PBMCs se obtuvieron mediante separación por gradiente de densidad con Ficoll® hipaque; de acuerdo con la actividad experimental se analizaron ex vivo o fueron congeladas en vapores de nitrógeno líquido hasta su uso. Un registro del número de viales congelados, número de células por vial y viabilidad (evaluada con azul de tripán), fue registrado bajo un código en base de datos. En ensayos con PBMCs de individuos jóvenes e individuos ≥60 años se compararon: Primero: Las subpoblaciones de monocitos que expresan diferencialmente los marcadores (CD14 y CD16), la respuesta de monocitos a dos tipos de estímulo proinflamatorio (agonistas de TLRs y citoquinas proinflamatorias), mediante la producción de citoquinas por CBA, la expresión de TLR 2, 3, 4 y 9, y el grado de diferenciación de monocitos a DCs maduras midiendo la expresión de HLA-DR, CD83, CD80 y CD40. Segundo: Las subpoblaciones de NKs (CD56/CD16) y la expresión de marcadores asociados con senescencia y activación de NKs como CD57, NKG2D, NKp30 y KLRG1. Tercero: La expresión diferencial de los marcadores: KLRG1 y CD57 en células vírgenes, de memoria y efectoras (determinadas por la expresión diferencial de los marcadores (CD45RA y CD62L) en Linfocitos T (CD3+) tanto CD4+ como CD8+. En el grupo que recibió la vacuna con TT se evaluó el compartimento de LT CD4+ y el grado de expansión de LTfh ex vivo en respuesta a la vacunación e in vitro en respuesta a la estimulación con el antígeno (TT). Finalmente, en leucocitos de pacientes con cáncer de mama antes y después de quimioterapia se midió: Primero: Las subpoblaciones de monocitos que expresan diferencialmente los marcadores (CD14 y CD16), y la expresión de PD-L1 y HLA-DR, el grado de diferenciación de monocitos a DCs maduras midiendo la expresión de HLA-DR, CD83, CD80 y CD40. Segundo: Las subpoblaciones de NKs (CD56/CD16) y la expresión de marcadores asociados con maduración y memoria como CD57, NKG2D, NKp30 y KLRG1 (23). Tercero: La expresión diferencial de los marcadores: KLRG1, CD57, PD1, CTLA4, LAG3 y TIM3 en células vírgenes, de memoria y efectoras (determinadas por la expresión diferencial de los marcadores (CD45RA y CD62L) en Linfocitos T (CD3+) tanto CD4+ como CD8+ utilizando citrus (análisis multiparamétrico automatizado de datos de citometría de flujo) y FlowSOM. Cuarto: La capacidad de internalización del CD3+, la fosforilación de pZAP70 y la proliferación como medida indirecta de la expresión de Ki-67, después de la estimulación in vitro con perlas acopladas a anticuerpos anti CD2/CD3 y CD28. Quinto: la producción de β-galactosidasa y la expresión de p16 y p21 (marcadores de senescencia celular) en Linfocitos T.spa
dc.description.notesFrontiersin.org/journals/immunology# https://www.frontiersin.org/articles/10.3389/fimmu.2020.604591/fulleng
dc.description.notesInfectio Revista de la Asociaron colombiana de infectología https://www.revistainfectio.org/index.php/infectio/article/view/898/0eng
dc.description.researchareaFundamentos de inmunidad y Medicina experimentalspa
dc.format.extentXXII, 156 páginasspa
dc.format.mimetypeapplication/pdfspa
dc.identifier.instnameUniversidad Nacional de Colombiaspa
dc.identifier.reponameRepositorio Institucional Universidad Nacional de Colombiaspa
dc.identifier.repourlhttps://repositorio.unal.edu.co/spa
dc.identifier.urihttps://repositorio.unal.edu.co/handle/unal/80020
dc.language.isospaspa
dc.publisherUniversidad Nacional de Colombiaspa
dc.publisher.branchUniversidad Nacional de Colombia - Sede Bogotáspa
dc.publisher.facultyFacultad de Medicinaspa
dc.publisher.placeBogotá, Colombiaspa
dc.publisher.programBogotá - Medicina - Doctorado en Ciencias Biomédicasspa
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dc.rights.accessrightsinfo:eu-repo/semantics/openAccessspa
dc.rights.licenseAtribución-NoComercial 4.0 Internacionalspa
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/spa
dc.subject.ddc610 - Medicina y salud::612 - Fisiología humanaspa
dc.subject.proposalInmunosenescenciaspa
dc.subject.proposalAgotamiento de LTspa
dc.subject.proposalCitometría de Flujospa
dc.subject.proposalCáncer de mamaspa
dc.subject.proposalToxoide tetánicospa
dc.subject.proposalImmunosenescenceeng
dc.subject.proposalT cells exhaustioneng
dc.subject.proposalFlow Cytometryeng
dc.subject.proposalBreast cancereng
dc.subject.proposalTetanus toxoideng
dc.titleEstudio celular de la inmunosenescencia en adultos mayores vacunados y en pacientes con cáncer de mamaspa
dc.title.translatedCellular study of immunosenescence in vaccinated older adults and patients with breast cancereng
dc.typeTrabajo de grado - Doctoradospa
dc.type.coarhttp://purl.org/coar/resource_type/c_db06spa
dc.type.coarversionhttp://purl.org/coar/version/c_ab4af688f83e57aaspa
dc.type.contentTextspa
dc.type.driverinfo:eu-repo/semantics/doctoralThesisspa
dc.type.redcolhttp://purl.org/redcol/resource_type/TDspa
dc.type.versioninfo:eu-repo/semantics/acceptedVersionspa
dcterms.audienceEspecializada
oaire.accessrightshttp://purl.org/coar/access_right/c_abf2spa
oaire.awardtitleEstudio clínico Fase I de inmunoterapia con vacunas sintéticas personalizadas en pacientes con cáncer de mama triple negativospa
oaire.awardtitleEstudio celular y molecular de la inmunosenescencia en pacientes con cáncer de mama y su relación con el antecedente de maltrato infantil.spa
oaire.awardtitleHacia la implementación de distintas estrategias de inmunoterapia del cáncer en Colombiaspa
oaire.fundernameCOLCIENCIAS. DEPARTAMENTO ADMINISTRATIVO DE CIENCIA TECNOLOGÍA E INNOVACIÓNspa
oaire.fundernameDirección Nacional de Investigación-Universidad Nacional de Colombiaspa

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