Publication: Un nuevo modelo predictivo basado en variables clínicas y en polimorfismos en genes de citocinas permite predecir la incidencia de EICR grave post-trasplante hematopoyético alogénico
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2018-11-27
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Universidad Complutense de Madrid
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Abstract
Un nuevo modelo predictivo basado en variables clínicas y en polimorfismos en genes de citocinas permite predecir la incidencia de EICR grave post-trasplante hematopoyético alogénico. El trasplante alogénico de progenitores hematopoyéticos (alo-TPH) es el tratamiento de elección para la curación de enfermedades como las leucemias agudas y otras neoplasias hematológicas, inmunodeficiencias severas o errores congénitos del metabolismo y la enfermedad de injerto contra receptor (EICR), reacción aloinmune de las células del donante contra células sanas de distintos tejidos del receptor, es una de las complicaciones más relevantes post-TPH y la principal causa de morbilidad y mortalidad del mismo. Entre un 30 y un 50% de los pacientes que reciben un trasplante alogénico desarrollan la EICR pero el anticipar dicha complicación sigue siendo un tema aún no resuelto. Hasta ahora se hace principalmente usando variables clínicas como la edad del paciente en el momento del TPH, la fuente de progenitores hematopoyéticos, la disparidad de sexo entre donante y receptor, la profilaxis de la EICR o el acondicionamiento. Sin embargo, en los últimos años, se está viendo también la importancia de las variables genéticas y, aunque la selección de donantes adecuados para el TPH se basa fundamentalmente en la compatibilidad del sistema HLA entre donante y receptor, se está estudiando la influencia de otros genes en los fenómenos alorreactivos ya que aún en trasplantes HLA idénticos se observan complicaciones como la EICR o el rechazo del injerto. Es necesario, por tanto, un mejor conocimiento de otros factores que influyen en las reacciones de alorreactividad donante/receptor entre los que se encuentran los antígenos menores de histocompatibilidad, las citocinas y sus receptores, las quimiocinas y sus receptores y otras proteínas relacionadas con el sistema inmunitario o con el metabolismo de fármacos. A pesar de la existencia de varios trabajos que intentan relacionar uno o dos polimorfismos genéticos en donantes o receptores con el éxito del trasplante alogénico, no existen trabajos que analicen de forma global un número elevado de polimorfismos con la aparición de la EICR...
A novel predictive approach for GVHD after allogeneic SCT based on clinical variables and cytokine gene polymorphisms. Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a curative therapeutic approach for patients with hematologic malignancies. Allo-SCT patients receive a donor graft containing hematopoietic stem cells, as well as various other cell types including alloreactive T cells. T cells promote hematopoietic engraftment, T-cell immunity reconstitution, and mediate graft-versus-leukemia effect, which may prevent tumour relapse. However, donor T cells also cause graft-versus-host disease (GVHD), which is the main complication after allo-SCT and the most important cause of non-relapse morbidity and mortality. There are two forms of GVHD, acute GVHD (aGVHD) and chronic GVHD (cGVHD). aGVHD is a complex process that takes place in three phases. In the first phase, conditioning regimen damages host tissues and raises levels of proinflammatory cytokines such as IL-1, IL-6, TNFα, and INFγ, thus activating host antigen-presenting cells, which stimulate donor T cells. In the second phase, this interaction induces proliferation and differentiation of donor T cells, which in turn leads to rapid intracellular biochemical cascades that induce transcription of genes for many proteins (including the cytokines TNFα, IFNγ, and IL-2) and promotes cellular activity. The third effector phase is a complex cascade of both cellular mediators and soluble inflammatory mediators such as TNFα, IFNγ, IL-1, and nitric oxide that results in tissue injury. Although the pathophysiology of cGVHD is less known, significant advances in our understanding have been made in recent years, and it is now evident that the clinical manifestations are the result of a complex immune disease involving both donor B cells and T cells. The long-standing hypothesis has been that cGVHD is similar to an autoimmune disorder. It is well established that the most important risk factor for the development of GVHD is the degree of human leukocyte antigen (HLA) matching between the recipient and the donor, although in HLA-identical grafts, 30-50% of recipients develop aGVHD and for cGHVD. Consequently, other non-HLA factors contribute to the development of this complication. Major clinical factors associated with GVHD include patient age, gender donor/recipient, stem cell source, GVHD prophylaxis, underlying disease, conditioning regimen, as well as, and for cGVHD, a previous history of aGVHD. Genetic differences in non-HLA genes between recipients and donors are also important, and the role of polymorphisms in human minor histocompatibility antigens innate immunity genes, genes involved in drug metabolism, and proinflammatory cytokines must be taken into account. During the past decade, single-nucleotide polymorphisms (SNPs) have been identified in genes involved in innate and adaptive immune responses, such as cytokines and their receptors, which have a role in the classic cytokine storm of GVHD. However, information regarding the diagnostic, prognostic, and predictive significance of these molecules in GVHD is limited...
A novel predictive approach for GVHD after allogeneic SCT based on clinical variables and cytokine gene polymorphisms. Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a curative therapeutic approach for patients with hematologic malignancies. Allo-SCT patients receive a donor graft containing hematopoietic stem cells, as well as various other cell types including alloreactive T cells. T cells promote hematopoietic engraftment, T-cell immunity reconstitution, and mediate graft-versus-leukemia effect, which may prevent tumour relapse. However, donor T cells also cause graft-versus-host disease (GVHD), which is the main complication after allo-SCT and the most important cause of non-relapse morbidity and mortality. There are two forms of GVHD, acute GVHD (aGVHD) and chronic GVHD (cGVHD). aGVHD is a complex process that takes place in three phases. In the first phase, conditioning regimen damages host tissues and raises levels of proinflammatory cytokines such as IL-1, IL-6, TNFα, and INFγ, thus activating host antigen-presenting cells, which stimulate donor T cells. In the second phase, this interaction induces proliferation and differentiation of donor T cells, which in turn leads to rapid intracellular biochemical cascades that induce transcription of genes for many proteins (including the cytokines TNFα, IFNγ, and IL-2) and promotes cellular activity. The third effector phase is a complex cascade of both cellular mediators and soluble inflammatory mediators such as TNFα, IFNγ, IL-1, and nitric oxide that results in tissue injury. Although the pathophysiology of cGVHD is less known, significant advances in our understanding have been made in recent years, and it is now evident that the clinical manifestations are the result of a complex immune disease involving both donor B cells and T cells. The long-standing hypothesis has been that cGVHD is similar to an autoimmune disorder. It is well established that the most important risk factor for the development of GVHD is the degree of human leukocyte antigen (HLA) matching between the recipient and the donor, although in HLA-identical grafts, 30-50% of recipients develop aGVHD and for cGHVD. Consequently, other non-HLA factors contribute to the development of this complication. Major clinical factors associated with GVHD include patient age, gender donor/recipient, stem cell source, GVHD prophylaxis, underlying disease, conditioning regimen, as well as, and for cGVHD, a previous history of aGVHD. Genetic differences in non-HLA genes between recipients and donors are also important, and the role of polymorphisms in human minor histocompatibility antigens innate immunity genes, genes involved in drug metabolism, and proinflammatory cytokines must be taken into account. During the past decade, single-nucleotide polymorphisms (SNPs) have been identified in genes involved in innate and adaptive immune responses, such as cytokines and their receptors, which have a role in the classic cytokine storm of GVHD. However, information regarding the diagnostic, prognostic, and predictive significance of these molecules in GVHD is limited...
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Tesis de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Medicina, leída el 17/01/2018