Protecting the thymic epithelial cells and thymopoiesis during hematopoietic stem cell transplantation

Descripción del proyecto

La protección del timo durante el trasplante alogénico de células madre hematopoyéticas

El trasplante alogénico de células madre hematopoyéticas (alloHSCT, por sus siglas en inglés) puede causar daños significativos en el timo, mermando su capacidad para regenerar células T funcionales. A menudo, esta situación se ve agravada por los regímenes de acondicionamiento y la enfermedad de injerto contra huésped, lo cual aumenta la susceptibilidad a las infecciones y los tumores malignos. El proyecto ProtecTHY, financiado por el Consejo Europeo de Investigación, tiene como objetivo proteger el timo del daño mediado por el alloHSCT mediante el estudio de sus mecanismos intrínsecos de protección. El equipo de investigación empleará un innovador sistema de cultivo de órganos completos y una colección única de muestras de timo humano para identificar cómo el alloHSCT altera su estructura y evaluar si los tratamientos clínicos existentes pueden restaurar la timopoyesis. Los hallazgos prepararán el camino para nuevas estrategias que mejoren los resultados del alloHSCT.

Objetivo

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a common, often last-resort treatment for haematological diseases, but it is plagued by long-term morbidity and high mortality. Direct alloHSCT-induced damage to the thymus and subsequent loss of thymopoiesis, ie the production of new T cells, is considered one of the main reasons for these complications. Our limited understanding of how the thymus is damaged during alloHSCT restricts the development of thymus-protecting protocols. The goal of ProtecTHY is to unravel the intrinsic protective mechanisms of the human thymus and assess how alloHSCT affects them, with the ultimate objective of devising measures to prevent thymic damage. We take advantage of an innovative whole organ culture system for the human thymus developed in my laboratory and our extensive pre-existing collection of human thymus tissue samples spanning a diverse age range. ProtecTHY specifically aims to 1) discover how the thymus protects itself from external insults over the course of the human lifetime, 2) reveal how alloHSCT disrupts the human thymus microanatomy and how that damage can be prevented with a cellular therapy, and 3) examine how thymic damage affects the circulating true naive T cells and if existing clinical treatments for alloHSCT complications can restore the loss of thymopoiesis. We will apply state-of-the-art spatial and single-cell multiomics to dissect these protective layers of the thymus both ex vivo and after alloreactive challenge in vitro. Moreover, by testing the effect of treatments already in clinical use, ProtecTHY can resolve their specific mechanisms of action and impact on the thymus. Our results are thus directly translatable to the human condition and can direct future treatments to enhance outcomes following alloHSCT. As a translational immunologist and clinical microbiologist with extensive experience in human thymus research, I am well equipped to uncover the mechanisms of thymic protection.