Dysregulation of the immune system and the Treg-mediated immune tolerance in heart-transplanted childrenConsequences in graft rejection and associated comorbidities

Resumen

Heart transplantation is a widely accepted and successful therapy for end-stage heart failure in children. Transplanted patients receive strong immunosuppressive treatments to avoid immune allograft rejection; however, the lack of specificity of these drugs produces pleiotropic effects over the immune system and potentially could affect cell subsets implicated in peripheral tolerance, such as regulatory T cells (Treg). Additionally, heart-transplanted children are thymectomized in order to gain perioperative access to the retrosternal field, which may cause profound alterations in the T-cell compartment that could compromise the correct immune homeostasis. Despite that the immune system has been extensively studied in adult transplantation, little is known about the overall impact that immunosuppression, thymectomization and transplantation may over the immune system in heart-transplanted children. Therefore, our main objective was to determine whether interventions derived from the heart transplantation procedure may induce a dysregulation in the immunological status of transplanted children, which could predispose to graft rejection and associated comorbidities, such as atopic diseases. By using multi-parametric flow cytometry, we analysed more than 200 immunological variables in heart-transplanted and non-transplanted children. We have shown that these patients presented a profound immune dysregulation early after transplantation, hallmarked by a Treg deficit and Tcell differentiation into effector phenotypes. The immune status in the first-year post-transplant provide a pro-inflammatory environment that could predispose to the onset of acute rejection. Immune dysregulation and the consequent Treg/Teffector cell imbalance will be a direct consequence of thymectomy and also due to the effect of some immunosuppressive drugs such as Basiliximab, causing dramatic effects on the Treg values. Treg and effector T-cell subset alterations together with other dysregulated immune variables lasted in time and were present in patients that have suffered acute rejection episodes and atopic diseases. Patients with atopic diseases showed an imbalance towards Th2 responses that could be associated to Treg failure in controlling helper T-cell expansion. Once studying the immunological status of transplanted children in the long term, those who have had signs of rejection presented augmented expression of chronic activation markers and high TemRA T-cell levels that could predispose to additional chronic rejection. Finally, after the evidence of the crucial role of Treg in the immune homeostasis and their degradation in heart-transplanted children, we propose a novel strategy to implement an immunotherapy with autologous Tregs to prevent graft rejection in these patients