T cell regeneration in pediatric allogeneic stem cell transplantation

Abstract

Delayed and/or insufficient T cell recovery post hematopoietic stem cell transplantation (HSCT) leads to an increased risk of morbidity and mortality. We evaluated thymic function and its association with T cell regeneration post HSCT and identified factors involved in the process among pediatric stem cell transplant recipients. T cell regeneration in 66 pediatric patients was prospectively followed by naive T cell phenotyping, measuring of T cell receptor excision circles (TRECs) and expression of Foxp3 by regulatory T cells for the first 18 months post HSCT. TRECs were lower pre-HSCT in children with a malignant than non-malignant primary disease or immunosuppressed controls (P ¼ 0.001). Naive T lymphocyte reconstitution and thymic recovery were slow in the recipients of allogeneic stem cell grafts post HSCT. Infections caused by herpesviruses had a prognostic impact on mortality. Children with low TRECs had a high mortality (P ¼ 0.05) and low TRECs were also associated with extensive chronic graft-versus-host disease from 6 months onwards. Low amount of Foxp3 pre-HSCT was associated with an increased mortality post HSCT (P ¼ 0.03). Our study indicates an association between impaired T cell regeneration and thymic dysfunction and the clinical post transplant complications in pediatric allogeneic stem cell transplantation.

Stem cell source-dependent reconstitution of FOXP3+ T cells after pediatric SCT and the association with allo-reactive disease

“…In line with several previous studies in adult patients 19,20 and with one other pediatric study, 22 we found in our pediatric patient group a strong inverse correlation between FOXP3 þ T-cell frequencies early after HSCT and the development of alloreactive disease. This correlation also held true for the number of FOXP3 þ T cells within the grafts and alloreactivity.…”

“…The one pediatric study available reports no significant differences in FOXP3 expression between the recipients of sibling and unrelated grafts 3 month post HSCT. 22 However, from our study, it now became clear that at earlier time points post-HSCT substantial differences in frequencies and activation status of FOXP3 þ T cells can be seen between stem cell sources. These findings suggest that the expansion of FOXP3 þ T cells early after UCB, MSD and MUD HSCT is driven by different mechanisms.…”

“…5,[17][18][19][20][21] In pediatric patients, data on such a correlation are very few. 22 The aim of this single-center study is to obtain a clearer insight into the reconstitution pattern of FOXP3 þ T cells in pediatric MSD, MUD and UCB HSCT recipients, and the possible relationship to the development of early allo-reactive disease. This study shows important differences between stem cell sources in early FOXP3 þ T-cell reconstitution patterns and suggests that these patterns have evolved via different mechanisms.…”

Impact of thymoglobulin prior to pediatric unrelated umbilical cord blood transplantation on immune reconstitution and clinical outcome

“…36 An early specific and diverse immune reconstitution is crucial for a good outcome after transplantation, since relapse and NRM (due to aGVHD and viral reactivation) are the most important limiting factors. 37 Currently, the improved immune reconstitution associated with lower viral reactivations, albeit at the cost of increased rates of aGVHD (but not cGVHD), suggests that omitting ATG in UCBT may be suitable for children treated for malignancy or children at risk of viral reactivation, while children with otherwise uncomplicated nonmalignant disorders may benefit from reduced aGVHD with inclusion of early ATG in the conditioning regimen. from Utrecht; M.B.B.…”

Multivariate analyses of immune reconstitution in children after allo-SCT: risk-estimation based on age-matched leukocyte sub-populations

“…1 Therefore, a slow immune reconstitution can be regarded as an indicator defining patient groups with a high risk of relapse and an increased susceptibility to viral and fungal infections. 7 The introduction of adoptive cell therapy to support the recipient's immune system can be effective with regard to treatment outcome for patients within the high-risk group. 6 Hence, a classification of patients into high-risk and low-risk groups with regard to cell reconstitution might be a helpful strategy to identify patients that might benefit from additional cell therapies such as donor lymphocyte infusions.…”