Dynamics of recent thymic emigrants in pediatric recipients of allogeneic hematopoetic stem cell transplantation

Abstract

After allogeneic hematopoietic stem cell transplantation (allo-HSCT), the recurrence of recent thymic emigrants (RTE) and self-tolerant T cells indicate normalized thymic function. From 2008 to 2019, we retrospectively analyzed the RTE-reconstitution rate and the minimal time to reach normal age-specific first percentiles for CD31+CD45RA+CD4+T cells in 199 pediatric patients after allo-HSCT for various malignant and non-malignant diseases. The impact of clinically significant graft-versus-host disease (GvHD), age at transplantation, underlying disease and cumulative area under the curve of busulfan on RTE-reemergence was assessed in multivariable longitudinal analysis. RTE-reconstitution (coefficient −0.24, 95% CI −0.33 to −0.14, p < 0.001) was slowed down by GvHD and the time to reach P1 was significantly longer (Event Time Ratio 1.49, 95% CI 1.25 to 1.78, p < 0.001). Older age at transplantation was also associated with a slower RTE-reconstitution (coefficient −0.028, 95% CI −0.04 to −0.02, p < 0.001) and time to reach P1 was significantly longer (Event Time Ratio 1.03, 95% CI 1.02 to 1.05, p < 0.001). RTE-reconstitution velocity was not influenced by underlying disease or cumulative busulfan exposure. In summary, duration until thymic reactivation was independent of both conditioning intensity and underlying disease and was negatively influenced by older age and GvHD.

CD19 CAR T cells are an effective therapy for posttransplant relapse in patients with B-lineage ALL: real-world data from Germany

“…Often, complete restoration of polyclonal and naïve T cells might take up to one year. 32,33,34 We speculate that patients with later relapses might have a more polyclonal T cell repertoire with more naïve cells, allowing a more rapid and potent expansion and proliferation of transduced T cells both during manufacturing and later. These interactions are currently being investigated in a prospective study.…”

Good engraftment after reduced intensity targeted busulfan‐based conditioning and matched related donor hematopoietic cell transplantation in hemoglobinopathies

“…Primary outcomes were overall survival and event‐free survival. Secondary outcomes were CD4 + T‐cell immune reconstitution defined as ≥50 CD4 + T cells per microliter 35 within first 100 days after HCT, reaching P5 percentiles of CD31 + CD45RA + CD4 + recent thymic emigrants (RTE) immune reconstitution in the first year after HCT 36 and myeloid donor chimerism (DC) 1 and 2 years after HCT. Events were defined as treatment failure, graft failure, higher grade GvHD (grade 2, 3, or 4), or need for second HCT.…”

Primary and secondary defects of the thymus

“…RTEs, the youngest subset of naïve T‐cells and a marker for thymic output, are most commonly characterized by the co‐expression of CD45RA and CD31 by CD4+ cells. Age‐specific standard values are available 120 . CD45RA can also be combined with phenotypical markers such as complement receptors 1 and 2, CCR7, PTK7, or CD103 13 .…”

“…Age-specific standard values are available. 120 CD45RA can also be combined with phenotypical markers such as complement receptors 1 and 2, CCR7, PTK7, or CD103. 13 However, homeostatic proliferation upon IL-7 stimulation without downregulation of CD31 on one hand, and CD31 reexpression by activated T-cells on the other hand, may affect the accuracy of estimating thymic output.…”

“…Mouse models of cancer where HSCT was combined with thymic transplantation, or with other interventions aimed at improving thymic regeneration, showed increased rates of tumor regression and overall survival 118,119 . Age‐related thymic involution may be the cause for slower T‐cell reconstitution after HSCT and higher morbidity and mortality in the elderly, and, conversely, higher total naïve T‐cell numbers and TREC levels as well as greater TCR diversity in a pediatric population compared to adult recipients 117,120–122 …”