Thymic hyperplasia after chemotherapy in adults with mature B cell lymphoma and its influence on thymic output and CD4⁺T cells repopulation

Abstract

To investigate the thymic regenerative potential in adults accepting chemotherapy for lymphoma. The dynamics of thymic activity in 54 adults from baseline to 12 mo post-chemotherapy was analyzed by assessing thymic structural changes with serial computed tomography (CT) scans, and correlating these with measurements of thymic output by concurrent analysis of single-joint (sj) T-cell receptor excision circles (sjTREC) and CD31+ recent thymic emigrants (RTE) in peripheral blood. Furthermore, the consequence of thymic renewal on peripheral CD4+ T cell recovery after chemotherapy was evaluated. Time-dependent changes of thymic size and thymic output assessed by both sjTREC levels and CD31+ RTE counts in peripheral blood were observed during and after chemotherapy. Enlargement of thymus over baseline following chemotherapy regarded as rebound thymic hyperplasia (TH) was identified in 20 patients aged 18−53 y (median 33 y). By general linear models repeated measure analysis, it was found that, patients with TH (n = 20) had a faster recovery of sjTREC levels and CD31+ RTE counts after chemotherapy than patients with comparable age, gender, diagnosis, disease stage, thymic volume and output function at baseline but without TH (n = 18) (p = 0.035, 0.047); besides, patients with TH had a faster repopulation of both naïve CD4+ T cell and natural regulatory CD4+ T cell subsets than those without TH (p = 0.042, 0.038). These data suggested that adult thymus retains the capacity of regeneration after chemotherapy, especially in young adults. The presence of TH could contribute to the renewal of thymopoiesis and the replenishment of peripheral CD4+ T cell pool following chemotherapy in adults.

Investigating Factors Associated with Thymic Regeneration after Chemotherapy in Patients with Lymphoma

“…Consistent with our previous findings (5), both the numbers of CD31 + RTE and levels of sjTREC approached a nadir at the end of treatment ( P  < 0.001). During follow-up, CD31 + RTE counts and sjTREC levels rose significantly and reached pretreatment levels at 9 and 6 months after the end of chemotherapy, respectively ( P  = 0.035 and 0.001, respectively).…”

“…Reactive TH after chemotherapy is a well-documented phenomenon in children, adolescents, and young adults, but is rare in older patients, suggesting a high thymic regenerative capacity in the young (4, 5, 8–11). However, by monitoring thymic output, it was determined that substantial output is maintained into late adulthood despite the decline of thymic function with age, and even the aged thymus retains the ability to renew thymopoiesis (34).…”

“…The fast restoration of thymic output within 1 year of follow-up observed in these adults suggested a renewed thymopoiesis. Thymus regeneration, manifesting as partial reversal of thymic atrophy concurrent with a renewed thymopoiesis, in young adults undergoing chemotherapy would contribute to immune recovery, enhancing the clinical relevance of developing strategies to booster thymic activity in this population (2, 5, 12). …”

“…Serial quantification of sjTREC in the DNA of PBMCs was performed using a TaqMan real-time quantitative PCR assay and a StepOnePlus instrument (Applied Biosystems, USA), as previously described (5). A standard curve based on a plasmid preparation containing the sjTREC target sequence was plotted, and sjTREC values for samples were calculated using StepOne software (Applied Biosystems, USA).…”

“…Enlargement of the thymus above baseline following chemotherapy, known as rebound thymic hyperplasia (TH), sometimes occurs during recovery from chemotherapy (4). TH may be related with robust thymic regeneration and is characterized by an increase in thymic size and density, concurrent with the restoration of thymic output of T cells (5–7). This phenomenon is common in children and adolescents and can occasionally be observed in young adults; however, it is rare in older patients (4, 8–11).…”