Thymopoiesis in Pre- and Post-Hematopoietic Stem Cell Transplantation

Abstract

Hematopoietic stem cell transplantation (HSCT) is an important therapeutic option for some hematological diseases. However, patients who undergo HSCT acquire a state of immunodeficiency that causes significant mortality. Reconstitution of thymic function is needed to support the immune system. One way to measure thymic function is through T-cell receptor excision circle (TREC) quantification. TRECs are generated by T-cell receptor gene rearrangements during T-cell maturation in the thymus and represent a reliable marker for thymic output. In this study, we aimed to assess aging and malignant hematological diseases as two important factors that may influence thymic output before HSCT. We observed that patients before HSCT presented signal joint TREC (sjTREC) numbers lower than 606.55 copies/μg DNA (low values) compared with healthy individuals, with an odds ratio (OR) of 12.88 [95% confidence interval (CI): 5.26–31.53; p < 0.001]. Our results showed that a group of older individuals (≥50 years old), comprising both healthy individuals and patients, had an OR of 10.07 (95% CI: 2.80–36.20) for low sjTREC values compared with younger individuals (≤24 years old; p < 0.001). Multiple logistic regression analysis confirmed that both older age (≥50 years old) and malignant hematological diseases and their treatments were important and independent risk factors related to thymic function impairment (p < 0.001). The median sjTREC value for patients of all ages was significantly lower than the sjTREC median for the subgroup of older healthy individuals (≥50 years old; p < 0.001). These data suggested that patients before HSCT and healthy individuals exhibited age-dependent thymic impairment, and that prior treatment for hematological diseases may exacerbate aging-related deterioration of natural thymic function. Furthermore, we analyzed these patients 9 months post-HSCT and compared patients who underwent autologous HSCT with those who underwent allogeneic HSCT. Both groups of patients achieved sjTREC copy numbers similar to those of healthy individuals. We did not find a close relationship between impaired thymic function prior to HSCT and worse thymic recovery after HSCT.

The RANKL-RANK Axis: A Bone to Thymus Round Trip

“…Remarkably, since RANKL is the master gene of osteoclastogenesis, it is tempting to speculate that the increased osteoclast activity may also boost hematopoiesis and consequent migration of thymic progenitors. Overall, these in vivo findings confirm the therapeutic effect of RANKL suggesting its putative use to boost immune reconstitution in transplanted elderly patients or in patients affected by primary thymic epithelial defects (104–106) (Figure 1D). Conversely, transient inhibition of RANKL in murine models indicate its effect on thymic negative selection of self-reactive T cells specific for tumor antigens, and resulting in an improvement of antitumor immune response (107, 108).…”

Thymic activity in immune recovery after allogeneic hematopoietic stem cell transplantation in children

“…These findings are in accordance with the observations published by Clave, Lisini et al, who described a group of 57 patients transplanted for either malignant or non-malignant diseases, and before transplantation TREC values were significantly lower in the 46 patients with hematological malignancies than in the 11 with non-malignant disorders [20]. Other studies confirmed that hematologic malignancies and chemotherapy are important and independent risk factors related to thymic inhibition [21][22][23]. Petridou et al published a study of 120 patients (30 with T-cell leukemia/non-Hodgkin's lymphoma, 30 age-and sexmatched with B-cell ALL and 60 healthy hospital controls) and reported that in a group with T-cell malignancies a reduction of TREC values was noted whereas in children with B-cell ALL only slightly and non-significantly lower TREC values were observed compared to healthy children controls [24].…”

“…CMV directly invades the thymus, causing disruption of its architecture, degradation of the thymic microenvironment and poor immune recovery after HSCT [33]. Toubert et al and Klaus da Rocha et al found an association between poor thymic recovery and a higher incidence of CMV reactivation in allo-HSCT patients [14,23]. Also results published by Lewin et al showed that low TREC levels were significantly correlated with severe opportunistic infections [34].…”

Clinical significance of T cell receptor excision circle (TREC) quantitation after allogenic HSCT

“…This is contradictory to most of the published data, which report significantly lower levels of TRECs in patients who develop infections [35]. In a study by da Rocha et al [36] a 3-fold lower risk of developing severe infections was observed in those patients who had effective sjTREC+ T-cell recovery at 6 months, and a 9-fold lower risk at 12 months. In another study, lower TREC levels at 9 months were related to CMV episodes, but not to other infections [36].…”