Higher T-cell Receptor Excision Circles Research Articles

Dynamic of plasma IL-22 level is an indicator of thymic output after allogeneic hematopoietic cell transplantation

AimsInterleukin-22 (IL-22) promotes thymus recovery and improves T-cell recovery in preclinical allogeneic hematopoietic cell transplant models. However, the correlation between IL-22 and thymus recovery is unknown in human transplant. Materials and methodsIn this study, plasma IL-22 levels of transplanted humans were analyzed peri-transplant. Thymic output was assessed by detecting blood signal joint T-cell receptor excision circles (TRECs). Flow cytometry was applied to measure T-cell subsets. Key findingsPlasma IL-22 level positively correlated with blood TRECs level at days 14 and 28 posttransplant. Multiple linear regression analysis showed plasma IL-22 level, occurrence of acute graft-versus-host disease (aGVHD) and age were significantly associated with blood TRECs level at day 28 after allotransplant. An increase of plasma IL-22 level during day 14 and day 28 correlated with faster recovery of blood TRECs and naïve T-cell levels in allotransplant recipients. Recipients with high TRECs levels at day 28 had lower incidence of aGVHD comparing with those who with low TRECs levels according to a median split of their TRECs levels, an effect also seen in the high IL-22 level and low IL-22 level cohorts. Other factors such as age and infection had impacts on plasma IL-22 level in allotransplants. SignificanceOur findings suggest that dynamic change of plasma IL-22 level is an indicator of thymic output and occurrence of aGVHD. Monitoring plasma IL-22 level might help to assess recovery of thymus function in human allotransplants.

Human thymopoiesis is influenced by a common genetic variant within the TCRA-TCRD locus.

The thymus is the primary lymphoid organ where naïve T cells are generated; however, with the exception of age, the parameters that govern its function in healthy humans remain unknown. We characterized the variability of thymic function among 1000 age- and sex-stratified healthy adults of the Milieu Intérieur cohort, using quantification of T cell receptor excision circles (TRECs) in peripheral blood T cells as a surrogate marker of thymopoiesis. Age and sex were the only nonheritable factors identified that affect thymic function. TREC amounts decreased with age and were higher in women compared to men. In addition, a genome-wide association study revealed a common variant (rs2204985) within the T cell receptor TCRA-TCRD locus, between the DD2 and DD3 gene segments, which associated with TREC amounts. Strikingly, transplantation of human hematopoietic stem cells with the rs2204985 GG genotype into immunodeficient mice led to thymopoiesis with higher TRECs, increased thymocyte counts, and a higher TCR repertoire diversity. Our population immunology approach revealed a genetic locus that influences thymopoiesis in healthy adults, with potentially broad implications in precision medicine.

V(D)J Recombination Excision Circles of B- and T-cells as Prognostic Marker in B-Cell Chronic Lymphocytic Leukemia

Background & Aims. T-cell receptor excision circles (TREC) and к-deleting recombination excision circles (KREC) are extrachromosomal DNA segments generated during V(D)J recombination process that characterize the diversity of the antigen repertoire of T- and B-cells. The aim of our study is to identify the prognostic value of the excision circles in the chronic lymphocytic leukemia (CLL) setting. Methods. The excision circles' levels were assessed by means of real time PCR in 109 patients with high-risk CLL and 16 matched healthy individuals. Results. KREC levels were significantly (p < 0.001) lower in CLL patients vs. the reference group. TREC levels were lower in groups with unmutated status of immunoglobulin heavy chain variable region genes (p < 0.05) and 11q deletions (p < 0.1). Moreover, the KREC levels were higher in NOTCH1 mutation carriers than in noncarriers (p < 0.05). The comparison of treatment outcomes demonstrated a correlation between a high TREC level and achievement of complete remission. The prognostic value of the bio-marker was confirmed by ROC-analysis: AUC<sub>TREC</sub> = 0.713 (p = 0.001) Conclusion. Association between excision circles' le' and clinical/laboratory CLL prognostic factors, as well complete remission achievement, makes possible the plementation of the test for early prediction of the treatm outcome.

High pre-transplant TREC levels indicate good prognosis after hematopoietic stem cell transplantation

BackgroundThymus-dependent T-cell reconstitution plays a role in immune recovery after stem cell transplantation (HSCT). High pre-HCST thymic function has been associated with higher survival, lower incidence of acute and chronic graft versus host disease (GVHD) and lower incidence of infections. The aim of this study was to analyze the relationship between pre-HSCT peripheral blood levels of T-cell receptor excision circles (TREC) and post-HSCT clinical events in recipients of HLA-identical hematopoietic stem cell transplants.MethodDelta deletion signal joint TRECs (sjTRECs) formed by the dREC-yJa rearrangement were quantified by real time PCR in peripheral blood lymphocytes of 62 HSCT recipients.ResultsUnivariate analysis revealed an association between low TREC levels and a higher incidence of grade II-IV acute GVHD (p=0.026), bacterial infection (p=0.005) and cytomegalovirus infection (p=0.033), whereas high TREC levels were associated with higher overall survival (p=0.028). In the multivariate analysis, low pre-HSCT TREC levels remained independently associated with lower survival (p=0.032; RR 2.6), occurrence of grade II-IV acute GVHD (p=0.031; RR: 2.5), bacterial infection (p=0.006, RR: 6.6) and cytomegalovirus infection (p=0.039; RR:2.8).ConclusionOur results corroborate the concept that pre-HSCT recipient´s thymic function is an important predictor of risk for acute grade II-IV GVHD and infection.

Prognostic Value of TREC, IL-7 and SCF Levels on Clinical Outcomes after Double Umbilical Cord Blood Transplantation in Adults

Umbilical cord blood (UCB) is an alternative source of hematopoietic stem cells (HSC) for allogeneic HSC transplantation but reconstitution of T cell immunity remains problematic even with double unit UCB transplantation (dUCBT). We previously reported that reconstitution of thymopoiesis plays a critical role in the clearance of CMV viremia, and is associated with improved overall survival in dUCBT recipients. Furthermore, we determined that T cell subset recovery after dUCBT depends on the production of IL-7 and SCF. In the present study we investigated whether thymic reconstitution after dUCBT depends on IL-7 and SCF and examined the prognostic role of T-cell receptor excision circles (TRECs), IL-7 and SCF on clinical outcomes after dUCBT. We analyzed 52 adult patients with hematologic malignancies who enrolled in parallel Phase I/II clinical trials of dUCBT at the Dana-Farber/Harvard Cancer Center. Forty three patients received reduced intensity conditioning with fludarabine, melphalan and antithymocyte globulin; nine patients received myeloablative conditioning with fludarabine, cyclophosphamide and TBI. Thirteen of these patients received human PTH and 13 patients received one untreated and one ex-vivo PGE2 treated UCB unit, per study protocols. GvHD prophylaxis was tacrolimus in combination with sirolimus or mycophenolate mofetil. Assessments were performed at baseline (before conditioning) and at 1, 2, 3, 6 and 12 months after dUCBT. The median follow-up time among survivors was 71 months (range 24-96). The incidence of grade II-IV aGvHD was 15.4% and 14 out of 48 patients (29%) alive after 3 months developed cGvHD. The cumulative incidence of relapse at 5 years was 43%. The 5-year non-relapse mortality (NRM), progression-free survival (PFS) and overall survival (OS) were 31%, 26%, and 41% respectively. Plasma levels of IL-7 increased 3-fold from baseline at 1 month after dUCBT (median 26.4 pg/mL), remained elevated during the first three months, and gradually declined to pre-transplant levels by 1 year. SCF increased more slowly reaching peak levels at 2 months after dUCBT (median 1335.7 pg/mL), and gradually decreased thereafter. All but one evaluable patient had detectable TRECs at baseline with a median value of 3304 copies/ug DNA. TRECs were absent or extremely low during the first 3 months after dUCBT. At 6 months, 69.7% of patients had detectable TRECs, albeit below normal range (median value of 248 copies/ug DNA), but at 12 months 86.6% of the patients had detectable levels with a normal median value of 2404 copies/ug. We observed a statistically significant inverse correlation between IL-7 and TREC levels at 2 months after UCBT (r=-0.48, p=0.036). Similarly, SCF inversely correlated with TRECs at 6 months (r=-0.5, p=.004) and 12 months after dUCBT (r=-0.48, p=.02). We hypothesize that this inverse correlation is likely due to the uptake of IL-7 and SCF by thymocytes leading to their differentiation into TREC-containing Recent Thymic Emigrants (RTE). In support of this hypothesis, IL-7 and SCF inversely correlated with naïve CD4CD45RA+ T cells at various time points after dUCBT. Next, we examined whether TREC, IL-7 and SCF levels might have a prognostic value for clinical outcomes after UCBT. In multivariable models, higher TREC levels were found to be independently associated with improved progression-free survival (PFS) (p=0.02) and overall survival (OS) (p=0.02), and with less non-relapse mortality (NRM) (p=0.002). In contrast, higher levels of IL-7 and SCF were associated with lower OS (p=0.005 and p<.0001 respectively) and a trend towards lower PFS. Furthermore, higher levels of IL-7 and SCF were adverse prognostic factors for NRM (p=0.07 and p=0.007) but not for relapse. Taken together, our findings suggest that adult dUCBT recipients develop thymic reconstitution as early as 6 months after transplantation and TREC values correlate with improved clinical outcomes of dUCBT. In contrast, higher levels of IL-7 and SCF are associated with poor quantitative T cell and thymic reconstitution and they are negative prognostic factors for OS and NRM, which mainly reflects mortality due to infections and GvHD. These findings emphasize the link between cytokine-mediated immune reconstitution of post-thymic T cells and clinical outcomes of transplantation in adult dUCBT recipients. Disclosures No relevant conflicts of interest to declare.

T-Cell Receptor Excision Circle Levels After Allogeneic Stem Cell Transplantation Are Predictive of Relapse in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome

In this retrospective study, 209 patients with malignant disease were analyzed for levels of T-cell receptor excision circles (TRECs) for the first 24 months after allogeneic stem cell transplantation. CD3(+) cells were separated by direct antibody-coupled magnetic beads, followed by DNA extraction according to a standard protocol. The δRec-ψJα signal joint TREC was measured with real-time quantitative PCR. Patients were grouped based on malignant disease: chronic myeloid leukemia, chronic lymphatic leukemia, acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndrome (MDS). Patients were further subdivided based on TREC levels below (low-TREC) or above (high-TREC) median at each time point. TREC levels were then correlated to relapse incidence and relapse-free survival (RFS). For patients with AML, low TREC levels 2 months post-transplantation were correlated to high relapse incidence at 5 years (P<0.05). In patients with chronic leukemia, high TREC levels were correlated with improved RFS (P<0.05). For patients with MDS, high TREC levels at 9 months post-transplantation were associated with higher RFS at 5 years (P<0.02) and lower relapse incidence (P<0.02). This study shows the potential use of TREC measurement in blood to predict relapse in patients with AML and MDS after allogeneic hematopoietic stem cell transplantation.

Maternal cigarette smoking and its effect on neonatal lymphocyte subpopulations and replication

BackgroundSignificant immunomodulatory effects have been described as result of cigarette smoking in adults and pregnant women. However, the effect of cigarette smoking during pregnancy on the lymphocyte subpopulations in newborns has been discussed, controversially.MethodsIn a prospective birth cohort, we analyzed the peripheral lymphocyte subpopulations of smoking (SM) and non-smoking mothers (NSM) and their newborns and the replicative history of neonatal, mostly naive CD4 + CD45RA + T cells by measurements of T-cell-receptor-excision-circles (TRECs), relative telomere lengths (RTL) and the serum cytokine concentrations.ResultsSM had higher lymphocyte counts than NSM. Comparing SM and NSM and SM newborns with NSM newborns, no significant differences in proportions of lymphocyte subpopulations were seen. Regardless of their smoking habits, mothers had significantly lower naive T cells and higher memory and effector T cells than newborns. NSM had significantly lower percentages of CD4 + CD25++ T cells compared to their newborns, which was not significant in SM. There were no differences regarding cytokine concentrations in newborns of SM and NSM. However, NSM had significantly higher Interleukin-7 concentrations than their newborns. Regardless of smoking habits of mothers, newborns had significantly longer telomeres and higher TRECs than their mothers. Newborns of SM had significantly longer telomeres than newborns of NSM.ConclusionsApart from higher lymphocyte counts in SM, our results did not reveal differences between lymphocyte subpopulations of SM and NSM and their newborns, respectively. Our finding of significantly longer RTL in newborns of SM may reflect potential harm on lymphocytes, such as cytogenetic damage induced by smoking.

T cell regeneration in pediatric allogeneic stem cell transplantation

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=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=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=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.

Different profiles of immune reconstitution in children and adults with HIV-infection after highly active antiretroviral therapy

BackgroundRecent advances in characterizing the immune recovery of HIV-1-infected people have highlighted the importance of the thymus for peripheral T-cell diversity and function. The aim of this study was to investigate differences in immune reconstitution profiles after highly active antiretroviral therapy (HAART) between HIV-children and adults.MethodsHIV patients were grouped according to their previous clinical and immunological status: 9 HIV-Reconstituting-adults (HIV-Rec-adults) and 10 HIV-Reconstituting-children (HIV-Rec-children) on HAART with viral load (VL) ≤400 copies/ml and CD4+ ≥500 cells/μL at least during 6 months before the study and CD4+ ≤300 cells/μL anytime before. Fifteen healthy-adults and 20 healthy-children (control subjects) were used to calculate Z-score values to unify value scales between children and adults to make them comparable.ResultsHIV-Rec-children had higher T-cell receptor excision circles (TREC) and lower interleukin (IL)-7 levels than HIV-Rec-adults (p < 0.05). When we analyzed Z-score values, HIV-Rec-children had higher TREC Z-score levels (p = 0.03) than HIV-Rec-adults but similar IL-7 Z-score levels. Regarding T-cell subsets, HIV-Rec-children had higher naïve CD4+ (CD4+CD45RA hi+CD27+), naïve CD8+ (CD8+CD45RA hi+CD27+), and memory CD8+ (CD8+CD45RO+) cells/μl than HIV-Rec-adults, but similar memory CD4+ (CD4+CD45RO+) counts. HIV-Rec-children had lower naïve CD8+ Z-score values than HIV-Rec-adults (p = 0.05).ConclusionOur data suggest that HIV-Rec-children had better thymic function than HIV-Rec-adults and this fact affects the peripheral T-cell subsets. Thus, T-cell recovery after HAART in HIV-Rec-adults could be the consequence of antigen-independent peripheral T-cell expansion while in HIV-Rec-children thymic output could play a predominant role in immune reconstitution.

Thymic Recovery among Pediatric Stem Cell Recipients.

BACKGROUND: Thymic recovery is an essential part of immune reconstitution post stem cell transplantation. The process is affected by the age of the recipient, use of radiotherapy in conditioning and graft versus host disease. The duration of impaired T cell function depends mainly on thymic recovery and is associated with an increased risk of complications such as infections. The aim of this study was to evaluate thymic recovery post-transplant in pediatric patients. And also to detect differencies in thymic recovery between recipients of autologous stem cell rescue and those of allogeneic grafts from sibling and unrelated donorsMATERIAL AND METHODS: Between 8/2001–8/2005 a total of 66 patients with a mean age of 7 yrs with either a malignant or non-malignant disease were studied. 31 received a matched unrelated, 21 a sibling graft and 14 were given autologous stem cell rescue. Thymic function was evaluated by quantifying TREC (T cell receptor excision circles) levels in peripheral blood mononuclear cells by real time quantitative PCR once prior to transplant and once every three months during the first year and at 18 months post-transplant. FOXP3 levels were evaluated simultaneously with those of TREC by real time quantitative PCR. The data was related to the clinical status of patients and the recovery of peripheral blood T cell numbers. In 29% (6/21) of the recipients of sibling grafts and 65% (20/31) of recipients of unrelated grafts had clinically significant (Gr II–IV) acute graft versus host disease. About 30 % in both groups developed chronic graft versus host disease.RESULTS: Comparison of TREC levels in children following SCT indicated that thymic recovery was brisk among recipients of autologous stem cell rescue by the 6 months and within the allogeneic group the recovery was significantly better in recipients of sibling grafts than in recipients of unrelated grafts (Figure 1.0). There was an significant negative association between the values of TREC and the occurrence of chronic graft versus host disease from 6 months to 18 months post-transplant. Children with low (below median) TREC values had increased mortality. Patients with low TREC experienced more infections during first six months post-transplant than children with high (above median) TREC values. Blood numbers of CD4 naive cells (CD45RA+) and CD27+ cells correlated significantly with TREC values.FOXP3 values were associated at three months post-transplant with acute graft versus host disease and with its chronic form at 12 and 18 months post-transplant. FOXP3 correlated with blood CD4 naive cells (CD45RA+) and CD27+ cells at 12 and 18 months post-transplant.There was a significant correlation between levels of TREC and FOXP3 at 12 and 18 months post stem cell transplant.CONCLUSIONS: Our data may indicate a difference in the kinetics of thymic recovery post-transplant between recipients of sibling and URD grafts and those of autologous stem cell rescue.Chronic GVHD seems to associate with thymic dysfunction and herpesviral infections with the pace of thymic recovery. [Display omitted]

Prognostic value of pretransplantation host thymic function in HLA-identical sibling hematopoietic stem cell transplantation

AbstractThymic function is critical for immune reconstitution after hematopoietic stem cell transplantation (HSCT). We evaluated recipient thymic function before HSCT by quantifying T-cell receptor excision circles (TRECs) in pretransplantation peripheral blood lymphocytes from 102 patients who received HSCs from an HLA-identical sibling for malignant (n = 87) or nonmalignant diseases (n = 15). Median TREC value before transplantation was 257 TRECs per 150 000 CD3+ cells (range, 0-42 746). We assessed 172 TRECs per 150 000 CD3+ cells as the most discriminating TREC value for survival in a first cohort of patients (n = 62). This cut-off was validated in a second independent prospective group of 40 patients. In the 102 patients, a TREC value greater than or equal to 172 was associated with a better survival (P < .000 01), a decreased incidence of grade II-IV acute graft-versus-host disease (GVHD; P = .017), chronic GVHD (P = .023), and bacterial (P = .003) and cytomegalovirus (CMV) infection (P = .024). In a multivariate analysis, low pretransplantation TREC values were associated with a higher incidence of CMV infection (hazard ratio [HR] = 2.0, P = .06) and severe bacterial infections (HR = 2.8, P = .036). Finally, high TREC values (HR = 6.6, P = .002) and ABO compatibility (HR = 2.7, P = .02) were associated with a better survival. Therefore, recipient host thymic function assessment could be helpful in predicting HSCT outcome and identifying patients who require a close immunologic monitoring.

T-cell receptor excision circles (TREC) in SHIV 89.6p and SIVmac251 models of HIV-1 infection.

T-cell receptor excision circles (TREC) may be a useful surrogate marker in HIV-1 infection for evaluating the likelihood of continued clinical stability and/or the response to therapeutics, including vaccines. Analysis of TREC in SHIV and SIV models of HIV-1 infection may provide additional information concerning the utility of TREC as a marker. We measured TREC in peripheral blood mononuclear cells (PBMC) from rhesus macaques in SHIV89.6p (n = 20) and SIVmac251 (n = 11) models of HIV-1 infection. TREC were also evaluated in tissues in the SIVmac251 model at end-point. In the SHIV89.6p model, TREC in PBMC were significantly lower at 12 weeks postinfection compared to preinfection levels. The decrease in TREC correlated with the decline in CD4+ T cells (r(s) = 0.496; P = 0.026), which in turn correlated inversely with serum viral loads at end-point (r(s) = -0.517; P = 0.019). Macaques that controlled SHIV89.6p infection to some degree (n = 6) had higher TREC at study end-point (P = 0.017). In the SIVmac251 model, TREC in PBMC were significantly reduced after 17 months of infection (P = 0.012) despite receiving highly active antiretroviral therapy (HAART) consisting of didanosine (ddI) and (R)-9-(2-phosphonylmethoxypropyl)-adenine (PMPA) when not cycling off therapy during scheduled treatment interruptions (STI). However, macaques that received continuous hydroxyurea (HU) in addition to the HAART regimen had higher end-point TREC compared to the non-HU group (P = 0.041), and the reduction in TREC observed at end-point within the HU group was not significant. In the SIVmac251 model, TREC correlated with the percentage of CD4+ T cells (r(s) = 0.426; P = 0.048) and CD4+CD28+ T cells (r(s) = 0.624; P = 0.002), and inversely with CD8+ T cells (r(s) = -0.622; P = 0.002), CD8+CD28- T cells (r(s) = -0.516; P = 0.014), and serum viral loads (r(s) = -0.627; P = 0.039). High levels of TREC were observed in the thymus, levels comparable to PBMC were seen in the lymph node, and low but detectable levels of TREC were present in bone marrow. The use of correlates of TREC as covariates in ANCOVA revealed that the decline in TREC in the SHIV 89.6p model reflected the decline in the percentage of CD4+ T-cells due to viral cytopathogenicity. In the SIVmac251 model, the decline in TREC was related to increased immune activation and proliferation due to viral replication, as reflected by decreases in percentages of CD4+CD28+ T cells and increases in CD8+ and CD8+CD28- T cells.

T-cell receptor excision circles: a novel prognostic parameter for the outcome of transplantation in multiple myeloma patients.

This study investigated whether T-cell receptor excision circles (TRECs) are a prognostic marker for the outcome of myeloma patients undergoing a tandem autologous peripheral blood stem cell transplantation (PBSCT). Twenty-five patients were enrolled. Samples were obtained at study enrollment, after conventional therapy, between first and second transplantation and 3, 6, 12 and 24 months after the second PBSCT. TRECs were quantified using real-time polymerase chain reaction. A high variation in TREC levels was found at diagnosis (median TREC level 136/10(5) peripheral blood mononuclear cells (PBMCs); range 1-1729), suggesting individual differences in thymic output of naive T cells. Patients with more than 136 TRECs/10(5) P BMCs at diagnosis had a statistically significant better overall survival (P=0.05) and event-free survival (P=0.045), whereas low TREC levels correlated with a higher incidence of infectious complications. Median TREC values were lowest after the first PBSCT (52/10(5) PBMCs) and reached the baseline 12 months after the second transplantation. Patients with high TREC levels after the second PBSCT had a significantly higher probability of being in complete or partial remission 30 months after the second PBSCT. TREC levels were not correlated with beta2-microglobulin and C-reactive protein levels at diagnosis. These data suggest that TRECs could be a relevant prognostic factor for patients who receive high-dose chemotherapy and autologous PBSCT.

T-cell repopulation and thymic volume in HIV-1–infected adult patients after highly active antiretroviral therapy

The origin of T cells after highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus 1 (HIV-1) is now under discussion. The possibility of renewed lymphopoiesis in aged thymuses is still controversial. In this work we combine the analysis of naïve T cells, T-cell receptor excision circles (TRECs), and computed tomography scanning of thymic tissue to further assess whether the thymus is involved in immune reconstitution. Fifteen antiretroviral-naïve HIV-1-infected patients were evaluated during 48 weeks of HAART. At baseline, significant correlation was present among age and both thymic volume and TRECs, and between naïve T cells and TRECs. After starting HAART, there was a significant increase at week 12 in naïve CD4(+) and CD8(+) T cells, TRECs, and thymic volume. The initial net increases in naïve T cells and TREC counts were significantly correlated. Changes in thymic volume and TRECs were also indirectly related; splitting the population into 2 groups of high and low baseline TREC levels, only the group with low TREC levels had significant increases in both TRECs and thymic volume. Thus, the increase in thymic volume might be functional, in response to depleted TREC levels. Taken together, our data strongly suggest a thymic role in immune reconstitution, at least in patients with depleted baseline TREC levels. (Blood. 2002;99:3702-3706)