The TREC to less CMV after UCBT

Umbilical cord blood (UCB) is increasingly being used as an alternative donor source for hematopoietic cell transplantation (HCT). In addition, double UCB transplantation has overcome the obstacle of cell dose and opened the use of UCB as a stem cell source for larger adults. T-cell reconstitution after HCT depends on both the homeostatic expansion of the adoptively transferred T cells from the UCB graft, as well as de novo stem cell–derived T-cell production. In this latter situation, the thymus is required for both positive and negative T-cell selection and durable immunity. The T cells transferred in UCB transplantation are immunologically naive and do not provide passive immunity to the transplant recipient. As a result, there has been concern for prolonged reconstitution of antigen-specific immunity and increased risk for viral infections after UCB transplantation.^1,2  In fact, some studies show fewer CMV-specific CD4⁺ and CD8⁺ T cells and a higher incidence of viral infections after UCB transplantation.^3,–5 

Cytomegalovirus (CMV) results in considerable HCT-associated morbidity and mortality.^2,6,–8  In this issue of Blood, Brown and colleagues examine the development of CMV-specific immunity after allogeneic UCB transplantation in 27 adults.⁹  Few studies have addressed immune recovery after UCB transplantation, particularly in adults. This study examines a cohort of patients receiving a unified conditioning regimen (fludarabine/melphalan/rabbit ATG) followed by a GVHD prophylaxis regimen of sirolimus/tacrolimus. Interestingly, these investigators show that 8 weeks after UCB transplantation, CMV-reactive cells can be detected by interferon-γ enzyme-linked immunospot assay (ELISPOT) in response to CMV antigens. However, the presence of these cells did not correlate with CMV reactivation or viral clearance. Instead, viral clearance correlated with the emergence of T-cell receptor rearrangement excision circle (TREC)–containing cells, which was, in turn, associated with an increase in CD4⁺CD45RA⁺ cells. Collectively, these results suggest that de novo T-cell production was needed for CMV-specific immunity after UCB transplantation. Strikingly, some patients in this cohort failed to clear viremia at 6 to 12 months after transplantation. The authors demonstrate that survival was associated with both viremia and the presence TREC-containing cells.

Immune recovery appears to be more rapid in pediatric patients when compared with adult UCB transplant recipients.^4,5  However, Brown et al found more rapid reconstitution of TREC-containing cells when compared with other adult UCB transplant recipients.^5,10  The authors hypothesize that the use of 2 UCB units has a cell dosage effect on thymic regeneration. If proven to be true, this finding may impact donor selection (single vs double UCB) and allow improvements in immune reconstitution after UCB transplantation for children and adults.

This study provides interesting insight into T-cell immune reconstitution among a cohort of adults after UCB transplantation with a uniform conditioning and GVHD prophylaxis regimen using CMV as a model for viral-specific immunity. Although T cells can be detected early after UCB transplantation, the ability of the recipient to effectively clear CMV viremia occurs only after de novo T-cell production. The presence of TREC-containing cells and correlation with overall survival emphasizes the importance of thymic function on immune reconstitution after UCB transplantation. Methods to either protect the thymus from conditioning therapy or accelerate thymopoiesis are desperately needed. This study suggests that perhaps the use of 2 UCB units may also accelerate thymic-based T-cell recovery. Thus, by using 2 UCB units, the TREC to T-cell recovery and CMV immunity may be a bit shorter.