Delayed immune reconstitution after cord blood transplantation is characterized by impaired thymopoiesis and late memory T-cell skewing

Abstract

Advances in immune assessment, including the development of T-cell receptor excision circle (TREC) assays of thymopoiesis, cytokine-flow cytometry assays of T-cell function, and higher-order phenotyping of T-cell maturation subsets have improved our understanding of T-cell homeostasis. Limited data exist using these methods to characterize immune recovery in adult cord blood (CB) transplant recipients, in whom infection is a leading cause of mortality. We now report the results of a single-center prospective study of T-cell immune recovery after cord blood transplantation (CBT) in a predominantly adult population. Our primary findings include the following: (1) Prolonged T lymphopenia and compensatory expansion of B and natural killer (NK) cells was evident; (2) CB transplant recipients had impaired functional recovery, although we did observe posttransplantation de novo T-cell responses to cytomegalovirus (CMV) in a subset of patients; (3) Thymopoietic failure characterized post-CBT immune reconstitution, in marked contrast to results in other transplant recipients; and (4) Thymopoietic failure was associated with late memory T-cell skewing. Our data suggest that efforts to improve outcomes in adult CB transplant recipients should be aimed at optimizing T-cell immune recovery. Strategies that improve the engraftment of lymphoid precursors, protect the thymus during pretransplant conditioning, and/or augment the recovery of thymopoiesis may improve outcomes after CBT. IntroductionUmbilical cord blood (CB), first demonstrated to have clinical utility by Gluckman et al as a source of hematopoietic stem cells in the setting of Fanconi anemia, 1 was later demonstrated to have utility as a source of unrelated donor stem cells for patients lacking matched-sibling donors. [2][3][4][5] Over the past decade, a large number of studies have demonstrated the clinical utility of CB transplantation (CBT) as a treatment for both malignant and nonmalignant diseases of children and adults. 4,6 The establishment of international cord blood banks, advances in supportive care and donor graft selection, and novel clinical approaches aimed at improving engraftment (eg, ex vivo expansion of CB-derived progenitors 7,8 and the infusion of pooled unrelated units 9 ) have improved outcomes and led to a dramatic increase in the number of CBTs performed worldwide.CB grafts obtained from matched unrelated donors offer advantages over bone marrow or peripheral blood stem cells (PBSC) such as noninvasive procurement, more rapid availability without the need for the more prolonged process of screening and obtaining stem cells from a matched unrelated donor (MUD), and the apparently greater tolerance for incompletely human leukocyte antigen (HLA)-matched products. 10 These advantages are paramount for recipients in historically underrepresented minority groups, for whom the prospect of locating a MUD registry donor remains relatively diminished. At our institution, more than twice the proportion of CB transplant recipients are minorities relati...

Impact of rabbit ATG-containing myeloablative conditioning regimens on the outcome of patients undergoing unrelated single-unit cord blood transplantation for hematological malignancies

“…8 The latter could be responsible for an increased risk of late engraftment and graft failure and for delayed post-transplant immune reconstitution leading to a high incidence of early nonrelapse mortality (NRM). 9 One of the strategies developed to reduce the risk of graft rejection has been to provide for in vivo recipient T-cell depletion in blood and lymphoid tissues by using antithymocyte globulin (ATG), a set of polyclonal antibodies directed against a wide range of immune cell epitopes. 10,11 However, ATG use in combination with a conditioning regimen before allo-SCT is still controversial, especially for patients receiving a myeloablative single-unit cord blood transplantation (allo-CBT).…”

Signature profiles of CMV-specific T-cells in patients with CMV reactivation after hematopoietic SCT

“…11 Several groups have monitored the recovery of CMVspecific immune responses after HSCT. These studies included CD8 þ tetramer detection in a sizeable cohort (24 patients, 12 87 patients 2 and 116 patients 13 ), multiple smaller-size cohorts that were assessed only for an IFNg production in CD4 þ and CD8 þ T-cells (52 patients 14 ; 30 patients; 15 32 patients 16 and 32 patients 17 ), and one study of CD4 þ T-cell production of IFNg and IL2 (42 patients 18 ). Overall, our understanding of protective factors remains limited.…”

Features of EBV reactivation after reduced intensity conditioning unrelated umbilical cord blood transplantation

“…7 In the first patient, EBV-LPD occurred late after UCBT (at 9 months post UCBT), highlighting the concern of a relatively slow immune reconstitution after UCBT. 21,22 However, immunosuppressive treatment at the time of the occurrence of EBV-LPD could have altered the specific immune recovery, as previously reported for CMV in the same setting. 23 All patients from the current report were screened weekly by DNA-PCR for EBV.…”