Delayed Immune Recovery after Umbilical Cord Blood Transplantation (UCBT) Is Characterized by Thymic Regeneration Failure.
Authors: Komanduri Krishna V. , St. John Lisa S. , Bryan Susan , Martin Sean , McMannis John D. , Molldrem Jeffrey J. , Champlin Richard E. , Cooper Laurence J. , Worth Laura , Petropoulos Demetrios , Couriel Daniel R. , de Lima Marcos , Shpall Elizabeth J. 
Published: October 2019

Abstract
UCBT is a potentially curative modality for many patients with relapsed or high-risk hematological malignancies who lack suitably matched hematopoietic progenitor cell donors. The advent of transplant approaches that combine multiple CB units to facilitate transplantation into adult recipients, as well as advances in conditioning regimens and supportive care, have significantly improved outcomes following UCBT. Despite these advances, infections and/or relapse associated with impaired T cell reconstitution remains an important source of morbidity and mortality. We prospectively assessed the quantitative and functional recovery of CD4+ and CD8+ T cells in 34 consecutively transplanted UCBT recipients. Functional studies of CD4+ and CD8+ T cells stimulated with a superantigen (staphylococcal enterotoxin B, SEB) and cytomegalovirus (CMV) antigens revealed that SEB-stimulated IFNγ responses by cytokine flow cytometry (CFC) were significantly lower in the UCBT recipients than in control bone marrow or peripheral blood stem cell transplant (SCT) recipients (median values of 0.99% (n=12) vs. 24.8% (n=24) in the CD4 compartment and 0.62% (n=14) vs. 6.37% (n=9) in the CD8 compartment, respectively). Despite this, many UCBT recipients had measurable donor-derived CMV-specific CD4+ and CD8+ T cells by 3 months (4 of 11, 44% in CD4+ T cells and 6 of 12, 50% amongst CD8+ T cells), indicating that primary immune responses were derived from the naïve CB graft precursors. Immunophenotypic studies demonstrated that a higher proportion of effector and late-effector memory cells (i.e., CCR7-CD45RA− and CCR7-CD45RA+ T cells) were present in UCBT recipients than SCT recipients. The median fraction of CCR7-negative T cells was 65% (n=12, UCBT recipients) vs. 30% (n=21, other SCT recipients) in the CD4 compartment, and 76% vs. 31%, respectively, in the CD8 compartment. Furthermore, the subgroup of UCBT recipients with a ratio of CCR7+ to CCR7-negative CD4+ T cells above the median at day 30 after SCT survived significantly longer (666 days vs. 224 days, p=0.03). Finally, we compared thymic regeneration (using a δ-chain T cell receptor excision, δTREC assay) in UCBT recipients with three other groups of SCT recipients, including longitudinally assessed autologous and allogeneic SCT recipients, as well another group of allogeneic SCT recipients assessed cross-sectionally. Thymic recovery was reduced at one and three months after UCBT, relative to all other SCT recipient groups. Median δTREC values (reported as δTRECs/million PBMC) at three months were 0.0 in UCBT recipients (n=12), 12 in autologous SCT recipients (n=11), 124 in allogeneic SCT recipients (n=27), and 2150 in a second group of allogeneic SCT recipients (n=31) (p<0.04 for all observations). These results demonstrate that T cell immune recovery in UCBT recipients is characterized by delayed functional recovery and a relative predominance of late memory (CCR7−) T cells, relative to other SCT recipients. However, naïve donor-derived CB cells are capable of primary pathogen-specific expansion in vivo. Finally, these data suggest that efforts to improve T cell immune reconstitution after UCBT should be directed at improving thymic regeneration, which is likely to be important in facilitating the recovery of naïve and early memory T cells.