Angiogenic Factors Correlate with T Cell Immune Reconstitution and Clinical Outcomes after Double-Unit Umbilical Cord Blood Transplantation in Adults

Umbilical cord blood (UCB) is a valuable graft source for allogeneic hematopoietic stem cell transplantation (HSCT) in patients who lack adult donors. UCB transplantation (UCBT) in adults results in delayed immune reconstitution, leading to high infection-related morbidity and mortality. Angiogenic factors and markers of endothelial dysfunction have biologic and prognostic significance in conventional HSCT, but their role in UCBT has not been investigated. Furthermore, the interplay between angiogenesis and immune reconstitution has not been studied. Here we examined whether angiogenic cytokines, angiopoietin-1 (ANG-1) and vascular endothelial growth factor (VEGF), or markers of endothelial injury, thrombomodulin (TM) and angiopoietin-2 (ANG-2), associate with thymic regeneration as determined by T cell receptor excision circle (TREC) values and recovery of T cell subsets, as well as clinical outcomes in adult recipients of UCBT. We found that plasma levels of ANG-1 significantly correlated with the reconstitution of naive CD4⁺CD45RA⁺ and CD8⁺CD45RA⁺ T cell subsets, whereas plasma levels of VEGF displayed a positive correlation with CD4⁺CD45RO⁺ T cells and regulatory T cells and a weak correlation with TRECs. Assessment of TM and ANG-2 revealed a strong inverse correlation of both factors with naive T cells and TRECs. The angiogenic capacity of each patient's plasma, as determined by an in vitro angiogenesis assay, positively correlated with VEGF levels and with reconstitution of CD4⁺ T cell subsets. Higher VEGF levels were associated with worse progression-free survival and higher risk of relapse, whereas higher levels of TM were associated with chronic graft-versus-host disease and nonrelapse mortality. Thus, angiogenic factors may serve as valuable markers associated with T cell reconstitution and clinical outcomes after UCBT.