Markers of Angiogenesis and Neovascularization Correlate with Functional Recovery of Thymic Epithelial Cells and T Cell Immune Reconstitution After Cord Blood Transplantation in Adults

Umbilical cord blood transplantation (UCBT) is increasingly used as an alternative source for allogeneic hematopoietic stem cell transplantation. A significant component of immune reconstitution after UCBT involves thymic regeneration, which can be measured by T-cell receptor rearrangement excision circles (TRECs). TREC levels are a strong predictive factor for overall survival in adult recipients of UCBT. Injury of the thymic microenvironment, particularly of thymic epithelial cells (TEC), during HSCT compromises thymopoiesis. Human UCB is enriched in endothelial precursors that can sustain thymopoiesis in immunodeficient mice transplanted with human thymic grafts, where they engraft and promote neovascularization and wound healing. We examined markers of angiogenesis and neovascularization ANG1 and VEGF associated with TEC function, thymic regeneration and T cell reconstitution in patients after double reduced intensity UCBT. 27 evaluable patients with a median age of 50 years with hematopoietic malignancies were treated with (Flu/Mel/rATG) conditioning followed by double UCBT; GvHD prophylaxis was tacrolimus and sirolimus. At various time points Which ones after UCBT, serum levels of IL-7 and SCF that are produced by TEC displayed a strong correlation (p<0.005) with ANG1 and VEGF indicating that functional recovery of TEC is associated with angiogenesis and neovascularization. In contrast, serum levels of IL-7 and SCF displayed a strong inverse correlation (p<0.001) with TREC, CD4⁺, CD8⁺ and Treg numbers suggesting that uptake of these cytokines by cognate IL-7R and Kit receptor on immature T cell progenitors resulted in their differentiation and expansion. IL-7 and SCF also displayed a strong inverse correlation (p<0.001) with the ability of T cells to differentiate into pathogen-specific effectors as determined by CMV-specific IFN-γ ELISpot. Conversely, VEGF and ANG1 levels positively correlated (p<0.001) with CD4⁺, CD4⁺CD25⁺ and CD4⁺CD45RA⁺ numbers. Our results are consistent with a model in which ANG1 and VEGF support TEC recovery leading to production of SCF and IL-7 by TEC and uptake of these cytokines by T cell progenitors resulting in their differentiation and expansion. These sequential steps in the process of thymic regeneration might represent novel therapeutic targets for improvement of immune reconstitution after UCBT.