Recovery of Thymic Epithelial Cells and T Cell Immune Reconstitution After Cord Blood Transplantation in Adults Depends On Angiogenesis and Neovascularization

Abstract 4175

Umbilical cord blood transplantation (UCBT) is increasingly used as alternative source for allogeneic hematopoietic stem cell transplantation. UCBT in adults results in delayed and insufficient immune reconstitution leading to high infection-related morbidity and mortality. A significant component of immune reconstitution after UCBT involves the 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. HSCT compromises thymopoiesis due to injury of the thymic microenvironment, particularly thymic epithelial cells (TEC). 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 hypothesized that thymic neovascularization induced by the UCB-derived endothelial progenitors might be a critical factor involved in the recovery of TEC, which subsequently support T cell development and expansion via production of interelukin-7 (IL-7) and stem cell factor (SCF; a kit ligand). In the present study we examined whether markers of angiogenesis and neovascularization ANG1 and VEGF were associated with TEC function as determined by assessment of IL-7 and SCF levels and with thymic regeneration as determined by TREC values and recovery of T cell subsets. 27 evaluable patients with a median age of 50 years with hematopoietic malignancies were treated with reduced intensity conditioning (Flu/Mel/rATG) followed by infusion with two sequential UCB grafts and GvHD prophylaxis with tacrolimus and sirolimus. Results are based on 27 evaluable patients. Assessments were done prior to transplantation and at 1, 2, 3, 6 and 12 months after UCBT. At various time points after UCBT, serum levels of IL-7 and SCF displayed a strong correlation (p<0.005) with the levels of ANG1 and VEGF indicating that functional recovery of TEC is associated and coincides 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 receptors expressed on immature T cell progenitors resulted in differentiation and expansion of these immature T cells. Similarly, IL-7 and SCF levels 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, underlying the potential clinical implications of these findings. Conversely, VEGF and ANG1 levels positively correlated (p<0.001) with CD4⁺, CD4⁺CD25⁺ and CD4⁺CD45RA⁺ numbers at various time points after UCBT. Our results are consistent with a model of TEC recovery supported by VEGF and ANG1, 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. Thus, T cell immune reconstitution after UCBT depends on TEC and is associated with indicators of angiogenesis. These sequential steps in the process of thymic regeneration might represent novel therapeutic targets for improvement of immune reconstitution after UCBT.