Recipient-specific tolerance after HLA-mismatched umbilical cord blood stem cell transplantation.

Background: Lower incidence and severity of acute graft versus host disease (GVHD) has been observed in leukemia patients receiving HLA-mismatched umbilical cord (UCB) transplants. However, despite the increased use of UCB in stem cell transplantation, the mechanisms underlying these favorable outcomes are not well delineated.

Methods: We analyzed antigen specific lymphocyte responses after transplant to determine whether the decreased allogeneic responsiveness of UCB lymphocytes is attributable to pan-unresponsiveness, lymphocyte repressive or recipient-specific tolerance.

Deficient IFN-gamma expression in umbilical cord blood (UCB) T cells can be rescued by IFN-gamma-mediated increase in NFATc2 expression.

Regulation of nuclear factor of activated T cells-c2 (NFATc2) gene expression is not clearly defined. We previously reported reduced NFATc2 protein expression in cord blood T lymphocytes. Here we show that NFATc2 expression in T cells is dependent in part on the presence of IFN-gamma during primary stimulation, as blocking of IFN-gamma blunted NFATc2 protein and mRNA upregulation.

Expansion of LTC-ICs and maintenance of p21 and BCL-2 expression in cord blood CD34(+)/CD38(-) early progenitors cultured over human MSCs as a feeder layer.

Allogeneic transplantation with umbilical cord blood (UCB) is limited in adult recipients by a low CD34(+) cell dose. Clinical trials incorporating cytokine-based UCB in vitro expansion have not demonstrated significant shortening of hematologic recovery despite substantial increases in CD34(+) cell dose, suggesting loss of stem cell function. To sustain stem cell function during cytokine-based in vitro expansion, a feeder layer of human mesenchymal stem cells (MSCs) was incorporated in an attempt to mimic the stem cell niche in the marrow microenvironment.