Decreased Responsiveness of Mature Dendritic Cells from Cord Blood to Chemotaxis Induced by CXCR4 Ligand CXCL12, and CCR7 Ligand CCL19 May Explain Lowered GVHD Associated with Cord Blood Tranplantation.

Cord blood has been successfully used as a transplantable source of hemopoietic stem cells with a relatively low incidence of graft-versus-host disease (GVHD). Mature dendritic cells (DC), as the most efficient antigen presenting cells, play a critical role in the pathogenesis of GVHD and their function is intimately linked to their capacity to migrate. Chemokines and their G-protein linked receptors are of particular importance in DC migration. CCR7 and CXCR4 are two chemokine receptors expressed on mature DC. Binding of CCR7 ligand, MIP-3β/CCL19 and CXCR4 ligand, SDF-1/CXCL12 induce chemotaxis of mature DC and are pivotal for DC to initiate their functions in vivo. We hypothesized that the relatively lowered level of GVHD elicited by cord blood, compared to adult cells, might be due, at least in part, to a reduced capability of cord blood DC to migrate to lymphoid organs to initiate immune reactions and to organs such as liver and skin where GVHD pathogenesis usually occurs. To begin testing this hypothesis, we randomly picked 16 cord blood donors and 14 adult blood donors and did paired comparison study on chemotactic responses of cord blood and adult blood DC to CXCL12 and CCL19. Monocytes were isolated from both cord blood and adult blood and cultured with GM-CSF and IL-4 for 5 days to generate immature DC. LPS was added into cell culture for an additional 1 day to induce the maturation of these DC. Mature DC were harvested on day 6. We found that cord blood DC expressed significantly reduced surface levels of CCR7 compared with that of adult blood DC (p = .00067) and migrated at significantly lower efficiency towards the CCR7 ligand, CCL19 than did adult blood DC (p=0.029). Cord blood DC expressed significantly higher surface expression of CXCR4 than adult blood DC (p = .0018), but migrated at significantly lower efficiency towards CXCR4 ligand, CXCL12 than adult blood DC (p=0.00012). The lowered responsiveness of mature cord blood DC to chemotaxis by CXCL12 may reflect the enhanced truncation of CXCR4 we found on these cells. Also, cord blood DC migrated less well than adult blood DC toward the combination of CXCL12 and CCL19 than adult blood DC (p = .0014). These results suggest that low incidence and pathogenesis of GVHD observed in cord blood might be due, at least in part, to reduced capability of cord blood mature DC to migrate to critical organs where immune reaction and inflammation occur, effects reflecting lowered expression of CCR7 and enhanced truncation of CXCR4 on mature cord blood DC.