Dendritic cell reconstitution is associated with relapse-free survival and acute GVHD severity in children after allogeneic stem cell transplantation

Abstract

DCs are potent APCs and key regulators of innate and adaptive immunity. After allo-SCT, their reconstitution in the peripheral blood (PB) to levels similar to those in healthy individuals tends to be slow. We investigate the age-and sex-dependant immune reconstitution of myeloid (mDC) and plasmacytoid DC (pDC) in the PB of 45 children with leukaemia or myelodysplastic syndrome (aged 1-17 years, median 10) after allo-SCT with regard to relapse, acute GVHD (aGVHD) and relapse-free survival. Low pDC/μL PB up to day 60 post SCT are associated with higher incidence of moderate or severe aGVHD (P = 0.035), whereas high pDC/μL PB up to day 60 are associated with higher risk of relapse (P o 0.001). The time-trend of DCs/μL PB for days 0-200 is a significant predictor of relapse-free survival for both mDCs (P o0.001) and pDCs (P = 0.020). Jointly modelling DC reconstitution and complications improves on these simple criteria. Compared with BM, PBSC transplants tend to show slower mDC/pDC reconstitution (P = 0.001, 0.031, respectively), but have no direct effect on relapse-free survival. These results suggest an important role for both mDCs and pDCs in the reconstituting immune system. The inclusion of mDCs and pDCs may improve existing models for complication prediction following allo-SCT.

Immune Reconstitution after Allogeneic Hematopoietic Cell Transplantation in Children

“…Relatively low pDC levels at days 0 to 60 after HCT are associated with moderate to severe aGVHD in children, which is in line with observations in adults [54][55][56]. On the other hand, high pDC peak levels at days 0 to 60 are associated with higher risk of relapse, whereas high overall levels of both cDCs and pDCs during the first 200 days after HCT are related to higher relapse-free survival (evaluated as the area under the curve of z-score graphs where a high initial pDC level would lead to a reduced z-score over a longer period of time) [38]. As DCs play an instrumental role in the initiation of immune responses and maintenance of homeostasis, the use of the presence and activation state of DC subsets as biomarkers may be included in future studies.…”

“…Associations between pDC reconstitution and the occurrence of GVHD show some conflicting data [38]. Relatively low pDC levels at days 0 to 60 after HCT are associated with moderate to severe aGVHD in children, which is in line with observations in adults [54][55][56].…”

“…Data on cDC and pDC reconstitution after allo-HCT in children are only available for BM transplantation (BMT) and levels seem to strongly depend on age and sex [24][25][26]38,53] (Table 1). These studies show an initial increase in both pDC and cDC early after transplantation.…”

Low Counts of Plasmacytoid Dendritic Cells after Engraftment Are Associated with High Early Mortality after Allogeneic Stem Cell Transplantation

“…Previous studies have analyzed the association of DCs with the complex pathophysiology of GVHD with controversial results: some studies in mice have shown that pDC or mDCs may initiate aGVHD whereas others have shown that pDC may protect against aGVHD [33][34][35]. In the clinical setting, all series, including ours, showed that a low DC counts in the PB after transplantation are consistently associated with a higher incidence of aGVHD both in adults and in children [13,15,16,24,36]. In our series, we observed that pDC counts in the graft had an opposite effect on GVHD to that of pDC counts in the PB.…”

Can Dendritic Cell Vaccination Prevent Leukemia Relapse?

“…Of note, strategies exploiting donor cDCs in the setting of allogeneic SCT merit consideration, since relapse-free survival after allogeneic SCT was correlated with higher counts of donor cDC and pDC per µL of peripheral blood in a cohort comprising pediatric AML and myelodysplastic syndrome patients. This result suggests that expanding donor cDCs and/or pDCs for administration following SCT will enhance response rates [124]. In addition, the importance of host cDC in cross-presenting LAA was recently highlighted in a mouse model of post-transplant AML [125].…”