Impaired Interferon-Alpha Production by Plasmacytoid Dendritic Cells after Cord Blood Transplantation in Children: Implication for Post-transplantation Toll-Like Receptor Ligand–Based Immunotherapy

Abstract

Plasmacytoid dendritic cells (pDCs) initiate both innate and adaptive immune responses, making them attractive targets for post-transplantation immunotherapy, particularly after cord blood transplantation (CBT). Toll-like receptor (TLR) agonists are currently studied for pDC stimulation in various clinical settings. Their efficacy depends on pDC number and functionality, which are unknown after CBT. We performed a longitudinal study of pDC reconstitution in children who underwent bone marrow transplantation (BMT) and single-unit CBT. Both CBT and unrelated BMT patients received antithymocyte globulin as part of their graft-versus-host disease prophylaxis regimen. pDC blood counts were higher in CBT patients than in healthy volunteers from 2 to 9 months after transplantation, whereas they remained lower in BMT patients. We showed that cord blood progenitors gave rise in vitro to a 500-fold increase in functional pDCs over bone marrow counterparts. Upon stimulation with a TLR agonist, pDCs from both CBT and BMT recipients upregulated T cell costimulatory molecules, whereas interferon-alpha (IFN-α) production was impaired for 9 months after CBT. TLR agonist treatment is thus not expected to induce IFN-α production by pDCs after CBT, limiting its immunotherapeutic potential. Fortunately, in vitro production of large amounts of functional pDCs from cord blood progenitors paves the way for the post-transplantation adoptive transfer of pDCs.

TRAIL-mediated killing of acute lymphoblastic leukemia by plasmacytoid dendritic cell-activated natural killer cells

“…No significant differences were observed in NK cell activation depending on the pDC source ( Supplemental Figure S1 ). Accordingly, we have previously showed that in vitro differentiated pDCs produce large amounts of IFN-α upon TLR stimulation and display the same phenotype as mature peripheral blood pDCs [ 26 ]. A direct TLR-9 stimulation of NK cells by CpG ODN was ruled out, as CpG ODN alone did not increase NK cell cytotoxic activity against pre-B ALL cell lines ( Supplemental Figure S2A ).…”

“…We and others recently described that human CD34 + precursors can be cultured and differentiated in pDCs in vitro [ 26 , 30 ]. This method allows the production of high numbers of functional pDCs that can be activated by TLR ligands.…”

“…Fortunately, we and others have described methods for in vitro expansion and differentiation of human pDCs from cord blood progenitors. Indeed, up to 10 7 functional human pDCs are obtained from cord blood units, making adoptive transfers of activated pDCs clinically feasible [ 26 , 30 , 41 ].…”

Andrographolide suppresses proliferation of human colon cancer SW620 cells through the TLR4/NF-κB/MMP-9 signaling pathway

“…As an important bridge between innate immune defense and acquired immunity, it can trigger signal transduction, which further leads to the release of inflammatory mediators by identifying pathogen-associated molecular patterns and certain endogenous ligands (8). A previous study found that TLR may play certain roles in pathogenesis and bio-immunotherapy (9).…”

Sensing danger: toll-like receptors and outcome in allogeneic hematopoietic stem cell transplantation

“…In a retrospective study where plasmacytoid dendritic cells (pDC) were investigated after bone marrow or cord blood transplantation, pDC from cord blood recipients displayed impaired activation in response to stimulation with the TLR9 agonist CpG, possibly explaining the increased infectious rates and lower rates of aGvHD and GVT effects after cord blood transplantation, emphasizing the importance of TLR9 in alloreactivity. 51…”