Immature DC Isolated After Co-Culture with PUVA-Treated Peripheral Blood Mononuclear Cells Downregulate Graft-Versus-Host Reactions in the Human Skin Explant Model
Xiao N. Wang,
Scott R. Marshall,
Michael von Bergwelt- Baildon,
Anne M. Dickinson.
Graft-versus-host disease (GvHD) remains the major barrier to successful allogeneic hematopoietic stem cell
transplantation (HSCT). Extracorporeal photopheresis (ECP) is a potent immunomodulatory treatment option for GvHD.
In contrast to conventional immunosuppressants, ECP is considered not to increase relapse and infection rates resulting
from generalised immunosuppression. ECP involves the mechanical separation of 5-10% of patient peripheral blood
mononuclear cells, which are then exposed to psoralen and UVA light (PUVA) before they are returned to the patient.
ECP has been shown to induce apoptosis in various cell types, in particular lymphocytes. Several studies describe downregulation
of pro-inflammatory cytokines as well as promotion of peripheral tolerance through enhanced production of Tregulatory
cells in the course of ECP-treatment. Modulation of antigen-presenting cells such as dendritic cells (DC) by
PUVA-treated lymphocytes might be implicated in these regulatory processes. We evaluated the impact of PUVA-treated
lymphocytes on immature DC and further demonstrated the functional capacity of such modified DC to modulate GVH
reactions using a well-established human skin-explant model of GvHD.
Addition of immature DC isolated after co-culture with PUVA-treated but not untreated MLR cells significantly downregulated
skin-GvH reactions (p=0.023, Mann-Whitney-Test). IFN-gamma levels were non-significantly decreased in
MLR and skin supernatants. We observed a non-significant increase in PD-L1 expression in iDC after co-culture with
PUVA-treated MLR cells whereas expression levels of IDO and ILT-3 were not affected. We conclude that iDC modulated
by PUVA-induced apoptotic cells potently downregulate allogeneic immune responses possibly through PD-L1-
Keywords: Allogeneic hematopoietic stem cell transplantation, extracorporeal photopheresis, ECP, graft-versus-host disease,
dendritic cells, apoptosis, tolerance, immunoregulation.
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