The Immunological Effects of Extracorporeal Photopheresis Unraveled: Induction of Tolerogenic Dendritic Cells In Vitro and Regulatory T Cells In Vivo

Abstract

Extracorporeal photopheresis (ECP) may represent an alternative to immunosuppression, as a means of reducing rejection after thoracic organ transplantation. The mechanism by which ECP exerts its protective effects has, until now, remained elusive. We analyzed peripheral blood mononuclear cells of four children with chronic heart and lung transplant rejection, who received ECP in addition to conventional immunosuppressive treatment. The effects of ECP were evaluated at each cycle, comparing blood samples from the same patient collected before and after treatment. In vitro, peripheral blood mononuclear cells treated with ECP undergo apoptosis and are phagocytosed by immature dendritic cells, which, in turn, acquire a tolerogenic phenotype. The frequency of T cells, with a regulatory phenotype and strong suppressive activity, was significantly increased in the blood of ECP-treated patients. The immunomodulatory effects of ECP may be explained by its ability to increase the frequency of regulatory T cells with inhibitory action on transplant immune rejection.

Extracorporeal photopheresis increases neutrophilic myeloid-derived suppressor cells in patients with GvHD

“…5,6,14,17,[34][35][36][37] Our studies demonstrate that ECP treatment rapidly augments PMN-MDSCs, which dampen Th1 and Th17 T-cell responses. Therefore, these studies suggest that, in addition to inducing lymphocyte apoptosis and modulating adaptive immunity, ECP acts on the innate arm of the immune system by rapidly inducing a neutrophilic immunomodulatory MDSC population.…”

“…3,4 Despite its clinical effectiveness, the immunomodulatory mechanisms of ECP are not fully understood. 5 Previous studies proposed triggering of lymphocyte, monocyte and natural killer cell apoptosis, 6 the induction of regulatory T cells (Tregs), [7][8][9] including enhancement of Treg function, 10 modulation of pro-inflammatory cytokines and/ or induction of tolerogenic dendritic cells [11][12][13][14] as potential modes of ECP action. Immature B-cell subsets and levels of B-cell activating factor have been shown to serve as clinical ECPresponse markers.…”

Extracorporeal Photopheresis: Scientific and Technical Considerations for Improving Clinical Management of Patients

“…Studies reported that the frequency of T-cells with a regulatory phenotype and suppressive activity is increased during ECP treatment in GVHD patients [12,24] despite the fact that the circulating count does not reach the level observed in healthy donors [25]. This suggests that the induction of Treg cells could add its contribution to the generation of tolerogenic DCs.…”

“…The lymphocytes die in 24-48 hour or even less time if activated, whereas monocytes are slow to progress toward apoptosis [10][11][12] and for few days, maintain the properties of differentiation and communication [13]. It appears in GVHD treated by ECP that the clinical benefits result from the processing of these apoptotic cells.…”

The Role of Photopheresis in the Treatment of Graft-Versus-Host Disease

“…• Clearance of apoptotic cells by antigen-presenting cells results in differentiation of those cells into a more tolerogenic phenotype 6,7 , leading to decreased stimulation of effector T cells or their deletion.…”