CD11c+ dendritic cells mediate antigen-specific suppression in extracorporeal photopheresis

Abstract

Summary Extracorporeal photopheresis (ECP) represents one of the most widespread and effective cell therapies for graft-versus-host disease and other T cell-mediated disorders. However, the key factors affecting the therapeutic efficacy of ECP remain unclear. We hypothesized that therapeutic effects are mediated by ECP-treated antigen-presenting dendritic cells (DC). To test this hypothesis, we used the experimental model of contact hypersensitivity (CHS). The ECP's therapeutic activity improved when the total cell dose of the ECP-treated cells was increased. We used different haptens during sensitization to demonstrate that the anti-inflammatory activity of ECP is antigen-specific. This confirmed the hypothesis that professional antigen-presenting cells are involved in the mode of action. Also, the ECP's therapeutic activity was abrogated by the depletion of CD11c+ DC, which represents fewer than 1% of all the ECP-exposed cells. Finally, we confirm the critical importance of CD11c+ DC for ECP activity by showing that only a few purified CD11c+ DC are sufficient to mediate its therapeutic effect. The finding that ECP-treated, physiological antigen-presenting DC alone mediate antigen-specific modulation of a pathological immune response may result in better-targeted interventions when treating patients.

A simplified extracorporeal photopheresis procedure based on single high‐dose ultraviolet A light irradiation shows similar in vitro efficacy

“…It was demonstrated in mouse models that only the transfer of ECP-treated APCs is sufficient to achieve a clear therapeutic success, whereas depletion of APCs within the transferred ECP-treated cells significantly reduced its efficacy. 25,26 In addition, in humans, monocytes have been described as critical mediators of ECP's efficacy, since monocyte can differentiate into DCs and can be loaded with the relevant antigens during ECP procedure and consequently can modulate an antigenspecific immune response. 27,28 Therefore, we assume that the increased monocyte survival with partially preserved activity by UVA only treatment might be beneficial to F I G U R E 4 Effect of various in vitro experimental ECP procedures on monocyte activation.…”

“…ECP‐treated monocytes failed to respond to stimulation, whereas UVA only ‐treated monocytes retained the ability to up regulate activation markers in response to LPS or IFN‐γ stimulation to some extent. It was demonstrated in mouse models that only the transfer of ECP‐treated APCs is sufficient to achieve a clear therapeutic success, whereas depletion of APCs within the transferred ECP‐treated cells significantly reduced its efficacy 25,26 . In addition, in humans, monocytes have been described as critical mediators of ECP's efficacy, since monocyte can differentiate into DCs and can be loaded with the relevant antigens during ECP procedure and consequently can modulate an antigen‐specific immune response 27,28 .…”

Extracorporeal photopheresis and the cellular mechanisms: Effects of 8‐methoxypsoralen and UVA treatment on red blood cells, platelets and reactive oxygen species

“…The following cellular clearance of the apoptotic bodies is an important feature in the restoration of a disbalanced immune homeostasis [13]. Other findings after ECP therapy are the induction of regulatory T cells (Tregs) [14,15] and the induction of tolerogenic dendritic cells [16,17]. The ECPinduced monocyte-to-dendritic cell maturation is probably mediated by platelets that are activated by the photopheresis procedure [18].…”

Optimierung der extrakorporalen Photopherese

“…Die Interaktion zwischen an Fibrinogen gebundenen aktivierten Thrombozyten und Monozyten führt zur Reifung der Monozyten zu antigenpräsentierenden Dendritischen Zellen (DC) [7]. Hackstein et al konnten in einem experimentellen Modell für Kontakt-Hypersensitivität zeigen, dass CD11c + DC für eine Antigen-spezifische Immunsuppression von Bedeutung sind [8]. Diese Zellinteraktionen sowie die Apoptoseinduktion bewirken eine Immunmodulation mit einer Induktion regulatorischer Zellen, v.a.…”