Human Apoptotic Cells, Generated by Extracorporeal Photopheresis, Modulate Allogeneic Immune Response

Abstract

The induction of specific and sustainable tolerance is a challenging issue in organ transplantation. The discovery of the immunosuppressive properties of apoptotic cells in animal models has paved the way for their use in human transplantation. In this work, we aimed to define a stable, reproducible, and clinically compatible production procedure of human apoptotic cells (Apo-cells). Using a clinically approved extracorporeal photopheresis technique, we have produced and characterized phenotypically and functionally human apoptotic cells. These Apo-cells have immunosuppressive properties proved in vitro and in vivo in NOD/SCID/γC mice by their capacity to modulate an allogeneic response following both a direct and an indirect antigen presentation. These results brought the rationale for the use of Apo-cells in tolerance induction protocol for organ transplantation.

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

“…The induction of regulated cell death in lymphocytes is important for the efficacy of ECP by providing antigenic material and favoring antigen loading and maturation of APCs, thereby eliciting antigen-specific immunoregulation. [9][10][11] Verification of sufficient apoptosis induction is central for quality control of clinical ECP products. 22 Here, singlehigh-dose UVA only (4-5 J/cm 2 ) treatment induced an apoptotic rate with increased kinetics in PBMCs in comparison to standard ECP.…”

“…Additionally, ECP is reported to induce immunosuppression upon allogeneic T‐cell activation 9 . Thus, monocytes treated with ECP or UVA only successfully reduced allogeneic T‐cell proliferation compared to controls.…”

“…[9][10][11] Thus, the antigen-loaded and differentiated APCs can induce a tumor-specific T-cell response or down regulate allogeneic T-cell responses. 9,11,12 Monocytes seem to be less susceptible to ECP-induced cell damage 13,14 and have been suggested to differentiate into DCs by interacting with the surface of the ECP device. 15 In addition, ECP treatment promotes the release of interleukin-1β and modulates the monocyte-induced T-cell response.…”

“…Although the mechanism of action is somewhat known, the induction of apoptosis in lymphocytes 7,8 and modulation of the activation of antigen‐presenting cells (APCs), such as dendritic cells (DCs) and monocytes, are key to the efficacy of ECP. The induction of regulated cell death during ECP is important as apoptotic cells up regulate prophagocytic, chemotactic, and immunomodulating signals for APCs 9–11 . Thus, the antigen‐loaded and differentiated APCs can induce a tumor‐specific T‐cell response or down regulate allogeneic T‐cell responses 9,11,12 .…”

Extracorporeal Photopheresis: A Case of Immunotherapy Ahead of Its Time

“…In contrast to the elusive switch from a predominant Th2 to a Th1 cytokine microenvironment harnessed by ECP, studies addressing the secretory capacity of peripheral blood mononuclear cells of GvHD patients and in vitro models of allogenic reactions revealed that ECP exposure can increase the production of Th2 cytokines including IL-10 and TGF-β [71-73] (Fig. 3).…”