Extracorporeal Photopheresis: A Case of Immunotherapy Ahead of Its Time

Abstract

Extracorporeal photopheresis (ECP) is a cell-based immunotherapy that involves the reinfusion of autologous leukocytes after exposure to psoralen and UVA. The treatment has been used for over 30 years, at first on patients with cutaneous T-cell lymphoma (CTCL) and later for the management of patients with graft-versus-host disease (GvHD), sclerosing disorders, atopic dermatitis, and other diseases that may share the common driving factor of a pathogenic T-cell clone or clones in blood circulation. Patients with clinical improvement mount an antigen-specific immune response that may have tolerance traits in the case of GvHD or anticlonal cytotoxic characteristics in the case of CTCL. The exact mechanisms that dictate one response or the other are not fully understood, but the evidence accumulated so far indicates that multiple events occur simultaneously and consequentially contribute to the end result. These include contact of cells with the outside (plastics and tubing of the ECP apparatus), exposure to psoralen and UVA that activates platelets, monocytes, and other myeloid cells, the release of damage-associated molecular patterns, differentiation of monocytes into dendritic cells, and generation and successive presentation of numerous antigens after the phagocytosis of apoptotic cells. Once reintroduced, the ECP product increases the frequency and activity of regulatory T cells (Tregs), shifts the systemic cytokine balance, and promotes extravasation of immune cells that together shape the effects of this treatment. In this review, we summarize the seminal work and most recent literature of the therapeutic mechanisms and reflect on future avenues of improvements and applications of ECP.

Replacement of 8-MOP/UV-A treatment by UV-C irradiation for further development of Extracorporeal Photopheresis

“…ECP therapy is suitable for the treatment of both acute and chronic GvHD, especially because ECP is rather modulating the overwhelming immune response than suppressing the immune system in an unspecific way [12]. Many, but certainly not all, cellular mechanisms of ECP therapy have been identified [13]. The initial immunological mechanism is probably the induction of apoptosis by extra-corporal treatment of the patient´s cells with 8-MOP and UV-A irradiation [14][15][16][17][18][19].…”

Extracorporeal photopheresis and its role in heart transplant rejection: prophylaxis and treatment

“…(4) Mature dendritic cells function as antigen-presenting cells by presenting the fragmented apoptotic peptides on their MHC receptors leading to an immune response. (5) Expansion of T-regulatory cells and expression of anti-inflammatory cytokines 8,[12][13][14][15][16][17][18][19][20][21][22][23] to accomplish ECP (Table 1). [9][10][11] This technique is hypothesized to modulate the immune response through various mechanisms including T-cell apoptosis, dendritic cell maturation, modulation of the cytokine profile, and T-regulatory (Treg) cell stimulation.…”

“…12,[14][15][16] When the buffy coat is separated from the other blood components via centrifugation and exposed to 8-MOP and UVA, Tcell apoptosis is induced. 17 However, apoptosis does not fully explain the role of ECP in solid organ rejection since only a relatively small proportion of T cells (approximately 10%) are affected by a single ECP cycle. 18 The American Council of ECP in 2018 highlights recent evidence that supports the vital role of dendritic cells in the mechanism of action of ECP.…”

Apoptotic Donor Cells in Transplantation

“…ECP was initially used to treat patients with cutaneous T-cell lymphoma (CTCL), but its indications for use have now extended to other conditions such as GVHD ( 96 ), scleroderma ( 97 ), and solid organ transplantation ( 98 – 100 ). In a standard ECP treatment, usually only 10% of total blood circulating mononuclear cells are obtained and exposed to 8-MOP, and the susceptibility to ECP-induced apoptosis varies from cell type to cell type ( 101 ). The exact mechanisms of the therapeutic effect of ECP still remains to be elucidated, but in CTCL it has been described that the ingestion of apoptotic cells by APCs results in production of anti-tumor cells targeting malignant lymphoid cells ( 102 ).…”

“…Circulating T regs with ECP therapy suppressed proliferation of allogenic effector T cells and their IFN-g secretion (104). The above described T cell responses have prompted its use together with conventional pharmacotherapy for the treatment of GVHD as well as acute rejection of cardiac allografts in humans (101,(105)(106)(107)(108)(109)(110).…”