Technology Insight: ECP for the treatment of GvHD—can we offer selective immune control without generalized immunosuppression?

Abstract

Hematopoietic stem-cell transplantation remains an important curative therapy for many conditions and its use is increasing annually. Graft-versus-host disease (GvHD) is the major cause of mortality and suffering following allogeneic hematopoietic stem-cell transplantation. Conventional treatments are associated with multiple side effects and are often ineffective. New therapeutic approaches for the control of GvHD are desperately required. Extracorporeal photochemotherapy (ECP) was developed in the 1970s for the treatment of cutaneous T-cell lymphoma and was approved by the FDA as the first selective immunotherapy for a cancer. ECP has also proved an effective therapy for immune-related conditions, particularly GvHD, even in patients refractory to conventional therapies. The treatment involves the mechanical separation of circulating white cells, which are exposed to psoralen and UVA light and then returned to the patient. ECP is extremely well tolerated with minimal side effects and is not associated with the increased rates of infection or relapse of malignant disease typical of conventional immunosuppressive agents. Thus, ECP appears to offer selective immune modulation without generalized immunosuppression, but its mechanism of action remains poorly understood. This review discusses the development of ECP, its use in the treatment of GvHD, as well as current theories of its mechanism of action.

Extracorporeal photopheresis reverses experimental graft-versus-host disease through regulatory T cells

“…Our data suggest that the early use of ECP treatment during the clinical course of a disease may warrant investigation not only for GVHD, but for other diseases with deficits in Tregs, such as autoimmune diseases and solid organ rejection. 4 Our studies do not address the role of cytokines such as IL-10 or TGF-␤, or determine whether a distinct subpopulation of Tregs is responsible for reducing GVHD following infusions of ECPtreated splenocytes. Levels of serum IL-10 were unchanged 4 days following the first infusion, and its production by CD4 ϩ T cells following 60-hour coculture with both allogeneic stimulators and apoptotic splenocytes was undetectable (data not shown).…”

“…Prevention of GVHD has been limited either to depletion of donor T cells or the use of broadly immunosuppressive drugs that cause profound immunodeficiency as well as toxicities such as hypertension, diabetes, and aseptic bone necrosis. 4,7 ECP appears to be an effective therapy for both acute and chronic GVHD, even in some patients who are refractory to conventional immunosuppressive therapy. While randomized, controlled, multicenter studies are still needed, few side effects have been associated with ECP treatment and several reports of the efficacy of ECP for the treatment of both acute and chronic GVHD are impressive.…”

“…While randomized, controlled, multicenter studies are still needed, few side effects have been associated with ECP treatment and several reports of the efficacy of ECP for the treatment of both acute and chronic GVHD are impressive. 3,4 PUVA treatment is known to induce the apoptosis of all exposed leukocytes, but it is unlikely that the direct induction of lymphocyte apoptosis fully accounts for its clinical efficacy, given that less than 10% of circulating leukocytes are exposed to PUVA during an ECP procedure. The effects of ECP on the immune system beyond the induction of apoptosis are still poorly understood, however, largely because of a lack of mechanistic animal models for the diseases historically treated with ECP.…”

Efficacy of bimonthly extracorporeal photopheresis in refractory chronic mucocutaneous GVHD

“…The mode of action of ECP in cGVHD remains poorly understood and may be multifactorial in nature. 9 The main proposed mechanism of action is that ECP induces apoptosis of activated T cells. The reinfusion of these cells is thought to cause immune homoeostasis through modulation of cytokine production.…”

Steady-State Cell Apoptosis and Immune Tolerance - Induction of Tolerance Using Apoptotic Cells in Type 1 Diabetes and Other Immune-Mediated Disorders

“…Mononuclear cells are collected with a standard cell separator and UVA irradiation is performed in a laboratory setting using a stand-alone irradiator; however, no commercially available UVA irradiator is compliant with European standards marking for the sale and use of medical devices for performing ECP. While there are chain-of-custody issues and potential risks of infection associated with these 'open' photopheresis systems, there are reports of similar clinical efficacy between both techniques; however, no head-to-head comparison studies have been reported to date (93). ECP is most commonly used to treat CTCL and GVHD.…”