Extracorporeal photopheresis (photochemotherapy) in the treatment of acute and chronic graft versus host disease: immunological mechanisms and the results from clinical studies

Abstract

Extracorporeal photopheresis (ECP) is an immunomodulatory alternative for treatment of graft versus host disease (GVHD). The blood is then separated into its various components through apheresis; buffy coat cells are thereafter treated with 8-methoxypsoralen before exposure to ultraviolet light and finally reinfused into the patient. There is a general agreement that this treatment has an anti-GVHD effect, but the mechanisms of action behind this effect are only partly understood. However, altered maturation of dendritic cells (DC) and thereby indirect modulation of T-cell reactivity seems to be one important mechanism together with DC-presentation of antigens derived from apoptotic donor T cells and induction of regulatory T cells. The treatment has been best studied in patients with chronic GVHD (both pediatric and adult patients), but most studies are not randomized and it is difficult to know whether the treatment is more effective than the alternatives. The clinical studies of ECP in adults with acute GVHD are few and not randomized; it is not possible to judge whether this treatment should be a preferred second- or third-line treatment. There is no evidence for increased risk of leukemia relapse or suppression of specific graft versus leukemia reactivity by this treatment, so specific antileukemic immunotherapy may still be possible. Thus, even though the treatment seems effective in patients with GVHD, further clinical (especially randomized) as well as biological studies with careful standardization of the treatment are needed before it is possible to conclude how ECP should be used in acute and chronic GVHD.

Mechanistic approaches for the prevention and treatment of chronic GVHD

“…While the mechanisms by which ECP results in clinical improvement are not completely known, it is thought that ECP can suppress alloimmune responses in part by altering the maturation and function of dendritic cells and through the induction of Tregs. 79 Regardless of the mechanism, responses in chronic GVHD patients have been associated with increased Treg cell counts, increased cellular activation, and inhibition of Tcon. 80,81 ECP has been evaluated in a phase 2 prospective randomized trial, with demonstrated efficacy in sclerodermatous chronic GVHD, including a reduction in steroid dose, meaningful decrease in skin sclerosis, and nonblinded investigator assessment of skin complete or partial responses.…”

Response of steroid‐refractory chronic graft‐versus‐host disease to extracorporeal photopheresis correlates with the dose of CD3+ lymphocytes harvested during early treatment cycles

“…The final mediator of immune tolerance is represented by a CD4+ lymphocyte subpopulation, namely, T‐regulatory cells (T‐reg) . The relevant role exerted by T‐regs has been confirmed by clinical observations .…”

“…Among treatments for steroid refractory graft‐versus‐host disease (GVHD), extracorporeal photopheresis (ECP) has shown efficacy and tolerability compared to other second‐line immunosuppressive treatments . ECP is considered an immunomodulatory, rather than immunosuppressive, treatment and is not associated with significant increase in opportunistic infections nor disease relapse …”

“…ECP involves the induction of apoptosis in treated lymphocytes; alloreactive T cells, which actively proliferate during GVHD, have higher susceptibility to apoptosis than resting lymphocytes . ECP, moreover, induces tolerogenic dendritic cells that stimulate a Th2 rather than Th1 response and, after the phagocytosis of apoptotic T cells, gives rise to a clonotypic immune reaction and leads to tolerance …”

Interleukin-6 in Allogeneic Stem Cell Transplantation: Its Possible Importance for Immunoregulation and As a Therapeutic Target

“…First-line treatment for grade II–IV aGVHD is high-dose steroids (15), and a complete response is observed in 20–40% of patients (16, 17). There is no consensus regarding the preferred therapy for steroid-refractory aGVHD; commonly utilized options include TNFα blockade, anti-IL-6 antibodies, mTOR inhibitors, mycophenolate mofetil, and extracorporeal photopheresis (18). Despite several therapeutic alternatives, patients with grade IV steroid-refractory aGVHD have a dismal long-term prognosis (15).…”