Extracorporeal photopheresis in the treatment of graft-vs-host disease.

Graft-vs-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic stem cell transplantation. GVHD was first described by Barnes and Mole as a fatal disease manifest by skin changes, diarrhea, and runting in irradiated mice given allogeneic spleen cells. Early human allogeneic bone marrow transplant patients were noted to manifest a similar syndrome of dermatitis, hepatitis, and enteritis occurring within the first 100 days after infusion of allogeneic stem cells. The etiology of GVHD is related to alloreactivity between immunocompetent donor lymphocytes and transplantation alloantigens on host tissues. The incidence of acute GVHD (aGVHD) ranges from 27% to 50% after sibling-matched related donors and from 42% to 72% after unrelated donor bone marrow or peripheral blood stem cell transplants. Despite aggressive immunosuppressive therapies, including high-dose corticosteroids, cyclosporine A, antithymocyte globulin, tacrolimus, and mycophenolate mofetil, the mortality from acute GVHD remains high. Chronic GVHD (cGVHD) is a syndrome of immune dysregulation whose onset has been arbitrarily defined as occurring at least 100 days after allogeneic stem cell infusion. Clinical features of cGVHD are distinguished from aGVHD in that they more closely resemble autoimmune disorders. Histopathologic changes include sclerodermatous skin changes from collagen deposition, pulmonary fibrosis, esophageal dysfunction, dry mouth or mucocutaneous ulcerations, cholestasis, and myositis or fasciitis and are thought to be initiated, in part, by autoantibodies to cell surface and intracellular proteins. The incidence of cGVHD ranges from 30% in siblingmatched donors to over 70% in matched unrelated donor transplants. Factors associated with cGVHD include increased donor and recipient age, prior aGVHD, and the use of alloimmune female donors. Conventional therapeutic approaches for cGVHD, including corticosteroids and immunosuppressive agents, have demonstrated limited efficacy in patients with extensive disease. Oral methoxsalen followed by ultraviolet A therapy (PUVA), while effective in alleviating the symptoms of chronic skin GVHD, has had no impact on visceral involvement. Novel agents demonstrating activity include T-cell directed therapies, such as humanized anti-CD25 antibody (dacluzimab) and pentostatin, as well as anti-TNF-a antibody (infliximab) and thalidomide. While aGVHD is understood as a disease of acute alloreactivity, the etiology of cGVHD is controversial and is believed to be either an extension of aGVHD and/ or a result of dysfunctional immune reconstitution with generation of autoantibodies and tissue autoreactive Tcell clones. Acute GVHD is believed to be a Th1-driven disease wherein inflammatory cytokines, such as IL-2 and IFN-c as well as the monokines IL-1 and TNF-a, contribute to tissue damage. In murine models, donor CD4-enriched cells of Th2 phenotype have been shown to prevent aGVHD without affecting engraftment, suggesting that they play a role in downregulating the Th1 response, and, in other studies, administration of a Th1 inhibitor (TAK-603) markedly reduced the mortality associated with aGVHD. Chronic GVHD has been proposed by others to be a Th2-mediated disease, but recent studies demonstrating upregulation of Th1 cytokines IFN-c and IL-12 in peripheral blood mononuclear cells implicate, in part, a Th1-derived mechanism similar to that seen in acute alloreactivity.