Graft-Versus-Host Disease: A Surge of Developments

This year approximately 20,000 individuals will receive an allogeneic hematopoietic cell transplant (HCT) as treatment for a malignant, or life-threatening non-malignant, hematopoietic disease. The process of HCT generally begins with administration of a preparative regimen to eradicate the underlying disease and immunosuppress the patient in order to prevent rejection of the subsequently transfused hematopoietic stem cells. Following HCT, donor T cells transplanted with or developing from the hematopoietic stem cells react with cells of the human leukocyte antigen (HLA)-matched but genetically non-identical host, providing a benefi cial graft-versus-tumor (GVT) response but also resulting in possibly life-threatening graft-versus-host disease (GVHD). The manifestations of GVHD vary over its course. Acute GVHD usually appears within several weeks of HCT and is characterized by a diffuse maculopapular rash, mucosal infl ammation causing crampy abdominal pain and diarrhea, and elevated liver function tests (Figure 1). GVHD that fi rst appears or persists more than three months after allogeneic HCT is termed chronic GVHD and resembles a chronic autoimmune disorder. Patients frequently develop lichen planus skin lesions, ocular and oral sicca, obliterative bronchiolitis, and hepatic abnormalities resembling primary biliary sclerosis. If no immunosuppression is given after allogeneic HCT, life-threatening or fatal GVHD inevitably develops. The fi rst successful application of allogeneic HCT to treat human leukemia in the early 1970s was made possible by the use of methotrexate, administered early after transplantation as prophylaxis against GVHD [1]. In the mid-1980s, prospective randomized trials were performed demonstrating that a combination of a calcineurin inhibitor (cyclosporin or tacrolimus) plus methotrexate was superior to either agent alone in preventing acute GVHD [2,3], and such combinations remain the standard of care today. Despite such prophylaxis, approximately 50% of patients receiving HCT will develop acute GVHD suffi ciently severe to require additional immunosuppression, usually in the form of a corticosteroid, and approximately 50% of patients will develop chronic GVHD requiring continued immunosuppression for up to several years. The majority of patients eventually develop tolerance, and immunosuppression can be completely withdrawn in these cases, but 10%–20% of recipients of HLAmatched hematopoietic cell transplants will die of refractory GVHD or of opportunistic infections associated with its prevention or treatment, and the mortality rate increases with increasing donor–recipient HLA disparity. An elusive goal of research has been to fi nd ways to prevent GVHD without dramatically increasing other transplant complications. Most clinical studies to date have focused on the use of alternative immunosuppressants or removal of T cells from the donor stem cell source. More intensive post-transplant immunosuppressive regimens and T cell depletion are both capable of dramatically reducing the incidence and severity of GVHD, but do so at the cost of an increased incidence of fatal post-transplant infections and tumor recurrence. Increased graft rejection may also occur if donor T cells are removed from the donor stem cell graft, because the reaction of these cells against