Graft-Versus-Host Disease, Rejection, and Venoocclusive Disease

Acute Graft-Versus-Host Disease

Acute GVHD is caused by the alloreactive, donor-derived T cells contained in the graft, which attack nonshared recipient's antigens on target tissues. A 3-step process generates the clinical syndrome. First, conditioning-induced tissue damage activates recipient antigen-presenting cells, which present recipient alloantigens to the donor T cells transferred with the graft and secrete cytokines , such as interleukin (IL)-12, favoring the polarization of T-cell response in the type 1 direction. Second, in response to recipient antigens, donor T cells become activated, proliferate, expand, and generate cytokines such as tumor necrosis factor (TNF)-α, IL-2, and interferon (IFN)-γ. In the 3rd step of the process, these cytokines cause tissue damage and promote differentiation of cytotoxic CD8 ⁺ T cells, which, together with macrophages, kill recipient cells and further disrupt tissues.

Acute GVHD usually develops 2-8 wk after transplantation. The primary manifestations depend on the sites of involvement and may include an erythematous maculopapular rash ( Figs. 163.1 and 163.2 ), persistent anorexia, vomiting and/or diarrhea, and liver disease with increased serum levels of bilirubin, alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP). Diagnosis may benefit from skin, liver, or gastrointestinal (GI) biopsy for confirmation. Endothelial damage and lymphocytic infiltrates are seen in all affected organs. The epidermis and hair follicles of the skin are damaged, the hepatic small bile ducts show segmental disruption, and there is destruction of the crypts and mucosal ulceration of the GI tract. Grade I acute GVHD (skin rash alone) has a favorable prognosis and often requires no treatment, or topical treatment alone. Grade II GVHD is a moderately severe multiorgan disease requiring immunosuppressive therapy. Grade III GVHD is a severe multiorgan disease, and grade IV GVHD is a life-threatening, often fatal condition ( Table 163.1 ).

The standard pharmacologic prophylaxis of GVHD after an unmanipulated allograft relies mainly on posttransplant administration of immunosuppressive drugs, such as cyclosporine or tacrolimus or combinations of either with methotrexate or prednisone, anti–T-cell antibodies, mycophenolate mofetil (MMF), and other immunosuppressive agents. Infusion of cyclophosphamide on days +3 and +5 after transplantation has been proposed as a strategy to deplete alloreactive donor T lymphocytes that become activated after exposure to recipient antigens. This approach has been successful in patients undergoing haploidentical transplantation. Pretransplantation infusion of either antithymocyte globulin (ATG) or monoclonal antibodies (mAbs) such as alemtuzumab is largely used to modulate alloreactivity of donor T cells, in particular in patients given the allograft from either an unrelated donor or a partially matched relative. An alternative approach, which has been widely used in clinical practice, is the removal of T lymphocytes from the graft ( T-cell depletion ). Other approaches, through clinical trials, are being used to selectively remove the α/β T cells, which are thought to be responsible for the development of GVHD, while preserving the γ/δ T cells in order to sustain GVL and the ability to fight infection. Any form of GVHD prophylaxis in itself may impair posttransplantation immunologic reconstitution, increasing the risk of infection-related deaths. Traditional T-cell depletion of the graft is also associated with an increased risk of leukemia recurrence in patients transplanted from an HLA-identical sibling or an unrelated volunteer.

Despite prophylaxis, significant acute GVHD develops in approximately 30% of recipients of HSCT from matched siblings and in as many as 60% of HSCT recipients from unrelated donors. These numbers are estimates, and the actual risk of acute GVHD is highly variable depending on several factors. Risk for development of GVHD is increased by diagnosis of malignant disease, older donor and recipient age, and in patients given an unmanipulated allograft, GVHD prophylaxis including only 1 drug. The most important risk factor for acute GVHD is the presence of disparities for HLA molecules in the donor-recipient pair.

Acute GVHD is usually initially treated with glucocorticoids; approximately 40–50% of patients show a complete response to corticosteroids. The risk of transplantation-related mortality is much higher in patients who do not respond to corticosteroids than in those showing a complete response. Promising results in children with steroid-resistant acute GVHD have been obtained using mesenchymal stromal cells , which are able to blunt the inflammatory response associated with acute GVHD. MMF, pentostatin, or mAbs targeting molecules expressed on T cells or cytokines released during the inflammatory cascade (including infliximab and etanercept targeting TNF, and tocilizumab targeting IL-6), which underlies the pathophysiology of GVHD, have been used in patients with steroid-resistant acute GVHD. There are no clear data showing the superiority of one of these approaches over the others. Extracorporeal photopheresis is another second-line treatment for GVHD and is most efficacious for skin GVHD. A patient's peripheral blood is exposed to a photosensitive compound and then exposed to ultraviolet light. The cells are then reinfused into the patient. It is thought that this process results in an increase in apoptosis of lymphocytes responsible for GVHD as well as the upregulation of antiinflammatory cytokines and regulatory T cells.