Acute GVHD

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 (APC), which present recipient alloantigens to the donor T cells transferred with the graft and secrete cytokines, such as interleukin 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-α (TNF-α), interleukin 2 (IL-2), and interferon-γ (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 from 2-5 wk post-transplantation. The primary manifestations are an erythematous maculopapular rash, persistent anorexia, vomiting and/or diarrhea, and liver disease with increased serum levels of bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase (Table 131-1). Diagnosis may benefit from skin, liver, or endoscopic 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 gastrointestinal tract. Grade I acute GVHD (skin rash alone) has a favorable prognosis and often does not require treatment (Fig. 131-1). Grade II GVHD is a moderately severe multiorgan disease requiring therapy. Grade III GVHD is a severe multiorgan disease, and grade IV GVHD is a life-threatening, often fatal condition. The standard prophylaxis of GVHD relies mainly on post-transplant administration of immunosuppressive drugs such as cyclosporine or tacrolimus, often in combination with methotrexate or prednisone, anti–T-cell antibodies, mycophenolate mofetil, or other immunosuppressive agents. An alternative approach that has been widely used in clinical practice is the removal of T lymphocytes from the graft (T-cell depletion). Any form of GVHD prophylaxis in itself may impair post-transplant immunologic reconstitution, increasing the risk of infection-related deaths. T-cell depletion of the graft has also been associated with an increased risk of leukemia recurrence in patients transplanted from an HLA-identical sibling or an unrelated volunteer.

Figure 131-1 Acute graft versus host disease of the skin with ear, arm, shoulder, and trunk involvement.

(Courtesy of Evan Farmer, MD.)