Graft Versus Host Disease (GVHD) and Rejection

Published on 25/03/2015 by admin

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Last modified 25/03/2015

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Chapter 131 Graft Versus Host Disease (GVHD) and Rejection

The major cause of mortality and morbidity after allogeneic hematopoietic stem cell transplantation (HSCT) is graft versus host disease (GVHD), which is caused by engraftment of immunocompetent donor lymphocytes in an immunologically compromised host that shows histocompatibility differences with the donor. These differences between the donor and the host may result in donor T-cell activation against recipient major histocompatibility complex (MHC) antigens or minor histocompatibility antigens. GVHD is usually subdivided in 2 forms: acute GVHD, which occurs within 3 mo after transplantation, and chronic GVHD, which, though related, is a different disease occurring later and displaying some clinical and pathological features that resemble those observed in selected autoimmune disorders (systemic sclerosis, Sjögren syndrome, etc.).

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.

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