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Key Points

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  • Disease summary:

    • Graft-versus-host disease (GVHD) occurs most commonly in the setting of allogeneic hematopoietic stem cell transplantation (HSCT), and is the most common cause of nonrelapse mortality in HSCT recipients.

    • GVHD is subdivided into acute and chronic forms, but an overlap syndrome also exists.

    • Since the widespread use of reduced-intensity conditioning and donor lymphocyte infusions, clinical presentation, rather than time of onset, is most helpful in differentiating acute from chronic GVHD.

    • While acute GVHD causes inflammation of the skin, gastrointestinal tract, and liver, chronic GVHD results in fibrosis of multiple organ systems.

    • In both acute and chronic GVHD, donor T cells attack genetically defined proteins on host cells, most commonly major human leukocyte antigens (HLAs) and minor histocompatibility antigens (mHAs).

    • The pathogenesis of acute GVHD is described as a three-phase process involving (1) activation of host antigen-presenting cells due to underlying tissue damage, (2) activation of donor T cells, and (3) cytokine and cell-mediated tissue injury.

    • The pathogenesis of chronic GVHD is less clearly defined, but thought to be due to alloreactive Th2 type CD4+ T cells, similar to other autoimmune diseases.

    • Genetic polymorphisms of various cytokines in both donors and recipients have been implicated in predicting risk and severity of acute and chronic GVHD.

  • Differential diagnosis:

    • Acute GVHD: eruption of lymphocyte recovery, various bacterial and viral infections, drug toxicity or allergy, graft rejection

    • Chronic GVHD: scleroderma, drug toxicity or allergy, various bacterial and viral infections, lichen planus, lichenoid drug eruption, eczema, ichthyosis

  • Pathogenesis:

    • Acute GVHD

      • Phase 1: activation of antigen-presenting cells, most importantly dendritic cells, as a result of tissue damage caused by underlying disease and HSCT conditioning regimen. Cytokines involved TNF-α, IL-1, IL-6, bacterial lipopolysaccharide, IL-10 (protective).

      • Phase 2: donor T-cell activation, including costimulatory signaling, in response to host histoincompatible antigens presented by activated antigen-presenting cells, Th1 differentiation. Cytokines involved: IL-2, IFN-γ.

      • Phase 3: complex cascade of cellular mediators (cytotoxic T cells, natural killer cells) and soluble inflammatory cytokines (TNF-α, IFN-γ, IL-1), further promote tissue inflammation and injury.

    • Chronic GVHD

      • The pathogenesis of chronic GVHD is not well understood, but is thought to be the result of an autoimmune process with Th2 differentiation of CD4+ T cells.

      • Animal studies have shown that T cells react to specific MHC class II molecules shared by donor and recipient.

      • As in acute GVHD, donor alloreactive CD4 and CD8 T cells, and dendritic cells target and attack host mHA on autosomal and Y chromosomes.

      • Both dysregulation of central and peripheral T-cell tolerance has been proposed.

      • Injury of the thymus from the conditioning regimen and acute GVHD prevents negative selection of autoreactive T cells.

      • Deficiency of T-regulatory cells has been shown to contribute to the pathogenesis of other autoimmune diseases.

  • Impact of GVHD on immune reconstitution:

    • Due to MHC expression, the thymus and bone marrow are primary targets in acute GVHD, resulting in depletion of T and B cells.

    • In acute GVHD, expansion of alloreactive T cells results in skewing of T-cell repertoire (clonal ...

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