TY - CHAP M1 - Book, Section TI - Graft-Versus-Host Disease A1 - Huang, Jennifer A1 - Saavedra, Arturo A2 - Murray, Michael F. A2 - Babyatsky, Mark W. A2 - Giovanni, Monica A. A2 - Alkuraya, Fowzan S. A2 - Stewart, Douglas R. Y1 - 2014 N1 - T2 - Clinical Genomics: Practical Applications in Adult Patient Care AB - 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 rejectionChronic GVHD: scleroderma, drug toxicity or allergy, various bacterial and viral infections, lichen planus, lichenoid drug eruption, eczema, ichthyosisPathogenesis:Acute GVHDPhase 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 GVHDThe 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 exhaustion and immune senescence) and subsequent apoptosis of both alloreactive and nonalloreactive T cells.Although the cause is yet undetermined, there is diminished homeostatic peripheral expansion of CD4+ T cells in GVHD.Risk factors:Acute GVHD: HLA and/or mHA mismatch, ... SN - PB - McGraw-Hill Education CY - New York, NY Y2 - 2024/03/28 UR - accessmedicine.mhmedical.com/content.aspx?aid=1102704360 ER -