Key Points
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 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, older donor or recipient age, gender mismatch, reduced intensity conditioning, donor lymphocyte infusions
Chronic GVHD: history of acute GVHD, HLA mismatch, donor-recipient mismatches for mHAs such as HA-1, HA-2, and HA-5, peripheral blood source of stem cells
Genetic polymorphisms-associated acute GVHD, chronic GVHD, and transplant related mortality (TRM):
Genetic polymorphisms of multiple cytokines have studied in relation to GVHD. However, most studies are single centered based on small patient populations. Although there are other cytokine polymorphisms implicated in the pathogenesis of GVHD, listed below are the ones most well studied.
TNF-α: located on chromosome 6, near the HLA region. Therefore, in HLA-matched sibling transplants, TNF-α genotype is the same in donor and recipient. Single-nucleotide polymorphisms (SNPs) which upregulate TNF-α have been shown to increase risk of acute GVHD and TRM. SNPs in the TNF receptor II (TNFRII) gene which downregulate TNFRII, resulting in increased soluble TNF-α, has been shown to increase incidence of chronic GVHD.
IL-1: of the 10 genes within the IL-1 family, SNPs in 3 (IL-1α, IL-1β, IL1Ra) have been correlated with acute GVHD, chronic GVHD, and TRM.
IL-6: SNPs in the promoter region of IL-6, which upregulate production, have been shown to increase the risk of acute GVHD, chronic GVHD, and TRM.
IL-10: normally inhibits T-cell proliferative responses and proinflammatory cytokine production. Most studies show that SNPs which downregulate IL-10 production increase the risk for acute and chronic GVHD, but there are conflicting data in other studies.
Plasma biomarkers:
The combination of values for IL-2Rα, TNFR1, HGF, and IL-8 has been shown to predict occurrence of acute GVHD.
High levels of elafin may predict severity of cutaneous GVHD.
Diagnostic Criteria and Clinical Characteristics
Diagnostic evaluation should include at least one of the following:
History and physical examination
Previous allogeneic HSCT or organ transplant
Characteristic clinical features (see later)
Biopsy of affected organs
Skin: apoptosis of basal keratinocytes at dermoepidermal junction, interface vacuolar change, follicular prominence
Gastrointestinal tract: patchy ulcerations, apoptotic bodies in base of crypts, crypt abscesses, loss and flattening of surface epithelium
Liver: endothelialitis, lymphocytic infiltration of portal areas, pericholangitis, bile duct destruction
Radiologic studies
Gastrointestinal tract: luminal dilatation with thickening of small bowel wall, air or fluid levels suggestive of ileus
Although acute GVHD usually occurs 20 to 40 days after HSCT, reduced-intensity conditioning may delay onset of acute GVHD.
Clinical features should include at least one of the following:
Skin: pruritic morbilliform rash that initially involves palms and soles but can become diffuse, often sparing the scalp. Can progress to generalized erythroderma, bullae, and desquamation.
Gastrointestinal tract: voluminous secretory diarrhea, bloody diarrhea, vomiting, anorexia, abdominal pain.
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