Graft-Versus-Host Disease



Graft-versus-host disease (GVHD) is a multiorgan inflammatory process that develops when immunologically competent T lymphocytes from a histoincompatible donor are infused into an immunocompromised host unable to reject them; divided into acute and chronic, historically based on time of presentation but best delineated by clinicopathologic findings

  • Acute:
    • Develops within 100 days after allogeneic hematopoietic stem cell transplant (HSCT)
    • Affects skin, GI tract, and/or liver
    • Graded from I to IV based on organ involvement, percent of body surface area involved (skin), volume of diarrhea (gut), and/or elevation of serum bilirubin (liver)
  • Chronic:
    • Develops 100 days after allogeneic HSCT
    • Presents with diverse features resembling autoimmune syndromes; affects multiple organ systems
    • Chronic subtypes
      • Progressive: extension of acute GVHD
      • Quiescent: after resolution of acute GVHD
      • De novo: no prior acute GVHD


  • Acute GVHD (grades II to IV): 10–80% of patients receiving T-cell–replete HSCT
    • 35–45% for human leukocyte antigen (HLA)–identical related donor bone marrow
    • 60–80% if 1-antigen HLA-mismatched unrelated donor bone marrow or peripheral stem cells
    • 35–65% if 2-antigen HLA-mismatched unrelated umbilical cord blood
  • Chronic GVHD: most common cause of late morbidity and mortality of allogeneic HSCT
    • 15–25% if HLA-identical related marrow
    • 40–60% if HLA-matched unrelated marrow
    • 54–70% if HLA-matched unrelated peripheral stem cells
    • 20% if unrelated umbilical cord blood
  • Flare-ups triggered by infection (usually viral)


  • HLA disparity (both major and minor antigens)
  • Older donor or recipient age
  • Stem cell source and dose
    • Highest risk: with peripheral stem cells
    • Lowest risk: with umbilical cord blood
  • Donor leukocyte infusions
  • Reactivation of viruses (e.g., HHV-6, CMV)
  • T-cell depletion decreases incidence.
  • Acute GVHD-specific
    • Higher intensity conditioning regimen
    • Prior pregnancies in female donors
    • Use of total body irradiation
  • Chronic GVHD specific
    • Severity of acute GVHD
    • Malignancy as indication for transplantation
    • Gender mismatch (female donor, male recipient)
    • Type of immunosuppressive prophylaxis


  • HLA gene complex on chromosome 6; inherited as haplotype
  • Full siblings: 25% chance HLA identical
  • Minor histocompatibility antigen differences likely account for GVHD in HLA-identical sibling stem cell transplants.


  • Transfusion: irradiation of all cellular blood products for patients at risk
  • Stem cell transplantation
    • Selection of a histocompatible donor
    • Immunosuppression (gold standard): cyclosporine or tacrolimus with a short course of methotrexate
    • Other options: corticosteroids, sirolimus, mycophenolate mofetil, and post-HSCT cyclophosphamide
    • Donor T-cell depletion with anti–T-cell antibodies ex vivo in graft or in vivo in recipient


  • Acute GVHD: interaction of donor and host innate and adaptive immune responses
    • Severity related to degree of HLA mismatch
    • Three phases ending in “cytokine storm”
      • Tissue damage by conditioning regimen
      • Priming and activation of donor T cells
      • Infiltration of activated T cells into skin, GI tract, and liver resulting in apoptosis
  • Chronic GVHD: findings similar to autoimmune disorders: donor T cells directed against host antigens, donor T-cell alloreactivity, B-cell dysregulation, regulatory T-cell deficiency; marked collagen deposition in target organs and lack of T-cell infiltration


  • HSCT
  • Transfusion of nonirradiated blood products to immunodeficient hosts: caused by viable donor lymphocytes engrafting in the recipient
  • Transfusion of nonirradiated blood from a donor homozygous for one of the recipient’s HLA haplotypes (1st- or 2nd-degree relative)
  • Intrauterine maternal–fetal transfusions and exchange transfusions in neonates
  • Solid organ grafts: contain immunocompetent T cells, into immunosuppressed recipient

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