Description

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
• Chronic: develops 100 days after allogeneic HSCT; presents with diverse features resembling autoimmune syndromes
• Chronic subtypes
  • Progressive: extension of acute GVHD
  • Quiescent: after resolution of acute GVHD
  • De novo: no prior acute GVHD

Epidemiology

• Acute GVHD (grades II–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)

Risk Factors

• 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
  • Gender mismatch
• Chronic GVHD specific
  • Severity of acute GVHD
  • Malignancy as indication for transplantation
  • Use of total-body irradiation
  • Type of immunosuppressive prophylaxis

General Prevention

• 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 low-dose cyclophosphamide
  • Donor T-cell depletion with anti–T-cell antibodies ex vivo in graft or in vivo in recipient

Pathophysiology

• Acute GVHD: interaction of donor and host innate and adaptive immune responses
  • Severity related to degree of HLA mismatch
  • 3 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 autoreactivity, B-cell dysregulation, regulatory T-cell deficiency; marked collagen deposition in target organs and lack of T-cell infiltration

Etiology

• Hematopoietic stem cell transplantation
• 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 1 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