Pathophysiology

Hyperacute rejection

• Humoral rejection (type II hypersensitivity reaction): recipient’s preformed cytotoxic antibodies against donor’s class I HLA molecules or blood group antigens → activation of the complement system and adhesion to cells → thrombosis of vessels → graft ischemia and necrosis
• Preformed antibodies against HLA antigens result from exposure to foreign HLA haplotypes during pregnancy, transfusion, or a previously rejected transplant.

Acute rejection

• Allorecognition → T lymphocyte induced cell-mediated and/or humoral immunity
• Acute cellular rejection (type IV hypersensitivity reaction)
  • Donor MHC class II antigens react with recipient CD4+ T cells, which then differentiate into Th1 helper T cells → cytokine (INF-γ) release → macrophage recruitment → parenchymal and endothelial inflammation
  • Donor MHC class I antigens react with recipient CD8+ T cells → direct cytotoxic cell damage
• Acute humoral rejection (type II hypersensitivity reaction): recipient antibodies, formed before or after transplantation, react against donor HLA antigens

Chronic rejection

• Combination of humoral rejection (type II hypersensitivity reaction) and cellular rejection (type IV hypersensitivity reaction)
• Donor MHC class II antigens react with recipient CD4+ T cells → differentiation into Th1 helper T cells → cytokine (INF-γ) release → macrophage recruitment → parenchymal and endothelial inflammation

Graft-versus-host disease

---

Etiology

• Graft-versus-host disease (GvHD) is common in transplantation of lymphocyte-rich organs, including:
  • Allogeneic hematopoietic stem cell transplantation
  • Transfusion of nonirradiated blood products
• HLA mismatch (especially HLA-A, HLA-B, and HLA-DR) is associated with an increased risk of GvHD.