Transplant rejection

Feature	Hyperacute Rejection	Acute Rejection	Chronic Rejection	Graft-vs-Host Disease (GVHD)
Onset	Mins-Hrs	Wks-Months (typ <3mo-1yr)	Months-Yrs	Variable (Acute <100d, Chronic >100d)
Patho/Etiology	Pre-formed Ab (Type II HSR); Thrombosis	Cell-mediated (T-cell vs donor MHC; Type IV HSR) &/or humoral	Chronic inflammation, fibrosis, atrophy; Complex	Donor T-cells attack recipient tissues
Presentation	Immediate graft failure, mottling, cyanosis	Graft dysfunction (e.g., ↑Cr, ↑LFTs), fever, tenderness	Gradual loss of fxn; Organ-specific sx	Acute: Rash, GI (diarrhea), Liver (jaundice). Chronic: Skin (sclerosis, lichenoid), sicca, multi-organ
Diagnosis	Clinical (intra-op); Bx: thrombosis/necrosis	Bx: Cellular infiltrate, endothelialitis	Bx: Fibrosis, arteriosclerosis (e.g., VOD, BOS)	Clinical; Bx of affected organ (skin, GI)
Mgmt/Tx	Irreversible; Graft removal	Immunosuppression (steroids, anti-lymphocyte Ab)	Poorly responsive; Optimize IS; Re-transplant	Immunosuppression (steroids); Supportive
Key Assoc.	ABO/HLA incompatibility; Prior sensitization	Most common type	Major cause of late graft loss	Allogeneic HSCT; Donor cells attack host
Buzzword	Pre-formed antibodies	T-cell mediated against graft	Fibrosis, insidious loss of function	Donor lymphocytes attack recipient

Concept	The Fight	Typical Scenario	Clinical Picture
Graft-vs-Host (GVHD)	Donor T-cells attack Recipient	Bone Marrow Transplant	Rash + Diarrhea + Jaundice (Systemic illness)
Host-vs-Graft	Recipient T-cells/Abs attack Donor Organ	Solid Organ Transplant	Failure of the transplanted organ

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
• Organ-Specific Findings (High Yield):
  • Lung: Bronchiolitis obliterans (small airway inflammation/scarring). t
  • Heart: Accelerated atherosclerosis (coronary artery disease).
  • Kidney: Chronic allograft nephropathy (vascular fibrosis, glomerulopathy).
  • Liver: Vanishing bile duct syndrome.

Graft-versus-host disease

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• Pathophysiology

  • Type IV Hypersensitivity reaction.
  • Donor T-cells (CD4+ and CD8+) recognize host MHC antigens as foreign and attack host cells.
  • Most common in allogeneic bone marrow/stem cell transplants.
  • Risk Factors: HLA mismatch, multiparous female donor, older donor/recipient.

• Acute GVHD

  • Onset: Typically < 100 days post-transplant.
  • Classic Triad:
    1. Skin: Maculopapular pruritic rash (often starts on neck, ears, and shoulders; involves palms and soles). Desquamation in severe cases.
    2. GI Tract: Severe diarrhea (often green, watery, bloody), abdominal pain, nausea/vomiting.
    3. Liver: Jaundice, hepatosplenomegaly, ↑ alkaline phosphatase, ↑ bilirubin.

• Chronic GVHD

  • Onset: Typically > 100 days post-transplant.
  • Characterized by chronic inflammation leading to fibrosis (mimics autoimmune disorders).
  • Clinical Features:
    • Skin: Scleroderma-like hardening/thickening of skin, lichen planus-like changes.
    • Eyes/Mouth: Sicca syndrome (dry eyes, dry mouth), dental caries.
    • Lungs: Bronchiolitis obliterans (non-productive cough, dyspnea, obstructive pattern).
    • GI: Esophageal webs, strictures, dysphagia.

• Graft-versus-Tumor (Leukemia) Effect

  • Beneficial aspect of GVHD.
  • Donor T-cells attack residual host malignant cells (e.g., leukemia cells), reducing relapse risk.
  • Balancing GVHD toxicity vs. this beneficial effect is key in transplant management.

• Prevention & Treatment

  • Prevention:
    • Irradiation of blood products (prevents Transfusion-Associated GVHD by inhibiting lymphocyte proliferation).
    • Prophylactic immunosuppression: Methotrexate + Calcineurin inhibitors (e.g., Cyclosporine, Tacrolimus).
  • Treatment: High-dose systemic Corticosteroids.