Transplant rejection mechanisms

MHC/HLA - The Body's Barcode

• MHC (Major Histocompatibility Complex), or HLA (Human Leukocyte Antigen) in humans, is the core genetic system for distinguishing self from non-self.
• Allorecognition: The process where a recipient's T-cells recognize donor HLA molecules as foreign, initiating rejection.
• Key Loci & Function:
  • Class I (HLA-A, B, C): On all nucleated cells; present endogenous antigens to CD8+ cytotoxic T-cells.
  • Class II (HLA-DP, DQ, DR): On antigen-presenting cells (APCs); present exogenous antigens to CD4+ helper T-cells.

📌 Mnemonic: Rule of 8s: Class I binds CD8 (1x8=8); Class II binds CD4 (2x4=8).

⭐ HLA-DR and -DQ mismatches are considered the most critical for initiating both transplant rejection and graft-versus-host disease.

Hyperacute Rejection - Instant Annihilation

• Mechanism: Type II Hypersensitivity. Occurs in minutes to hours due to pre-existing recipient antibodies (e.g., anti-ABO, anti-HLA) binding to donor antigens.
• Pathology: Leads to complement activation, endothelial damage, widespread thrombosis, and ischemic necrosis.

⭐ Prevented by pre-transplant ABO blood typing and lymphocytotoxic cross-match tests to detect reactive antibodies in the recipient against donor cells.

Acute Rejection - The Weeks-Long War

Occurs weeks to months post-transplant; most common type. Often reversible with immunosuppressants.

Two main mechanisms:

• Cellular (More Common): T-cell mediated (Type IV hypersensitivity).

  • Host CD8+ and CD4+ T-cells are sensitized against donor MHC antigens.
  • Histology: Dense interstitial lymphocytic infiltrate & endotheliitis (vasculitis).

• Humoral: Antibody-mediated (Type II hypersensitivity).

  • Antibodies develop post-transplant against donor antigens.
  • Histology: Necrotizing vasculitis, neutrophils, and C4d deposition.

⭐ C4d deposition in peritubular capillaries is a key indicator of antibody-mediated rejection, acting as a footprint of complement activation.

Chronic Rejection - The Slow Burn

• Mechanism: Months to years post-transplant; a slow, progressive T-cell and B-cell mediated response (Type III & IV Hypersensitivity).
• Pathology: Chronic inflammation leads to fibrosis, parenchymal atrophy, and obliterative vasculopathy (graft arteriosclerosis).
  • Results in gradual, irreversible loss of graft function.
• Organ-Specific Findings:
  • Lung: Bronchiolitis obliterans.
  • Liver: Vanishing bile duct syndrome.
  • Kidney: Graft nephropathy (fibrosis & atrophy).

⭐ Chronic rejection is the leading cause of long-term graft failure and is often refractory to treatment.

GVHD - When Grafts Attack

• Pathophysiology: Donor T-cells from the graft recognize the recipient's tissues as foreign and attack. This is a Type IV Hypersensitivity reaction, primarily seen in immunocompromised hosts (e.g., bone marrow transplant).
• Clinical Triad:
  • Skin: Diffuse maculopapular rash.
  • Liver: Jaundice, ↑ LFTs.
  • GI Tract: Diarrhea, cramping, bleeding.
• 📌 Mnemonic: See, Yellow, Go (Skin rash, Jaundice, GI upset).

⭐ High-Yield: The same mechanism can be beneficial, causing a "graft-versus-leukemia" effect where donor T-cells attack residual cancer cells.

High‑Yield Points - ⚡ Biggest Takeaways

• Hyperacute rejection is a Type II HSR due to pre-formed recipient antibodies attacking the graft within minutes.
• Acute rejection is primarily T-cell mediated (Type IV HSR), occurring weeks to months post-transplant; may also be antibody-mediated.
• Chronic rejection involves T-cells and antibodies (Type II & IV HSR), leading to irreversible fibrosis and arteriosclerosis over months to years.
• Graft-vs-Host Disease (GVHD) results from donor T-cells attacking host tissues, common after bone marrow transplant.