Transplantation Immunopathology

Basics of Transplantation - Mismatch Mayhem

• Graft Types:
  • Autograft: Self tissue (e.g., skin).
  • Isograft (Syngeneic): Identical twin.
  • Allograft: Same species, genetically different.
  • Xenograft: Different species (e.g., pig valve).
• Major Histocompatibility Complex (MHC) / HLA System:
  • Genes on Chromosome 6p. Highly polymorphic.
  • Class I (HLA-A, B, C): On all nucleated cells. Present to CD8+ T cells.
  • Class II (HLA-DP, DQ, DR): On Antigen Presenting Cells (APCs). Present to CD4+ T cells.

  ⭐ HLA matching is most critical for kidney & bone marrow transplants; HLA-DR is key.

• Minor Histocompatibility Antigens: Non-MHC proteins; can cause slower rejection despite HLA match.
• Allorecognition Pathways:
  • Direct: Recipient T-cells recognize intact donor MHC on donor APCs.
  • Indirect: Recipient APCs process donor MHC, present peptides to recipient T-cells.

Graft Rejection - Immune System Strikes

Host immune response to foreign donor tissue (allograft), mainly via mismatched Major Histocompatibility Complex (MHC) antigens (HLAs in humans).

• Pathways:

  • Cell-mediated: Primarily CD8+ CTLs (direct cytotoxicity); CD4+ Th1 cells (cytokine release, e.g., IFN-γ, activating macrophages).
  • Humoral: Donor-Specific Antibodies (DSA) activate complement cascade & Antibody-Dependent Cell-mediated Cytotoxicity (ADCC).

• Types & Timeline:

  • Hyperacute: Mins-hrs. Pre-formed antibodies (e.g., ABO, HLA). Type II Hypersensitivity Reaction (HSR). Results in thrombosis, ischemia.
  • Acute: Days-weeks (can extend to months). Primarily T-cell driven (cellular rejection); humoral mechanisms (antibody-mediated rejection) can also occur.

    ⭐ Acute cellular rejection (T-cell mediated) is the most common form of graft rejection, typically occurring within the first 6 months post-transplant.

  • Chronic: Months-years. Slow, progressive graft damage leading to fibrosis and vascular abnormalities (e.g., graft arteriosclerosis). Involves mixed T-cell/antibody roles, and non-immune factors. Type III & IV HSR elements.

📌 Mnemonic: "Hot ACid Chills" for rejection types: Hyperacute, Acute, Chronic.

Graft vs Host Disease - When Grafts Attack

• Immune attack by donor T-lymphocytes (graft) against recipient tissues (host).
• Common complication of allogeneic Hematopoietic Stem Cell Transplantation (HSCT).
• Prerequisites (Billingham's Postulates):
  • Graft contains immunocompetent T cells.
  • Host possesses antigens foreign to donor T cells.
  • Host is immunoincompetent, unable to reject graft cells.
• Types:
  • Acute GvHD: Occurs < 100 days post-transplant.
    • Targets: Skin (maculopapular rash), Liver (jaundice, ↑LFTs), GIT (diarrhea, abdominal pain).
  • Chronic GvHD: Occurs > 100 days post-transplant.
    • Features resemble autoimmune disorders: Skin (sclerosis, lichenoid changes), eyes/mouth (sicca syndrome), lungs (bronchiolitis obliterans).

⭐ The triad of dermatitis, hepatitis, and enteritis is characteristic of acute GvHD.

Immunosuppressive Therapy - Taming the Beast

• Goal: Prevent rejection/GVHD; minimize drug toxicity (infection, malignancy).
• Strategy: Combination therapy, lower individual drug doses.
• Phases:
  • Induction: Intense, peri-transplant (Basiliximab, ATG).
  • Maintenance: Long-term (CNI + Antimetabolite ± Steroids).
  • Anti-rejection: Acute episodes (Pulse steroids, ATG).
• Key Drugs/Classes:
  • Calcineurin Inhibitors (CNIs): Tacrolimus, Cyclosporine.
    • ↓ IL-2 production.
    • Nephrotoxic, Neurotoxic, HTN, Diabetes.
  • Antiproliferatives: Mycophenolate Mofetil (MMF), Azathioprine.
    • MMF: Inhibits IMPDH (lymphocyte purine synthesis).
    • GI (MMF), myelosuppression.
  • mTOR Inhibitors: Sirolimus, Everolimus.
    • Block IL-2 signaling.
    • Hyperlipidemia, myelosuppression, poor wound healing.
  • Corticosteroids: Prednisone.
    • Broad anti-inflammatory, ↓ cytokines.
    • Cushingoid, osteoporosis, hyperglycemia.
  • Antibodies: Basiliximab (Anti-CD25), ATG (T-cell depleting).

⭐ Calcineurin inhibitors (Tacrolimus, Cyclosporine) are notorious for causing nephrotoxicity, a major dose-limiting side effect.

High‑Yield Points - ⚡ Biggest Takeaways

• Hyperacute rejection is immediate, mediated by pre-formed anti-donor antibodies (ABO/HLA).
• Acute cellular rejection (days-weeks) is T-cell driven (Type IV HSR), often reversible with immunosuppression.
• Acute humoral rejection involves donor-specific antibodies and C4d deposition in vessels.
• Chronic rejection (months-years) features graft arteriosclerosis and interstitial fibrosis, poorly responsive.
• Graft-versus-Host Disease (GVHD) occurs when donor T-cells attack recipient tissues, especially in BMT.
• Mainstay immunosuppressants include calcineurin inhibitors, antimetabolites, and steroids.