Transplantation Immunopathology

Transplantation Immunopathology

Transplantation Immunopathology

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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. MHC Class I and II interactions with 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.

Monocyte-mediated innate alloresponse in cardiac graft

📌 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). Graft-versus-host disease (GVHD) skin rash

⭐ 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.

Practice Questions: Transplantation Immunopathology

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Which of the following drugs shows nephrotoxicity during administration?

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Flashcards: Transplantation Immunopathology

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Paracortical hyperplasia is caused by stimuli that trigger _____-cell mediated immune responses (eg. viral infections)

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Paracortical hyperplasia is caused by stimuli that trigger _____-cell mediated immune responses (eg. viral infections)

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