Immunology of Transplantation

Immunology of Transplantation

Immunology of Transplantation

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Basic Transplant Immunology - Code Crackers

  • Key Antigens:
    • Major Histocompatibility Complex (MHC) / Human Leukocyte Antigen (HLA): Primary targets.
      • Class I (HLA-A, B, C): On all nucleated cells. Present antigens to CD8+ T-cells.
      • Class II (HLA-DR, DQ, DP): On Antigen-Presenting Cells (APCs). Present antigens to CD4+ T-cells.
    • Minor Histocompatibility Antigens (mHA): Peptides from polymorphic proteins; contribute to rejection.
  • Allorecognition Pathways: Recipient T-cell recognition of alloantigens. HLA Class I and II MHC Structure Diagram
*   Direct: Donor APCs activate recipient T-cells. Key in acute rejection.
*   Indirect: Recipient APCs present processed donor antigens. Key in chronic rejection.

⭐ HLA genes are the most polymorphic in the human genome, critical for immune specificity and transplant matching.

Graft Rejection Mechanisms - Unwanted Guests

📌 Rejection types: HAC (Hyperacute, Acute, Chronic)

  • Hyperacute Rejection (Minutes-Hours)
    • Pre-formed recipient anti-donor Abs (ABO, HLA).
    • Type II hypersensitivity.
    • Causes: Thrombosis, ischemic necrosis.
    • Prevention: ABO crossmatching, lymphocytotoxic crossmatch.

    ⭐ Hyperacute rejection is mediated by pre-existing ABO or HLA antibodies.

  • Acute Rejection (Days-Weeks, <6 months)
    • Cellular (ACR): T-cell (CD8+, CD4+) mediated; Type IV hypersensitivity.
      • Direct & indirect allorecognition.
      • Path: Lymphocytic infiltrate, tubulitis, endotheliitis.
    • Humoral (AMR): Antibody-mediated (de novo DSA); Type II hypersensitivity.
      • Path: C4d deposition, vasculitis.
    • Treatment: ↑ Immunosuppression (steroids, anti-lymphocyte Abs).
  • Chronic Rejection (Months-Years)
    • Alloimmune (T/B cells) & non-alloimmune factors.
    • Path: Chronic inflammation, fibrosis, graft arteriosclerosis, organ-specific (e.g., bronchiolitis obliterans - lung).
    • Often irreversible.

Pathways of T-cell mediated graft rejectionoka

Immunosuppressive Drugs - Peace Keepers

Immunosuppressant mechanisms in transplant immunology

  • Goal: Prevent & treat rejection, minimize toxicity.
  • Phases: Induction (peri-op), Maintenance (lifelong), Rejection treatment (pulse).
  • Key Classes:
    • Calcineurin Inhibitors (CNIs): Cyclosporine, Tacrolimus.
      • MOA: ↓ IL-2 production → ↓ T-cell activation.
      • SE: Nephrotoxicity (⚠️), neurotoxicity, HTN, hyperglycemia. Cyclosporine: gingival hyperplasia. Tacrolimus: ↑ diabetes risk.

      ⭐ Cyclosporine and Tacrolimus are calcineurin inhibitors, vital for preventing T-cell mediated rejection.

    • Antiproliferatives: Azathioprine (AZA), Mycophenolate (MMF).
      • AZA MOA: Inhibits purine synthesis. SE: Bone marrow suppression (BMS).
      • MMF MOA: Inhibits IMPDH → ↓ B & T cell proliferation. SE: GI upset, BMS.
    • mTOR Inhibitors: Sirolimus, Everolimus.
      • MOA: Inhibit mTOR → ↓ T-cell proliferation.
      • SE: Hyperlipidemia, poor wound healing, mouth ulcers.
    • Corticosteroids: Prednisolone.
      • MOA: Broad anti-inflammatory.
      • SE (long-term): Cushingoid, osteoporosis, ↑ infection risk.
    • Biologics: Anti-thymocyte globulin (ATG) (T-cell depletion), Basiliximab (IL-2R antagonist).

GVHD & Tolerance - Special Ops

  • Graft-versus-Host Disease (GVHD): Donor T-cells attack recipient tissues.
    • Acute GVHD: <100 days. Targets: Skin (rash), Liver (jaundice, ↑LFTs), GIT (diarrhea).
    • Chronic GVHD: >100 days. Multi-organ, autoimmune-like features.
  • Pathophysiology (Acute GVHD):
    • Phase 1: Host tissue damage (conditioning regimen).
    • Phase 2: Donor T-cell activation, proliferation.
    • Phase 3: Cellular & inflammatory effector damage.
  • Prevention: Immunosuppression (e.g., Cyclosporine, Methotrexate), T-cell depletion.
  • Tolerance: Graft acceptance without ongoing immunosuppression.
    • Mechanisms: Clonal anergy/deletion, regulatory T-cells (Tregs).
    • Chimerism (donor/recipient cell coexistence) promotes tolerance.

Acute and chronic skin GVHD manifestations

⭐ GVHD is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT), primarily mediated by donor T-cells attacking recipient tissues like skin, liver, and the GI tract.

High‑Yield Points - ⚡ Biggest Takeaways

  • Major Histocompatibility Complex (MHC/HLA) matching is paramount to prevent graft rejection.
  • T-cells (CD4+ helpers, CD8+ cytotoxics) are central mediators of acute cellular rejection.
  • Hyperacute rejection is immediate, caused by pre-formed anti-donor antibodies (ABO, HLA).
  • Acute rejection can be cellular (T-cell mediated) or humoral (antibody-mediated, C4d+).
  • Chronic rejection features gradual fibrosis and graft vascular disease (arteriosclerosis).
  • Key immunosuppressants include calcineurin inhibitors, antimetabolites, and corticosteroids.
  • Graft-versus-Host Disease (GVHD): Donor T-cells attack recipient in bone marrow/stem cell transplants.

Practice Questions: Immunology of Transplantation

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Which of the following drugs shows nephrotoxicity during administration?

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Flashcards: Immunology of Transplantation

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Organ implanted in different anatomic location in the recipient as it was in the donor is known as _____ transplantation

TAP TO REVEAL ANSWER

Organ implanted in different anatomic location in the recipient as it was in the donor is known as _____ transplantation

heterotopic

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