Immunology of Transplantation

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.

*   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.

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Immunosuppressive Drugs - Peace Keepers

• 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.

⭐ 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.