Transplantation Immunology

HLA & Graft Basics - Body's ID Check

• HLA (Human Leukocyte Antigen): Body's ID system. Encoded by Major Histocompatibility Complex (MHC) genes on Chromosome 6. Highly polymorphic.
  • Class I (HLA-A, B, C): On all nucleated cells. Presents endogenous antigens to CD8+ T cells.
  • Class II (HLA-DR, DQ, DP): On Antigen-Presenting Cells (APCs) e.g., macrophages, B-cells, dendritic cells. Presents exogenous antigens to CD4+ T cells.
• Graft Types & Rejection Risk:
  • Autograft (self) & Isograft (identical twin): No rejection.
  • Allograft (human-to-human, non-identical): Rejection risk. Most common type.
  • Xenograft (animal-to-human): High rejection risk.
• HLA matching (especially A, B, DR) is crucial for allograft survival.

⭐ HLA-DR matching has the most significant impact on graft survival for kidney transplants.

Allorecognition Pathways - Immune System's War

Recipient immune system recognizes donor alloantigens (MHCs) as foreign, initiating rejection. Two pathways:

• Direct Allorecognition:
  • Recipient T-cells engage intact MHCs on donor APCs.
  • Migratory donor APCs (e.g., dendritic cells) reach recipient lymphoid organs.
  • Activates CD8+ T-cells (target donor cells via MHC I) & CD4+ T-cells (help via MHC II).
  • Dominant in early acute rejection.
• Indirect Allorecognition:
  • Recipient APCs process & present peptides from donor MHC/minor histocompatibility antigens.
  • Presented on recipient MHC II to recipient CD4+ T-cells.
  • Like conventional antigen presentation.

⭐ Indirect allorecognition, mediated by recipient APCs presenting donor peptides, is key in chronic rejection.

Rejection & GVHD - When Transplants Rebel

Graft Rejection: Host immune system attacks donor organ.

• Hyperacute:
  • Mins-hrs; pre-formed anti-donor Abs (ABO, HLA).
  • Type II HSR; widespread thrombosis, ischemic necrosis.
• Acute:
  • Days-weeks (typically < 6 months).
  • Cellular (T-cell, Type IV HSR): Lymphocytic infiltrate.
  • Humoral (Ab-mediated, Type II HSR): Vasculitis, C4d.

  ⭐ C4d deposition in peritubular capillaries is a diagnostic marker for antibody-mediated acute rejection.

• Chronic:
  • Months-years; mixed Type III & IV HSR.
  • Progressive fibrosis, arteriosclerosis (e.g., Bronchiolitis obliterans - lung).

Graft-versus-Host Disease (GVHD): Donor T-cells attack recipient tissues.

• Common in Bone Marrow/Stem Cell Transplants.
• Key sites: Skin (rash), GIT (diarrhea), Liver (jaundice).
• Acute GVHD: < 100 days post-transplant.
• Chronic GVHD: > 100 days post-transplant.

Immunosuppression - Calling a Truce

• Goal: Prevent host-vs-graft (rejection) & graft-vs-host disease (GVHD).
• Phases & Typical Regimens:
  • Induction: Peri-op, potent agents (e.g., Anti-thymocyte Globulin (ATG), Basiliximab).
  • Maintenance: Long-term (e.g., Calcineurin Inhibitor (CNI) + Antimetabolite ± Steroids).
  • Anti-rejection: High-dose steroids, biologics for acute episodes.
• Core Drug Classes (Mechanism of Action):
  • Calcineurin Inhibitors (CNIs): Tacrolimus, Cyclosporine (↓IL-2 synthesis).
  • Antiproliferatives: Mycophenolate Mofetil (MMF), Azathioprine (↓lymphocyte proliferation).
  • mTOR Inhibitors: Sirolimus, Everolimus (↓IL-2 signaling).
  • Corticosteroids: Prednisone (Broad anti-inflammatory effects).
  • Biologics (Antibodies): Basiliximab (IL-2R Ab), Rituximab (CD20 Ab for AMR).

⭐ Tacrolimus and Mycophenolate Mofetil form a common cornerstone of maintenance immunosuppression in solid organ transplantation.

High‑Yield Points - ⚡ Biggest Takeaways

• MHC (HLA) compatibility, especially HLA-DR, is key for graft survival.
• Hyperacute rejection: Minutes to hours; pre-formed anti-donor antibodies (ABO, HLA).
• Acute rejection: Days to weeks; primarily T-cell mediated (Type IV HSR); also antibody-mediated.
• Chronic rejection: Months to years; fibrosis, vascular issues; mixed cellular/humoral.
• GVHD: Donor T-cells attack recipient; common in bone marrow transplants.
• Immunosuppressants (calcineurin inhibitors, steroids) prevent rejection.
• Crossmatching detects pre-formed anti-donor antibodies against donor antigens.