🧬 Fundamental concepts
Transplantation refers to the transfer of cells, tissues, or organs from a donor to a recipient. The immune system’s primary role—to distinguish self from non-self—poses a major barrier, as grafts from genetically non-identical individuals are recognized as “altered self” and targeted for destruction.
Even identical twins (syngeneic) may have minor antigenic differences due to somatic mutations, though rejection is rare. In practice, all non-autologous grafts require lifelong immunosuppression to prevent rejection.
🏷️ Graft types
Tissue moved within the same individual (e.g., skin grafts, saphenous vein CABG). No immunosuppression needed.
Between genetically identical individuals (monozygotic twins). No rejection expected.
Between genetically different members of the same species (most organ transplants). Requires immunosuppression.
Between different species (e.g., porcine heart valves). Hyperacute rejection is common due to pre-formed antibodies.
⚡ Mechanisms of graft rejection
Recognition of alloantigens (primarily MHC molecules) triggers both cellular and humoral responses. Key players:
- CD4+ T helper cells – secrete cytokines (IL-2, IFN-γ, TNF) that activate macrophages and CD8+ T cells.
- CD8+ cytotoxic T cells – directly kill graft cells via perforin/granzyme and FasL.
- Antibodies – bind to endothelial cells, activate complement, and cause vascular damage.
IFN-γ and TNF upregulate MHC class I and II on graft cells, increasing their visibility to immune effectors. This “cytokine storm” amplifies the rejection response.
⏳ Rejection timelines & patterns
| Type | Timeframe | Mechanism / pathology |
|---|---|---|
| Hyperacute | Minutes – hours | Pre-formed antibodies (anti-ABO, anti-HLA) → complement activation → thrombosis, ischemic necrosis. |
| Acute | Days – weeks | Primary cellular response: CD4+ and CD8+ T cells, alloantibodies. Reversible with immunosuppression. |
| Accelerated acute | Days | Memory T cell response (anamnestic); faster than primary acute rejection. |
| Chronic | Months – years | Chronic DTH, macrophage infiltration, intimal smooth muscle proliferation → vessel occlusion, fibrosis. |
🔴 Hyperacute rejection
- Onset: within minutes to hours after revascularization.
- Pathogenesis: pre-existing antibodies (from prior transfusion, pregnancy, or transplant) bind to donor endothelial antigens → complement cascade → neutrophil infiltration, thrombosis, and hemorrhagic necrosis.
- Gross appearance: dusky, mottled organ with poor perfusion.
- Prevention: ABO-compatible donor and negative crossmatch (CDC or flow cytometry).
🟡 Acute rejection
- Onset: days to weeks post-transplant (peak at ~1 week).
- Pathology: mononuclear cell infiltrate (CD4+ & CD8+ T cells) in the interstitium and vascular endothelium. In kidney transplants: tubulitis and intimal arteritis.
- Treatment: high-dose corticosteroids, anti-thymocyte globulin, or monoclonal antibodies (OKT3, basiliximab).
- Prognosis: usually reversible if detected early; common cause of early graft loss.
🟠 Chronic rejection
- Onset: months to years; the leading cause of late graft failure.
- Pathology: concentric intimal hyperplasia (vascular smooth muscle proliferation), fibrous obliteration of arteries, interstitial fibrosis. In lung transplant: obliterative bronchiolitis.
- Risk factors: prior acute rejection episodes, inadequate immunosuppression, donor age.
- Treatment: recalcitrant to therapy; often requires retransplantation.
🩸 Graft-versus-host disease (GVHD)
Definition: A complication of bone marrow (hematopoietic stem cell) transplantation, wherein mature donor T lymphocytes attack recipient tissues that express allogeneic MHC molecules.
• Maculopapular rash (erythematous, often generalized)
• Diarrhea (secretory, often bloody)
• Jaundice / liver dysfunction (elevated bilirubin, transaminases)
Prevention: T-cell depletion of the donor marrow (ex vivo) or post-transplant immunosuppression (methotrexate, cyclosporine, or anti-CD52 antibodies).
Acute GVHD (days to weeks) vs. chronic GVHD (months, resembles autoimmune disease with scleroderma-like features).
💊 Immunosuppressive agents
Standard protocols combine corticosteroids, calcineurin inhibitors, and antiproliferative agents. Monoclonal antibodies are increasingly used for induction and treatment of refractory rejection.
| Agent | Target / mechanism | Key notes |
|---|---|---|
| Cyclosporine / Tacrolimus | Calcineurin inhibition → ↓ IL-2 transcription | Nephrotoxic; drug interactions via CYP3A4 |
| Mycophenolate mofetil | Inhibits IMPDH → ↓ purine synthesis | GI upset, leukopenia |
| Sirolimus (rapamycin) | mTOR inhibitor → blocks IL-2 signal transduction | Interstitial pneumonitis, hyperlipidemia |
| Basiliximab / Daclizumab | Anti–IL-2 receptor (CD25) monoclonal antibody | Induction therapy; blocks T-cell proliferation |
| Muromonab (OKT3) | Anti-CD3; depletes T cells via apoptosis | First-generation; cytokine release syndrome |
| Belatacept | CTLA-4–Ig fusion protein; blocks B7:CD28 costimulation | Less nephrotoxic than calcineurin inhibitors |
| Alemtuzumab | Anti-CD52; depletes T and B cells | Profound lymphopenia; used in induction |
📋 Corticosteroids (methylprednisolone, prednisone)
Broad anti-inflammatory effect via inhibition of cytokine gene transcription. First-line for acute rejection. Side effects: hyperglycemia, osteoporosis, infections.
🧠 Clinical pearls & exam tips
• Kidney: biopsy shows tubulitis, intimal arteritis (Banff classification).
• Heart: endomyocardial biopsy; cellular rejection graded by ISHLT.
• Liver: portal inflammation, bile duct damage, endothelialitis.
- Crossmatching: donor-specific antibodies are detected by complement-dependent cytotoxicity (CDC) or flow cytometry. A positive crossmatch is a contraindication to transplantation (hyperacute risk).
- Minor histocompatibility antigens: can cause rejection even in HLA-matched transplants (e.g., H-Y antigens).
- Chronic rejection is often antibody-mediated (donor-specific antibodies, C4d deposition in tissue).
- GVHD prophylaxis: T-cell depletion, post-transplant cyclophosphamide, or methotrexate + calcineurin inhibitor.
• Hyperacute = minutes to hours, pre-formed antibodies.
• Acute = days to weeks, T-cell mediated.
• Chronic = months to years, vascular intimal hyperplasia.
• GVHD = donor T cells attacking recipient (skin, liver, GI).