Transplant immunology

• Learning Objectives:

  • Describe the role of transplantation
  • Outline the role of HLA typing, anti-HLA antibody screening, and cross-matching in solid organ transplant
  • Explain the immunological mechanisms of allograft rejection
  • Explain the mechanism of Graft versus Host Disease
  • Outline principles of management of transplant patients
• Transplantation includes Haemopoietic Stem Cell (HSC) Transplantation, Solid Organ Transplantation, and Tissue Transplantation
• Sources of Donors:

  • Self – autologous / autograft
  • Another human – allogeneic / allograft (Live Donors, Brainstem Death vs. Circulatory Death Donors)
  • Another species – Xenogeneic / xenograft
• Tissue Transplantation involves non-vascularised, non-haemopoietic tissues like bone grafts, heart valves, corneas, and blood vessels
• HSC Transplantation includes Bone Marrow Allogeneic, Bone Marrow Autologous, Stem Cells Purified from Blood, and Cord blood stem cells
• Solid Organ Transplantation:

  • Common organs transplanted: Kidney, Liver, Heart, Lung, Pancreas, Islet cell transplantation, Small bowel, Vascularised composite grafts
• Indications for Solid Organ Transplantation:

  • Irreversible organ failure secondary to a disease with low risk of recurrence
  • Recipient free of infection and malignancy
  • Recipient fit for major surgery and psychologically suitable
• Ethical Issues in Transplantation:

  • Allocation of scarce resources
  • Living donor program
  • Red Market (Illegal organ trade)
  • Xenotransplantation – risk to public health
• Testing Pre-Transplant:

  • Recipient listed: Blood group x 2, HLA type x 2, Anti-HLA antibodies at listing and 3 monthly
  • Donor available: Blood group, HLA type, Antibody Crossmatch
• Classification of Rejection:

  • Hyperacute, Acute antibody-mediated, Acute cellular, Chronic rejection
• Three Key Concepts:

  • HLA match
  • Highly Polymorphic HLA genes on Chromosome 6
  • Better matching decreases the immunological barrier and leads to better outcomes
• Mechanisms of Tissue Damage:

  • Hyperacute, Acute antibody-mediated, Acute cellular, Chronic rejection
• Mechanisms of Rejection:

  • Acute Cellular Rejection (2 weeks - 6 months)
  • Chronic Rejection (years)
• Hyperacute Rejection:

  • Preformed antibodies to graft
  • Can cause hyperacute rejection
  • Contraindication (Except for liver transplants): Blood group antibodies (ABO & other), Anti-HLA antibodies
• HLA Antibodies Sensitisation History:

  • Factors leading to sensitisation: Transfusion, Pregnancy, Previous allograft
  • Transfusion of a potential transplant recipient should ALWAYS be made at a senior level
  • Anti-HLA antibodies are also produced after tissue transplantation
  • Other factors leading to sensitisation: Infection, Implanted devices e.g. Left ventricular assist devices
• Acute Cellular Rejection:

  • Infiltrating T cells cause inflammation
  • Inflammation impairs organ function
  • Heart Muscle example: Acute cellular rejection (lymphocytes) in normal myocardium
• Transplant Outcomes:

  • Survival rates at 1 year: Kidney (98%), Heart (85%), Liver (>90%), Lung (90%)
  • Survival rates at 10 years: Kidney (>70%), Heart (70%), Liver (70%), Lung (40%)
  • Improvements over the years, mostly in early outcomes
  • Outcomes affected by donor and recipient factors
• Immunosuppression at Time of Surgery:

  • Live Donor: Start 1 week pre-op
  • Cadaveric Donor: Start immediately pre-op
  • Medications used: 1 gm Methylprednisolone, Basiliximab (Anti-CD25 Monoclonal Antibody)
• Immunosuppression Post Transplant Options:

  • Calcineurin Inhibitors: Inhibit Cytokine Action e.g. Tacrolimus, Ciclosporin
  • Anti-Proliferative Agent: Mycophenolate
  • Steroids: Prednisolone
  • mTOR inhibitors: Sirolimus
• Immunosuppression Post Transplant Dual Regimen vs. Triple Regimen:

  • Dual Regimen: Antiproliferative Agent/mTOR inhibitor + Calcineurin Inhibitor
  • Triple Regimen: Dual Regimen + Steroids
• Post-Transplant Immunosuppression:

  • All patients significantly immunosuppressed
  • Increased risk of: Infection, Malignancy (e.g., SCC of the skin, Kaposi’s Sarcoma, Lymphoma, Cervical Cancer), Cardiovascular Complications, Diabetes, Hypertension, Hyperlipidemia
  • Need to carefully consider drug interactions
• The Future of Transplantation:

  • Portable Kidney
  • Laboratory Grown Kidney from patient’s own cells
  • Bio-Artificial “Cyborg” Kidney
• Solid Organ Transplantation Summary:

  • Main problem is rejection
  • Modern testing prevents hyperacute rejection
  • Most cellular rejection can be reversed, and over 80% of antibody-mediated rejection
  • Early outcomes have improved significantly, late attrition of grafts largely unchanged
• Haemopoietic Stem Cell Transplantation:

  • What is transplanted: Bone marrow, Allogeneic (from someone else) or Autologous (patient's own) Haemopoietic Stem cells
  • Indications: Malignant diseases (Leukaemia, lymphoma), Solid organ tumors, Multiple myeloma, Genetic diseases (Immunodeficiency, Haematological Storage disorders), Autoimmune disease (rare)
  • Process: Collection and processing of bone marrow/stem cells, conditioning, infusion, patient isolation until white cells recover
• Haemopoietic Stem Cell Transplantation Complications:

  • Non-engraftment, Infection, GvHD (Graft vs Host Disease), Recurrence, Toxicity of conditioning regimen
• Graft vs Host Disease (GVHD):

  • Acute GVHD: Affects skin, GIT, Liver, Bone marrow
  • Ranges from mild to life-threatening
  • Chronic GVHD: Symptoms include skin thickening, Sicca syndrome, Pneumonitis, Immunodeficiency
• Transplant Immunology Summary:

  • HSC recipient immune system replaced by donor immune system
  • Main problem: Graft vs Host Disease in HSC, rejection in solid organ transplants
  • Reduce problems through matching and immunosuppression
• Summary:

  • Transplant outcomes are improving
  • Understanding of immunological mechanisms necessary for rational treatment
  • Desired improvements: More targeted immunosuppression, Organ-specific tolerance
• For more information:

  • Visit www.beaumonthospital.ie
  • Departments: H & I (Histocompatibility & Immunogenetics)
  • Users Handbook (pdf): http://www.cancer.gov/cancertopics/understandingcancer/StemCells/AllPages/Print