L25 - Transplant Rejection GVHD

• Transplantation


  Restoring function when an organ or tissue is irreparably damaged or congenitally absent/defective
• Graft/Transplant


  Tissue or organ that is transplanted
• Donor


  The individual from whom tissue or organ is taken
• Recipient


  The individual in whom the tissue or organ is applied
• Basis of transplantation


  • Immunological
  • Genetic & Antigenic relationship between donor & recipient
• Types of transplants


  • Autograft (self graft)
  • Syngeneic (Isograft) (same genetic constitution, e.g. identical twins)
  • Allograft (homograft) (same species but different genetic constitution)
  • Xenograft (heterograft) (different species)
• Transplantation Antigens


  Human Leukocyte Antigens (HLA)
• HLA


  • They are allo-antigens
  • They are encoded by HLA genes
  • The HLA genes are clustered in the Major Histocompatibility Complex (MHC) or HLA complex on the short arm of chromosome 6
  • The complex contains 3 classes of genes: Class I, Class II, and Class III
• Graft Rejection Processes - I

  1. APCs of recipient present donor's antigen along with MHC to recipient's CD4 T cells

  2. Activated CD4 T cells recognizes the foreign MHC molecules and mount an immune response

  3. Leading to destruction of the Graft by Cytotoxic CD8 T cells
• Graft Rejection Processes - II

  1. Some graft cells get detached from the graft

  2. Carried to the lymph nodes where they are engulfed by recipient's APC

  3. Recipient's APC process the class I and class II peptide molecules and present it to CD4 T cells

  4. Cytokines produced by CD4 T cells activate B cells (abs) & CD8 T cells against donor antigens
• Types of allograft rejection

  • Acute rejection
  • Hyperacute rejection
  • Chronic rejection
• Acute rejection


  • The first set response
  • Lymphocytes and Macrophages invade the graft
  • Blood vessels occluded by thrombi, vascularity diminishes, ischemic necrosis sets in
  • Graft changes to scab and sloughs off
• Hyperacute rejection


  • Occurs in minutes
  • Mediated by pre-existing antibodies
  • Activation of Complement leads to Vascular Thrombosis
  • Graft remains pale due to no vascularization (called 'White graft response')
• Chronic rejection


  • Occurs months or years after engraftment
  • Main pathologic finding is Atherosclerosis of the Vascular endothelium
  • Minor histocompatibility antigens and immunosuppressive drugs also play a role
• Mechanism of allograft rejection

  1. Both cell mediated and humoral immune mechanisms play a role

  2. HLA antigens on graft, when presented to recipient's CD4 T cells, the CD4 T cells are activated

  3. Activated CD4 T cells secrete IL-2

  4. IL-2 in-turn activates B cells (Abs) and Cytotoxic CD8 T cells against graft antigens

  5. The cytokines IL-2, TNF α and IFN ϒ are important mediators of graft rejection
• Immune Mechanisms


  • Cytotoxicity: Cytotoxic CD8 T cells secrete enzymes - Perforins and granzymes, activate apoptotic pathway leading to apoptotic death of graft cells
  • Cytokine -IFN ϒ promotes the influx of activated monocytes into the graft, destroy the graft cells by mediating Type IV hypersensitivity reaction
  • Antibodies formed by B cells can destroy the graft through Activation of classical complement pathway, Antibody dependent cell-mediated cytotoxicity (ADCC)
• Tolerance


  A state where adverse immune response to transplant antigens is eliminated while the rest of the immune system remains intact
• How to make a graft survive?

  1. Immunosuppression

  2. Experimental animals: Neonatal thymectomy, Chronic lymphatic drainage, Administration of antilymphocyte serum (ALS)

  3. Clinical situation: Steroids, Azathioprene, Cyclosporin A, Tacrolimus, Rapamycin, Antithymocyte globulin
• Privileged sites for Transplantation

  Anterior chamber of eye, Cornea, Brain - All these sites lack effective lymphatic drainage
• Graft Versus Host Reaction (GVHR)

  • Graft mounting an immune response against the host
  • Requirements: Graft contains immunocompetent T cells, Host must be immunocompromised, Recipient must express antigens foreign to the donor
• Graft Versus Host Disease (GVHD)


  • Acute GVHR occurs 7-30 days after bone marrow transplantation
  • GVH reaction can be reduced by treating the donor tissue with antithymocyte globulin or monoclonal antibodies before grafting, Cyclosporine can also be used
• Recommended reading: Helbert M. Immunology for medical students, 3rd edition. Elsevier; 2016. ISBN-13: 9780702067976 (Available in clinical key)
• Recommended reading: Male D, Brostoff J, Roth D & Roitt I. Immunology, 8th edition. Elsevier; 2012. ISBN13:978072436829. (Available in clinical key)