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  1. 1. Transplant Immunology Historical Perspective Histocompatibility Antigens Major Histocompatibility Complex Human Leukocyte Antigens (HLA) Genetics Structure Function HLA and Disease Transplantation Types of Transplants Rejection Mechanism Immunosuppressive Strategies
  2. 2. primary graft regraft from same strain regraft from new strain first set rejection (2 - 3 weeks) second set rejection (3 - 5 days) first set rejection (2 - 3 weeks) Donor Strain X Recipient Strain Y Donor Strain Z Experimental Transplantation Donor Strain X Recipient Strain Y Recipient Strain Y
  3. 3. bi-directional primary grafts regrafts from offspring first set rejections Strain X Strain Y Inheritance of Histocompatibility Antigens second set rejections Strain XY ?
  4. 4. Major Histocompatibility Complex Class II Class I DP DQ DR B C A Chromosome 6 Major Histocompatibility Gene Loci
  5. 5. Major Histocompatibility Complex Class II Class I DR B A DR1, DR2, DR3, DR4, DR5 ….. B5, B7, B8, B12, B13, B14, B15… Chromosome 6 Example Antigens A1, A2, A3, A9, A10, A11, ….. Major Histocompatibility Gene Loci
  6. 6. variable domains constant domains  (heavy) chain  -2-microglobulin  chain  chain antigen presentation grooves Histocompatibility Antigen Structure class I class II
  7. 7. Human Leukocyte Antigens
  8. 8. Inheritance of HLA antigens X Paternal Phenotype Offspring Phenotype Maternal Phenotype A1, A2, B8, B12, DR3, DR7 A3, A9, B5, B7, DR1, DR2 A1, A3, B7, B8, DR2, DR3
  9. 9. Inheritance of HLA antigens A1 DR3 A2 B12 A3 A1 A9 A3 B8 DR7 DR3 DR2 DR1 DR2 B7 B8 B7 B5 X Paternal Chromosomes Offspring Maternal Chromosomes HLA phenotype: A1, A2, B8, B12, DR3, DR7 HLA phenotype: A3, A9, B5, B7, DR1, DR2 HLA phenotype: A1, A3, B7, B8, DR2, DR3 Haplotype 1: A1, B8, DR3 Haplotype 2: A3, B7, DR2
  10. 10. Humoral and Cellular Immunity Tc APC Th Tc Tc B APC Tc Tc plasma cell Y Y Y Y Y Y Y Tc lymphokines lymphokines
  11. 11. MHC Molecules and Antigen Presentation cell mediated immunity Th Tc APC antigen presentation via class II molecules antigen presentation via class I molecules lymphokines
  12. 12. HLA and Disease Associations System Disease Associated Antigen(s) Endocrine Insulin-Dependent Diabetes Thyrotoxicosis DR3, DR4 B8, DR3 Neurologic Narcolepsy Multiple Sclerosis Lupus erythematosis Rheumatoid Arthritis Ankylosing Spondylitis Systemic DR2 A3, B7, DR2 B8, DR3 DR1, DR4 B27
  13. 13. HLA and Disease Mechanisms <ul><li>Defective Immune Regulation </li></ul><ul><li>HLA molecule contributes to the disease process through the presentation of self-peptides </li></ul><ul><li>Molecular Mimicry </li></ul><ul><li>HLA molecule cross-reacts with microbial antigens </li></ul><ul><li>Pathogen Receptor </li></ul><ul><li>HLA molecule serves as a receptor for viruses that may be associated with certain diseases </li></ul><ul><li>Coincidental Association </li></ul><ul><li>The disease gene is located near or within the MHC </li></ul>
  14. 14. Types of Transplants Classification Description Histocompatibility Autologous (autograft) Within the same individual or organism Antigens are always identical Syngeneic (isograft) Between genetically identical members of the same species Between members of the same species not genetically identical Between members of different species Allogeneic (allograft) Xenogeneic (xenograft) Antigen are always identical Antigens may be similar but usually are not Antigens are always dissimilar
  15. 15. Graft Rejections Classification Description Immunology Hyperacute Occurs within minutes or hours after transplantation Caused by high levels of preexisting antibody Accelerated Usually occurs within 3 to 5 days after transplantation Occurs approximately 2 to 3 weeks after transplantation May occur months or years after transplantation Acute Chronic May be due to low-level antibody or memory T cells Usually due to T cells but may involve antibody May involve antibodies and T cells
  16. 16. Antibody Mediated Graft Rejection Y Y C C Y Y Y Y Y Y Damaged endothelium causes platelet accumulation and thrombus formation Complement fixation leads to neutrophil recruitment and endothelial destruction Antibody reacts with the endothelial lining of the blood vessel wall A B C
  17. 17. Cell Mediated Graft Rejection Cytotoxin production and graft destruction Direct antigen recognition Indirect antigen recognition T c T h APC T c Y Y Y Y T c B T h graft cell graft cell Lymphokine network I II K
  18. 18. Pre-Transplant Immunological Evaluations Evaluation Objective ABO blood group ABO compatibility between donor and recipient avoids hyperacute rejection HLA phenotype HLA antibody and crossmatch test HLA matching delays the onset of chronic rejection and may avoid accelerated rejection in regraft patients Avoiding those donors against whom recipient antibodies are reactive prevents hyperacute and accelerated rejections
  19. 19. Immunosuppression Strategies Immune Suppressant Immunological Effects Corticosteroids Decrease the availability and activity of lymphocytes and antigen presenting cells T cell antisera Cyclosporin A, FK506 Eliminate naïve and memory T cells inhibits helper T cell associated functions, e.g. IL-2 production and interaction Antimetabolites Inhibit T cell activation and proliferation
  20. 20. Case Study 1. Recipient selection for a cadaveric kidney transplant
  21. 21. Case Study 2. Living donor selection for a kidney transplant