Transplantation immunology

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  • 1. Transplantation Immunology Haris Saddique MPhil Scholar Department of Biotechnology University of Malakand Kpk , Pakistan
  • 2. POINTS TO BE DISCUSSED • • • • • • • Introduction Types of grafts, Transplantation antigens Mechanisms of graft rejection Tempo of Rejection Graft versus Host Reaction (GVHR) Prevention of rejection
  • 3. INTRODUCTION Transplantation: the process of taking cells, tissues, or organs from one individual and placing them into a different individual or different site of the same individual Graft: transplanted cells, tissues, or organs. Donor: the individual who provides the graft. Recipient: the individual who receives the graft. Also called the host.
  • 4. Types of Grafts • Autologous or autograft (self) • e.g., BM, peripheral blood stem cells, skin, bone • Syngeneic or isograft (identical twin) • Allogeneic or allograft (another human except identical twin) • Xenogeneic or xenograft (one species to another)
  • 5. Transplantation antigens • Major histocompatibility antigens (MHC molecules) • Minor histocompatibility antigens • Other alloantigens
  • 6. MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) • Is located on short arm of chromosome 6 • It includes 3 regions: class Ia (loci A, B, C) class Ib (loci E, F, G, H), class II (loci DR, DQ, DP) and class III • Genes of class Ia and class II are highly polymorphic, while those of class Ib and class III are not • Polymorphism means occurence of several allelles i.e genes encoding various MHC antigens located at the same locus
  • 7. Map of Human MHC
  • 8. MAJOR HISTOCOMPATIBILITY ANTIGENS • Histocompatibility antigens are expressed on all nucleated cells (class I) and on APC, B cells, monocytes/macrophages (class II) • They are targets for rejection • They are inherited from both parents as MHC haplotypes and are co-dominantly expressed
  • 9. MINOR HISTOCOMPATIBILITY ANTIGENS • They also participate in rejection but to lesser degree • Disparity of several minor antigens may result in rejection, even when MHC antigens are concordant between donor and recipient • They include normal cellular constituents • They are peptides derived from polymorphic cellular proteins bound to MHC class I molecules
  • 10. • Also cause grafts rejection, but slow and weak • Mouse H-Y antigens encoded by Y chromosome • HA-1 ~ HA-5 linked with non-Y chromosome
  • 11. OTHER ALLOANTIGENS • Human ABO blood group antigens • Some tissue specific antigens – Skin > kidney > heart > pancreas > liver – VEC antigen – SK antigen
  • 12. Rejection • First Set Rejection • Skin graft in mice 10-14 days • Second Set Rejection • Skin graft in mice in 3-6 days
  • 13. MECHANISM OF ALLOGRAFT REJECTION The immune responses in allogeneic transplantation:  T cell mediated rejection of allograft  Antibody mediated rejection of allograft  NK cell mediated rejection of allograft
  • 14. T cell mediated rejection of allograft (mechanism of cellular immunity) 1) Recognition of alloantigens 2) Activation of T cells and rejection of allograft
  • 15. Alloantigen Recognition • Direct presentation (Donor APC) • Unprocessed allogeneic MHC • Indirect presentation (Host APC) • Processed peptide of allogeneic MHC
  • 16. Recognition of alloantigen • Direct recognition ------acute rejection • Indirect recognition ------chronic rejection
  • 17. Direct recognition of alloantigen • Recognition of an intact MHC molecule in the graft by T cells.
  • 18. Indirect recognition of alloantigen • the donor MHC molecules may be processed and presented by recipient APCs that enter grafts, and the processed MHC molecules are recognized by T cells like conventional foreign antigens.
  • 19. Major Histocompatibility Complex (MHC) •Class I HLA A, B, C bind to TCR on CD8 T-Cell •Class II DR, DP, DQ bind to TCR on CD4 T-Cell
  • 20. Activation of T cells and rejection of allograft Host T cells may be activated by both direct recognition and indirect recognition • Direct pathway : CD4+T ---- Th CD8+T ---- CTc ---- killing graft cells • Indirect pathway : CD4+T ---- infiltrate the graft and recognize donor alloantigens being displayed by host APCs that have entered the graft ---- Th CD8+T ---- can not directly kill the foreign cells in the graft
  • 21. Antibody-mediated rejection of allograft (mechanism of humoral immunity) Ⅰ. Complement activated by antibody involved in transplantation rejection Ⅱ. Antibody participate in transplantation rejection through ADCC and opsonization  Antibody bound to the surface of infected cell is recognize by igG receptor on the surface of phagocytic cell e.g NK Cells
  • 22. NK cell mediated rejection of allograft • NK have receptor for allogeneic MHC proteins of graft • CKs secreted by activated Th cells can promote NK activation. • Participate in transplantation rejection through ADCC
  • 23. Tempo of Rejection Solid Organ • Hyperacute – Minutes to hours – Preexisting antibodies (IgG) Intravascular thrombosis – Hx of blood transfusion, transplantation or multiple pregnancies • Acute Rejection – Few days to weeks – CD4 + CD8 T-Cells – Humoral antibody response – Parenchymal damage & Inflammation • Chronic Rejection – Chronic fibrosis – Accelerated arteriosclerosis – 6 months to yrs – CD4, CD8, (Th2) – Macrophages Stem Cell Not Applicable 10 – 30 Days Lysis of donor stem cells 30 days – 6 months Lysis of donor stem cells
  • 24. Graft versus Host Reaction (GVHR)  When grafted tissue has mature T cells, they will attack host tissue leading to GVHR.  Major problem for bone marrow transplant.  Methods to overcome GVHR:  Treat bone marrow to deplete T cells.  Use autologous bone marrow.  Use umbilical cord blood
  • 25. Prevention & Treatment of Allograft Rejection • ABO Compatible (Prevent hyperacute rejection in solid organs) (Prevent transfusion reaction in BM/PBSC) • MHC allele closely matched • Calcineurin inhibitors – Cyclosporine binds to Cyclophillin – Tacrolimus (FK506) binds to FK Binding Proteins (FKBP) – Calcineurin activates Nuclear Factor of Activated T-Cells (NFAT) – NFAT promotes expression of IL-2 • IMPDH Inhibitors (Inosine Monophosphate Dehydrogenase) – Mycophenolate Mofetil (MMF) – Inhibits guanine nucleotide synthesis – Active metabolite is Mycophenolic acid (MPA)