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Transplantation Immunology

Transplantation Immunology. Understand the transplantation antigens involved in rejection Review the concepts of allorecognition by T cells vs. antibody/B cells Examine the similarities and differences between the immune response in T cell-mediated and antibody-mediated rejection

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Transplantation Immunology

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  1. Transplantation Immunology

  2. Understand the transplantation antigens involved in rejection Review the concepts of allorecognition by T cells vs. antibody/B cells Examine the similarities and differences between the immune response in T cell-mediated and antibody-mediated rejection Introduce the effector mechanisms of T cell-mediated and antibody-mediated rejection Learning objectives

  3. Transplantation Antigens Transplant compatibility is primarily dictated by two sets of antigens: Major Histocompatibility Complex (MHC)/ HLA • Class I antigens • Class II antigens • HLA Expression is primarily regulated by IFN-g ABO blood group antigens (A, B, O, AB) • Polysaccharide structures on surface of RBCs and endothelium • Recognized by natural antibodies in individuals lacking the donor ABO antigen

  4. Human Leukocyte Antigens (HLA) All antigens are “seen” by T cells only after they are presented on Major HistoCompatibility (MHC) antigens (in humans: HLA) Two main types of HLA antigens: • Expressed on most nucleated cells body-wide • Level of expression varies between tissues • High expression on lymphocytes, levels inducible on nucleated cells • Restricted expression on APCs (B cells, monocytes/ macrophages, dendritic cells) • Inducible on other cells (epithelium, endothelium)

  5. Why are there allo-antigens? HLA Polymorphism HLA polymorphisms are focused around the peptide binding grooves: Immunity: The Immune Response in Infectious and Inflammatory Disease DeFranco, Locksly and Robertson • Effects of the position of HLA polymorphisms: • - Possible conformational changes in a-helices or exposed loops • - Different peptides presented by different HLA alleles

  6. Why do Transplants Reject?HLA Polymorphism • HLA polymorphisms are concentrated in the amino acids encoded in the peptide-binding groove: • Conformational changes in α-helices • Repertoire of peptides to present • Each HLA allotype is able to present a different repertoire of peptides to T cells. www.hla.alleles.org

  7. The Basis For Allograft Rejection Improved immunosuppression * Matching for HLA-A, -B & DR only* Opelz G. et. al., Transplantation 2007

  8. Recognition of transplantation antigens: Features of adaptive immunity in transplantation Transplantation antigens that differ between donor and recipient (allo-antigens) can only be recognized by cells with antigen-specific receptors - T cells and B cells In an alloimmune response, allospecific T and B cells each recognize allo-antigen in a different way…

  9. Allo-antigen: T cell’s point of view T cells can only recognize antigens when presented as peptides on HLA molecules Alloantigens can be any set of peptides presented by mismatched HLA between donor and recipient

  10. T cell Antigen Recognition in Transplantation Alloantigen can be recognized by T cells in 3 different ways: Direct Recognition Indirect Recognition Semi-Direct Recognition

  11. Direct Antigen Recognition intact donor HLA presented to recipient T cells by donor APC This type of antigen presentation is unique to transplantation

  12. Different HLA Alleles Present Different Peptides Different HLA alleles to preferentially present different peptides from the same protein • Estimated that 5% of all T cells are alloreactive • T cells responding to an entirely new repertoire of peptides presented on donor HLA • Most of these peptides when presented on donor HLA are recognized as foreign because they have not been tolerized in the thymus – • DIRECT ANTIGEN RECOGNITION Klein et. al., NEJM. 2000

  13. Indirect Antigen Recognition Peptides derived from donor HLA presented to recipient T cells by recipient HLA This type of antigen presentation is the same way all adaptive immune responses are initiated

  14. Semi-Direct Antigen Recognition intact donor HLA presented to recipient T cells by recipient APC Donor HLA is passively acquired on a membrane-patch from donor cells What recipient alloreactive T cells see in this type of antigen presentation is exactly the same as in Direct Antigen Recognition

  15. Types of transplant graft rejection All rejection can be split into two basic types: Antibody-mediated rejection (ABMR) - Hyperacute rejection Acute - Early ‘Chronic’ - Late T-cell mediated rejection (TCMR) Both can occur simultaneously – Mixed ABMR and TCMR

  16. Allo-ag: B cell’s point of view To B cells/ antibody, alloantigen = intact proteins, not peptides Antibodies recognize mismatched structures on the surface of the HLA molecule (ie. epitopes on the intact HLA molecule): Many of the commonly observed HLA ab specificities are focused on “hot spots” (epitopes) that are accessible on the outermost parts of the HLA molecules Top view of HLA class I

  17. HLA Abs are Generated Against Non-self Epitopes Donor: B7 B8 Recipient: B8 B52 Non-donor: B27 B81

  18. THE REJECTION PROCESS

  19. Allograft rejection T cell mediated rejection Donor and recipient APCs move to 2ry lymphoid organs APCs meet T cells in lymphoid organs T cell activation T cells provide help to B cells Development of plasma cells Y Effector T cells home to graft Antibody mediated rejection Plasma cells home to bone marrow HLA Antibody production Y Y Y HLA Antibody enters the blood and reaches the graft Y Y Y Y Y T cell & monocyte infiltrate

  20. Types of transplant graft rejection All rejection can be split into two basic types: Antibody-mediated rejection (AbMR) - Hyperacute rejection Acute - Early ‘Chronic’ - Late T-cell mediated rejection (TCMR) Both can occur simultaneously – Mixed AbMR and TCMR

  21. Events in the alloimmune response 1. Kidney response to injury • The injury to the transplant incurred by the surgery and cold ischemia/reperfusion leads to: • activation of endothelium – facilitates adherence and extravasation of recipient inflammatory cells • activation of donor antigen presenting cells (APCs) – production of proinflammatory cytokines and chemokines to promote inflammation • recruitment and activation of recipient APCs Donor APCs Recipient APCs

  22. Events in the allograft response 2. Recipient and donor APCs move to lymphoid organs Secondary lymphoid organs (SLO’s) (lymph nodes, spleen) The APC activation program create changes in APC trafficking patterns allowing for migration to SLO’s ALL ADAPTIVE IMMUNE RESPONSES BEGIN IN SLO’s

  23. Immunologic Mechanisms of TCMR – when does the damage start? Kidney epithelial function begins to deteriorate as early as Day 2 post-transplant, well before tubulitis is observed: Slc = solute carrier transcripts Einecke et. al., Am. J. Transpl. 2007

  24. Immunologic Mechanisms of TCMR – what cells are where and when T cells are the first infiltrates that enter the allograft in the perivascular space followed by macrophages T cell/ macrophage infiltrates increase in the peritubular space 2 days following entry into the allograft Einecke et. al., Am. J. Transpl. 2009

  25. Immunologic Mechanisms of TCMR – is cytotoxicity required? Kidney allografts undergo equal amount of damage in the absence of the major cytotoxic mechanisms: Kayser et. al., Am. J. Transpl. 2008

  26. Effector T cell function: DTH-like response by CD4+/CD8+ T cells The delayed type hypersensitivity (DTH) response: The most effective effector function of T cells Gives responding macrophages a very cytotoxic phenotype Requires IFN-g produced by effector T cells (CD4+ AND/OR CD8+) CD4+/ CD8+ T cell Kuby, Immunology, 6th Ed, 2007

  27. The Current Model of TCMR Response to injury/ Immune surveillance Effector/ effector memory T cell (CD4 or CD8) Response to injury Macrophage/DC - APC Epithelium

  28. The current model of TCMR Effector/ effector memory T cell (CD4 or CD8) IFN-g, LT, TNF IL-12, IL-18, etc Antigen presentation, Increase inflammation by cytokine production DTH response Macrophage/DC - APC Epithelium

  29. The current model of TCMR Effector/ effector memory T cell (CD4 or CD8) Macrophage/DC - APC Epithelium Dedifferentiation: Loss of mass, polarity, cadherins, function; nephron shutdown, little apoptosis IFN-g, LT, TNF IL-12, IL-18, etc Antigen presentation, Increased inflammation by cytokine production DTH response

  30. Mechanism of AbMR Pathophysiology Mechanism is similar between all types of AbMR (hyperacute AbMR is depicted in the figure below): Chronic active AbMR shows a slower process of graft damage but focuses on the same target as hyperacute/ acute (microvascular endothelium) Kuby, Immunology, 6th Ed, 2007

  31. AbMR and DSA AbMR requires DSA in the recipient’s serum – 1st criteria for diagnosis Usual associations of DSA and type of AbMR: Pre-existing DSA can be detected by the HLA laboratory

  32. THE EFFECTS OF COMPLEMENT-FIXING DSA ON ALLOGRAFT SURVIVAL Patients with complement-fixing DSA show an increased risk for graft loss: Loupy, Lefaucheur, et. al., NEJM 369: 1215, 2013

  33. Ab effector functions: IgG subclasses IgG subclasses differ the most primarily at the hinge region which dictates function: Kuby, Immunology, 6th Ed, 2007

  34. Ab effector functions: IgG subclasses

  35. POTENTIAL EFFECTOR MECHANISMS The scenarios are different depending on the subclass of IgG Non-complement fixing IgG’s (IgG2, IgG4): Monocyte/ macrophage Monocyte/ macrophage Lytic enzymes, ROS’s FcR FcR Endothelium

  36. POTENTIAL EFFECTOR MECHANISMS proinflamm. cytokines, Lytic enzymes, ROS’s Monocyte/ macrophage NK cell The scenarios are different depending on the subclass of IgG Complement fixing DSA IgG1/IgG3: C’ R’s C’ products FcR’s IFN-g ADCC? ADCC? ADCC? Endothelium Hidalgo L, 2013

  37. Minimizing the risk for rejection: So why not HLA match every donor? • Not enough donors for all of the patients who need a transplant • Many patients die waiting for a donor • Good graft survival is often possible without matching using modern immunosupression therapies

  38. In Search of Transplant Tolerance Def. a durable state of antigen-specific unresponsiveness, induced by exposure to antigen, in a patient who is otherwise fully immunologically competent Very successful in hundreds in animal models of transplantation but very limited success in human transplantation Why? • all animal models tested all have a ‘naïve’ immune system, human transplant rejection is generally mediated by memory cells • cellular immunity is the only arm of the immune system examined, humoral immunity is often under-represented and ignored

  39. Xenotransplantation Promising, but controversial and unlikely to be applicable in the near future Better to meet the demand? Nonhuman primates (concordant) - have not been particularly successful, and does not address organ shortage Transgenic pigs (discordant): - organs are similar size and structure being engineered to have human antigens and can be bred in large numbers and under controlled conditions - Aim is to prevent hyperacute rejection of xenografts

  40. Xenotransplantation Problems: - graft survival is poor (<30 days in animal studies) - risk of zoonosis? development of new pathogens? - Incomplete understanding of how a human immune system would deal with an organ where MHC molecules are not recognized by any receptors

  41. QUESTIONS???

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