Immunology year Chapter 19 Transplantation Immunology

2006-7yearImmunology2 Contents Introduction Introduction Immunologic Basis of Allograft Rejection Immunologic Basis of Allograft Rejection Classification and Effector Mechanisms of allograft rejection Classification and Effector Mechanisms of allograft rejection Prevention and Treatment of Allograft Rejection Prevention and Treatment of Allograft Rejection Xenotransplantation Xenotransplantation

Immunology year Introduction

2006-7yearImmunology4 Conceptions Transplantation Transplantation Grafts Grafts Donors Donors Recipients or hosts Recipients or hosts Orthotopic transplantation Orthotopic transplantation Heterotopic transplantation Heterotopic transplantation

2006-7yearImmunology5 Nobel Prize in Physiology or Medicine 1912 Alexis Carrel (France) Alexis Carrel (France) Work on vascular suture and the transplantation of blood vessels and organs Work on vascular suture and the transplantation of blood vessels and organs Great events in history of transplantation

2006-7yearImmunology6 Nobel Prize in Physiology or Medicine 1960 Peter Brian Medawar (1/2) Peter Brian Medawar (1/2) Discovery of acquired immunological tolerance Discovery of acquired immunological tolerance – The graft reaction is an immunity phenomenon – 1950s, induced immunological tolerance to skin allografts in mice by neonatal injection of allogeneic cells Great events in history of transplantation

2006-7yearImmunology7 Nobel Prize in Physiology or Medicine 1990 Joseph E. Murray (1/2) Joseph E. Murray (1/2) Discoveries concerning organ transplantation in the treatment of human disease Discoveries concerning organ transplantation in the treatment of human disease – In 1954, the first successful human kidney transplant was performed between twins in Boston. – Transplants were possible in unrelated people if drugs were taken to suppress the body's immune reaction Great events in history of transplantation

2006-7yearImmunology8 Nobel Prize in Physiology or Medicine 1980 George D. Snell (1/3), Jean Dausset (1/3) George D. Snell (1/3), Jean Dausset (1/3) Discoveries concerning genetically determined structures on the cell surface that regulate immunological reactions Discoveries concerning genetically determined structures on the cell surface that regulate immunological reactions – H-genes (histocompatibility genes), H-2 gene – Human transplantation antigens (HLA) ----MHC Great events in history of transplantation

2006-7yearImmunology9 Nobel Prize in Physiology or Medicine 1988 Gertrude B. Elion (1/3), George H. Hitchings (1/3) Gertrude B. Elion (1/3), George H. Hitchings (1/3) Discoveries of important principles for drug treatment Discoveries of important principles for drug treatment – Immunosuppressant drug (The first cytotoxic drugs) azathioprine Great events in history of transplantation

2006-7yearImmunology10 Today, kidney, pancreas, heart, lung, liver, bone marrow, and cornea transplantations are performed among non-identical individuals with ever increasing frequency and success

2006-7yearImmunology11 Classification of grafts Autologous grafts (Autografts) Autologous grafts (Autografts) – Grafts transplanted from one part of the body to another in the same individual Syngeneic grafts (Isografts) Syngeneic grafts (Isografts) – Grafts transplanted between two genetically identical individuals of the same species Allogeneic grafts (Allografts) Allogeneic grafts (Allografts) – Grafts transplanted between two genetically different individuals of the same species Xenogeneic grafts (Xenografts) Xenogeneic grafts (Xenografts) – Grafts transplanted between individuals of different species

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Skin from an inbred mouse grafted onto the same strain of mouse Skin from an inbred mouse grafted onto a different strain of mouse ACCEPTED REJECTED Genetic basis of transplant rejection Inbred mouse strains - all genes are identical Transplantation of skin between strains showed that rejection or acceptance was dependent upon the genetics of each strain

2006-7yearImmunology14 6 months Transplant rejection is due to an antigen- specific immune response with immunological memory Immunological basis of graft rejection Primary rejection of strain skin e.g. 10 days Secondary rejection of strain skin e.g. 3 days Primary rejection of strain skin e.g. 10 days Naïve mouse Lyc Transfer lymphocytes from primed mouse

2006-7yearImmunology15 Grafts rejection is a kind of specific immune response Grafts rejection is a kind of specific immune response – Specificity – Immune memory Grafts rejection Grafts rejection – First set rejection – Second set rejection

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Immunology year Part one Immunologic Basis of Allograft Rejection

2006-7yearImmunology18 Major histocompatibility antigens (MHC molecules) Major histocompatibility antigens (MHC molecules) Minor histocompatibility antigens Minor histocompatibility antigens Other alloantigens Other alloantigens I. Transplantation antigens

2006-7yearImmunology19 1. Major histocompatibility antigens Main antigens of grafts rejection Main antigens of grafts rejection Cause fast and strong rejection Cause fast and strong rejection Difference of HLA types is the main cause of human grafts rejection Difference of HLA types is the main cause of human grafts rejection

2006-7yearImmunology20 2. Minor histocompatibility antigens Also cause grafts rejection, but slow and weak Also cause grafts rejection, but slow and weak Mouse H-Y antigens encoded by Y chromosome Mouse H-Y antigens encoded by Y chromosome HA-1 ～ HA-5 linked with non-Y chromosome HA-1 ～ HA-5 linked with non-Y chromosome

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2006-7yearImmunology22 3. Other alloantigens Human ABO blood group antigens Human ABO blood group antigens Some tissue specific antigens Some tissue specific antigens – Skin ＞ kidney ＞ heart ＞ pancreas ＞ liver – VEC antigen – SK antigen

2006-7yearImmunology23 Cell-mediated Immunity Cell-mediated Immunity Humoral Immunity Humoral Immunity Role of NK cells Role of NK cells II. Mechanism of allograft rejection

2006-7yearImmunology24 1. Cell-mediated Immunity Recipient's T cell-mediated cellular immune response against alloantigens on grafts Recipient's T cell-mediated cellular immune response against alloantigens on grafts

2006-7yearImmunology25 Molecular Mechanisms of Allogeneic Recognition ？T cells of the recipient recognize the allogenetic MHC molecules ？Many T cells can recognize allogenetic MHC molecules –1–1–1– of specific T cells recognize conventional antigens – 1– 1– 1– 1%-10% of T cells recognize allogenetic MHC molecules

2006-7yearImmunology26 ？ The recipient’ T cells recognize the allogenetic MHC molecules Direct Recognition Direct Recognition Indirect Recognition Indirect Recognition

2006-7yearImmunology27 Direct Recognition Recognition of an intact allogenetic MHC molecule displayed by donor APC in the graft Recognition of an intact allogenetic MHC molecule displayed by donor APC in the graft Cross recognition Cross recognition – An allogenetic MHC molecule with a bound peptide can mimic the determinant formed by a self MHC molecule plus foreign peptide – A cross-reaction of a normal TCR, which was selected to recognize a self MHC molecules plus foreign peptide, with an allogenetic MHC molecule plus peptide

2006-7yearImmunology28 Cross recognition Cross recognition

2006-7yearImmunology29 Passenger leukocytes Passenger leukocytes – Donor APCs that exist in grafts, such as DC, M Φ – Early phase of acute rejection ？ – Fast and strong ？

2006-7yearImmunology30 ？ Many T cells can recognize allogenetic MHC molecules Allogenetic MHC molecules (different residues) Allogenetic MHC molecules (different residues) Allogenetic MHC molecules–different peptides Allogenetic MHC molecules–different peptides All allogenetic MHC molecules on donor APC can be epitopes recognized by TCR All allogenetic MHC molecules on donor APC can be epitopes recognized by TCR

2006-7yearImmunology31 Indirect recognition Uptake and presentation of allogeneic donor MHC molecules by recipient APC in “normal way” Uptake and presentation of allogeneic donor MHC molecules by recipient APC in “normal way” Recognition by T cells like conventional foreign antigens Recognition by T cells like conventional foreign antigens

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2006-7yearImmunology33 Recipient T cell TCR Peptide Donor MHC molecule Donor APCRecipient APC Recipient MHC molecule Peptide from donor MHC molecule

2006-7yearImmunology34 Slow and weak Slow and weak Late phase of acute rejection and chronic rejection Late phase of acute rejection and chronic rejection Coordinated function with direct recognition in early phase of acute rejection Coordinated function with direct recognition in early phase of acute rejection

2006-7yearImmunology35 Difference between Direct Recognition and Indirect Recognition Direct Recognition Indirect Recognition Allogeneic MHC molecule Intact allogeneic MHC molecule Peptide of allogeneic MHC molecule APCs Recipient APCs are not necessary Recipient APCs Activated T cells CD4 ＋ T cells and/or CD8 ＋ T cells Roles in rejection Acute rejection Chronic rejection Degree of rejection VigorousWeak

2006-7yearImmunology36 Activated CD4 + T by direct and indirect recognition Activated CD4 + T by direct and indirect recognition – CK secretion – M Φ activation and recruitment Activated CD8 + T by direct recognition Activated CD8 + T by direct recognition – Kill the graft cells directly Activated CD8 + T by indirect recognition Activated CD8 + T by indirect recognition – Can not kill the graft cells directly Role of CD4 ＋ T cells and CD8 ＋ T cells

Immunology year

2006-7yearImmunology38 Role of CD4 ＋ T cells and CD8 ＋ T cells CD4 + TH 1 CD8 + CTL CD8 + preCTL

2006-7yearImmunology39 Important role in hyperacute rejection Important role in hyperacute rejection (Preformed antibodies) (Preformed antibodies) – Complements activation – ADCC – Opsonization Enhancing antibodies Enhancing antibodies /Blocking antibodies /Blocking antibodies 2. Humoral immunity

2006-7yearImmunology40 3.Role of NK cells KIR can’t recognize allogeneic MHC on graft KIR can’t recognize allogeneic MHC on graft CKs secreted by activated Th cells can promote NK activation CKs secreted by activated Th cells can promote NK activation

2006-7yearImmunology41 Inflammation lysis ADCC lysis IL2, IFN  TNF , NO 2 IL2, IL4, IL5 IL2, TNF , IFN  Rejection Mechanisms of graft rejection

Immunology year Part two Classification and Effector Mechanisms of Allograft Rejection

2006-7yearImmunology43 Host versus graft reaction (HVGR) Host versus graft reaction (HVGR) – Conventional organ transplantation Graft versus host reaction (GVHR) Graft versus host reaction (GVHR) – Bone marrow transplantation – Immune cells transplantation Classification of Allograft Rejection

2006-7yearImmunology44 I. Host versus graft reaction (HVGR) Hyperacute rejection Hyperacute rejection Acute rejection Acute rejection Chronic rejection Chronic rejection

2006-7yearImmunology45 Occurrence time Occurrence time – Occurs within minutes to hours after host blood vessels are anastomosed to graft vessels Pathology Pathology – Thrombotic occlusion of the graft vasculature – Ischemia, denaturation, necrosis 1. Hyperacute rejection

2006-7yearImmunology46 Mechanisms Mechanisms – Preformed antibodies Antibody against ABO blood type antigen Antibody against ABO blood type antigen Antibody against VEC antigen Antibody against VEC antigen Antibody against HLA antigen Antibody against HLA antigen

2006-7yearImmunology47 – Complement activation Endothelial cell damage Endothelial cell damage – Platelets activation Thrombosis, vascular occlusion, ischemic damage Thrombosis, vascular occlusion, ischemic damage

2006-7yearImmunology48 Hyperacute rejection of a kidney allograft with endothelial damage, platelet and thrombin thrombi, and early neutrophil infiltration in a glomerulus Hyperacute rejection of a kidney allograft with endothelial damage, platelet and thrombin thrombi, and early neutrophil infiltration in a glomerulus

2006-7yearImmunology49 Occurrence time Occurrence time – Occurs within days to 2 weeks after transplantation, 80-90% of cases occur within 1 month Pathology Pathology – Acute humoral rejection Acute vasculitis manifested mainly by endothelial cell damage Acute vasculitis manifested mainly by endothelial cell damage – Acute cellular rejection Parenchymal cell necrosis along with infiltration of lymphocytes and M Φ Parenchymal cell necrosis along with infiltration of lymphocytes and M Φ 2. Acute rejection

2006-7yearImmunology50 Mechanisms Mechanisms – Vasculitis IgG antibodies against alloantigens on endothelial cell IgG antibodies against alloantigens on endothelial cell CDC CDC – Parenchymal cell damage Delayed hypersensitivity mediated by CD4+Th1 Delayed hypersensitivity mediated by CD4+Th1 Killing of graft cells by CD8+Tc Killing of graft cells by CD8+Tc

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2006-7yearImmunology52 Acute rejection of a kidney with inflammatory cells in the interstitium and between epithelial cells of the tubules

2006-7yearImmunology53 Occurrence time Occurrence time – Develops months or years after acute rejection reactions have subsided Pathology Pathology – Fibrosis and vascular abnormalities with loss of graft function 3. Chronic rejection

2006-7yearImmunology54 Mechanisms Mechanisms – Not clear – Extension and results of cell necrosis in acute rejection – Chronic inflammation mediated by CD4+T cell/M Φ – Organ degeneration induced by non immune factors

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2006-7yearImmunology56 Kidney Transplantation----Graft Rejection

2006-7yearImmunology57 Chronic rejection in a kidney allograft with arteriosclerosis

2006-7yearImmunology58 II.Graft versus host reaction (GVHR) Graft versus host reaction (GVHR) Graft versus host reaction (GVHR) – Allogenetic bone marrow transplantation – Rejection to host alloantigens – Mediated by immune competent cells in bone marrow Graft versus host disease (GVHD) Graft versus host disease (GVHD) – A disease caused by GVHR, which can damage the host

2006-7yearImmunology59 Graft versus host disease Graft versus host disease

2006-7yearImmunology60 Graft versus host disease Graft versus host disease

2006-7yearImmunology61 Conditions Enough immune competent cells in grafts Enough immune competent cells in grafts Immunocompromised host Immunocompromised host Histocompatability differences between host and graft Histocompatability differences between host and graft

2006-7yearImmunology62 Bone marrow transplantation Bone marrow transplantation Thymus transplantation Thymus transplantation Spleen transplantation Spleen transplantation Blood transfusion of neonate Blood transfusion of neonate In most cases the reaction is directed against minor histocompatibility antigens of the host In most cases the reaction is directed against minor histocompatibility antigens of the host

2006-7yearImmunology63 1. Acute GVHD Endothelial cell death in the skin, liver, and gastrointestinal tract Endothelial cell death in the skin, liver, and gastrointestinal tract Rash, jaundice, diarrhea, gastrointestinal hemorrhage Rash, jaundice, diarrhea, gastrointestinal hemorrhage Mediated by mature T cells in the grafts Mediated by mature T cells in the grafts

2006-7yearImmunology64 Acute graft-versus-host reaction with vivid palmar erythema Acute graft-versus-host reaction with vivid palmar erythema

2006-7yearImmunology65 2. Chronic GVHD Fibrosis and atrophy of one or more of the organs Fibrosis and atrophy of one or more of the organs Eventually complete dysfunction of the affected organ Eventually complete dysfunction of the affected organ

2006-7yearImmunology66 Early, chronic graft-versus-host reaction with widespread, almost confluent hyperpigmented lichenoid papules and toxic epidermal necrosis-like appearance on knee Early, chronic graft-versus-host reaction with widespread, almost confluent hyperpigmented lichenoid papules and toxic epidermal necrosis-like appearance on knee Late, chronic graft-versus -host reaction with hyperpigmented sclerotic plaques on the back Late, chronic graft-versus -host reaction with hyperpigmented sclerotic plaques on the back

2006-7yearImmunology67 Both acute and chronic GVHD are commonly treated with intense immunosuppresion Both acute and chronic GVHD are commonly treated with intense immunosuppresion Uncertain Uncertain Fatal Fatal

Immunology year Part three Prevention and Therapy of Allograft Rejection

2006-7yearImmunology69 Tissue Typing Tissue Typing Immunosuppressive Therapy Immunosuppressive Therapy Induction of Immune Tolerance Induction of Immune Tolerance

2006-7yearImmunology70 I. Tissue Typing ABO and Rh blood typing ABO and Rh blood typing Crossmatching (Preformed antibodies) Crossmatching (Preformed antibodies) HLA typing HLA typing – HLA-A and HLA-B – HLA-DR

2006-7yearImmunology71 Laws of transplantation Laws of transplantation

2006-7yearImmunology72 II. Immunosuppressive Therapy Cyclosporine(CsA), FK506 Cyclosporine(CsA), FK506 – Inhibit NFAT transcription factor Azathioprine, Cyclophosphamide Azathioprine, Cyclophosphamide – Block the proliferation of lymphocytes Ab against T cell surface molecules Ab against T cell surface molecules – Anti-CD3 mAb----Deplete T cells Anti-inflammatory agents Anti-inflammatory agents – Corticosteroids----Block the synthesis and secretion of cytokines

2006-7yearImmunology73 Removal of T cells from marrow graft

2006-7yearImmunology74 III. Induction of Immune Tolerance Inhibition of T cell activation Inhibition of T cell activation – Soluble MHC molecules – CTLA4-Ig – Anti-IL2R mAb Th2 cytokines Th2 cytokines – Anti-TNF- α ， Anti-IL-2 ， Anti-IFN- γ mAb Microchimerism Microchimerism – The presence of a small number of cells of donor, genetically distinct from those of the host individual

Immunology year Part IV Xenotransplantation

2006-7yearImmunology76 Lack of organs for transplantation Lack of organs for transplantation Pig-human xenotransplantation Pig-human xenotransplantation Barrier Barrier

2006-7yearImmunology77 Hyperacute xenograft rejection (HXR) Hyperacute xenograft rejection (HXR) – Human anti-pig nature Abs reactive with Gal α 1,3Gal – Construct transgenic pigs expressing human proteins that inhibit complement activation Delayed xenograft rejection (DXR) Delayed xenograft rejection (DXR) – Acute vascular rejection – Incompletely understood T cell-mediated xenograft rejection T cell-mediated xenograft rejection