Transplantation Immunology Laura Stacy March 22, 2006

Objectives Name the different types of grafts Name the different types of grafts Distinguish among the first-set, second-set, and chronic rejection Distinguish among the first-set, second-set, and chronic rejection Differentiate between host vs. graft rejection Differentiate between host vs. graft rejection Describe serologic tests used for transplantation Describe serologic tests used for transplantation Understand the molecular basis of immune response Understand the molecular basis of immune response Appreciate the different tissues and organs that can be transplanted Appreciate the different tissues and organs that can be transplanted

Outline Introduction Introduction The Immunology of Allogeneic Transplantation The Immunology of Allogeneic Transplantation Recognition of Alloantigens Recognition of Alloantigens Activation of Alloreactive T Cells and Rejection Activation of Alloreactive T Cells and Rejection Effector Mechanisms of Allograft Rejection Effector Mechanisms of Allograft Rejection Hyperacute Rejection Hyperacute Rejection Acute Rejection Acute Rejection Chronic Rejection Chronic Rejection Xenogeneic Transplantation Xenogeneic Transplantation Blood Transfusion Blood Transfusion Bone Marrow Transplantation Bone Marrow Transplantation Graft vs. Host Disease Graft vs. Host Disease Immunologic Analysis Immunologic Analysis

Introduction A major limitation to the success of transplantation is the immune response of the recipient to the donor tissue. (Abbas pg 369) A major limitation to the success of transplantation is the immune response of the recipient to the donor tissue. (Abbas pg 369)

Terms Autologous graft Autologous graft Syngeneic graft Syngeneic graft Allogeneic graft Allogeneic graft Xenogeneic graft Xenogeneic graft Alloantigens Alloantigens Xenoantigens Xenoantigens Alloreactive Alloreactive xenoreactive xenoreactive

First- and Second-set Allograft Rejection Figure 16.1

The Immunology of Allogeneic Transplantation Alloantigens elicit both cell-mediated and humoral immune responses. (Abbas pg 371) Alloantigens elicit both cell-mediated and humoral immune responses. (Abbas pg 371) Recognition of transplanted cells that are self or foreign is determined by polymorphic genes that are inherited from both parents and are expressed co-dominantly. (Abbas pg 371) Recognition of transplanted cells that are self or foreign is determined by polymorphic genes that are inherited from both parents and are expressed co-dominantly. (Abbas pg 371)

Recognition of Alloantigens Direct Presentation Direct Presentation Recognition of an intact MHC molecule displayed by donor APC in the graft Recognition of an intact MHC molecule displayed by donor APC in the graft Basically, self MHC molecule recognizes the structure of an intact allogeneic MHC molecule Basically, self MHC molecule recognizes the structure of an intact allogeneic MHC molecule Indirect Presentation Indirect Presentation Donor MHC is processed and presented by recipient APC Donor MHC is processed and presented by recipient APC Basically, donor MHC molecule is handled like any other foreign antigen Basically, donor MHC molecule is handled like any other foreign antigen

Molecular Basis of Direct Recognition Figure 16-4

Direct and Indirect Recognition Figure 16-3

Activation of Alloreactive T cells and Rejection of Allografts Donor APCs migrate to regional lymph nodes and are recognized by the recipient’s T cells (Abbas pg 375) Donor APCs migrate to regional lymph nodes and are recognized by the recipient’s T cells (Abbas pg 375) Alloreactive T cells in the recipient may be activated by both pathways, and they migrate into the graft and cause graft rejection (Abbas pg 375) Alloreactive T cells in the recipient may be activated by both pathways, and they migrate into the graft and cause graft rejection (Abbas pg 375)

CD4 + and CD8 + CD4 + differentiate into cytokine producing effector cells CD4 + differentiate into cytokine producing effector cells Damage graft by reactions similar to DTH Damage graft by reactions similar to DTH CD8 + cells activated by direct pathway kill nucleated cells in the graft CD8 + cells activated by direct pathway kill nucleated cells in the graft CD8 + cells activated by the indirect pathway are self MHC-restricted CD8 + cells activated by the indirect pathway are self MHC-restricted

Effector Mechanisms of Allograft Rejection Hyperacute Rejection Hyperacute Rejection Acute Rejection Acute Rejection Chronic Rejection Chronic Rejection

Hyperacute Rejection Characterized by thrombotic occlusion of the graft Characterized by thrombotic occlusion of the graft Begins within minutes or hours after anastamosis Begins within minutes or hours after anastamosis Pre-existing antibodies in the host circulation bind to donor endothelial antigens Pre-existing antibodies in the host circulation bind to donor endothelial antigens Activates Complement Cascade Activates Complement Cascade Xenograft Response Xenograft Response

Hyperacute Rejection: the early days Mediated by pre-existing IgM alloantibodies Mediated by pre-existing IgM alloantibodies Antibodies come from carbohydrate antigens expressed by bacteria in intestinal flora Antibodies come from carbohydrate antigens expressed by bacteria in intestinal flora ABO blood group antigens ABO blood group antigens Not really a problem anymore Not really a problem anymore

Hyperacute Rejection: Today Mediated by IgG antibodies directed against protein alloantigens Mediated by IgG antibodies directed against protein alloantigens Antibodies generally arise from Antibodies generally arise from Past blood transfusion Past blood transfusion Multiple pregnancies Multiple pregnancies Previous transplantation Previous transplantation

Hyperacute Rejection 1. Preformed Ab, 2. complement activation, 3. neutrophil margination, 4. inflammation, 5. Thrombosis formation

Acute Rejection Vascular and parenchymal injury mediated by T cells and antibodies that usually begin after the first week of transplantation if there is no immunosuppressant therapy Vascular and parenchymal injury mediated by T cells and antibodies that usually begin after the first week of transplantation if there is no immunosuppressant therapy Incidence is high (30%) for the first 90 days Incidence is high (30%) for the first 90 days

Acute Rejection 1.T-cell, macrophage and Ab mediated, 2.myocyte and endothelial damage, 3.Inflammation

Chronic Rejection Occurs in most solid organ transplants Occurs in most solid organ transplants Heart Heart Kidney Kidney Lung Lung Liver Liver Characterized by fibrosis and vascular abnormalities with loss of graft function over a prolonged period (Abbas 381) Characterized by fibrosis and vascular abnormalities with loss of graft function over a prolonged period (Abbas 381)

Chronic Rejection 1.Macrophage – T cell mediated 2.Concentric medial hyperplasia 3.Chronic DTH reaction

Types of Rejection Acute Rejection: CD4 controlled CD8 mediated (8-11 days) Acute Rejection: CD4 controlled CD8 mediated (8-11 days) Hyperacute Rejection: pre-existing antibodies to donor tissue (7 min) Hyperacute Rejection: pre-existing antibodies to donor tissue (7 min) Chronic Rejection: Mixed CD4 and antibody – ”DTH like” (3 m to 10 years) Chronic Rejection: Mixed CD4 and antibody – ”DTH like” (3 m to 10 years) Xenograft Rejection: pre-existing antibodies to donor tissue (7 min) Xenograft Rejection: pre-existing antibodies to donor tissue (7 min)

Xenogeneic Transplantation A major barrier to xenogeneic transplantation is the presence of natural antibodies that cause hyperacute rejection. (Abbas pg 386) A major barrier to xenogeneic transplantation is the presence of natural antibodies that cause hyperacute rejection. (Abbas pg 386)

Most Common Transplantation -Blood Transfusion- TransfuseNot transfused

Question Why are antibodies normally formed in response to ABO blood groups? 1.Due to prior exposure to blood 2.Maternal exposure 3.Gut flora 4.Plant pollen

Question Why are antibodies normally formed in response to ABO blood groups? 1. Prior exposure to blood 2. Maternal exposure 3. Gut flora 4. Plant pollen

Bone Marrow Transplantation Rescue procedure for hemopoietic reconstitution subsequent to cancer chemo- or radio- therapy Rescue procedure for hemopoietic reconstitution subsequent to cancer chemo- or radio- therapy

Graft vs. Host Disease Caused by the reaction of grafted mature T-cells in the marrow inoculum with alloantigens of the host Caused by the reaction of grafted mature T-cells in the marrow inoculum with alloantigens of the host Acute GVHD Acute GVHD Characterized by epithelial cell death in the skin, GI tract, and liver Characterized by epithelial cell death in the skin, GI tract, and liver Chronic GVHD Chronic GVHD Characterized by atrophy and fibrosis of one or more of these same target organs as well as the lungs Characterized by atrophy and fibrosis of one or more of these same target organs as well as the lungs

Heart Transplantation Heart transplantation is indicated for those in end-stage heart disease with a New York Heart Association of class III or IV, Heart transplantation is indicated for those in end-stage heart disease with a New York Heart Association of class III or IV, ejection fractions of <20%, ejection fractions of <20%, maximal oxygen consumption of (VO 2 ) <14 ml/kg/min, and maximal oxygen consumption of (VO 2 ) <14 ml/kg/min, and expected 1-year life expectancy of <50%. expected 1-year life expectancy of <50%.

Heart Transplantation Survival is 80% at five years but at five year 50% also have coronary vascular disease due to chronic rejection. Survival is 80% at five years but at five year 50% also have coronary vascular disease due to chronic rejection.

Transplantation Kidney 25,000 patients are waiting for kidney transplantation Kidney 25,000 patients are waiting for kidney transplantation savings in three years compared to the cost of three years of renal dialysis. savings in three years compared to the cost of three years of renal dialysis. Liver One-year survival exceeds 75% and five-year is 70%. Liver One-year survival exceeds 75% and five-year is 70%.

Pancreas Transplantation Graft survival is 72% at one-year and this is further improved if a kidney is transplanted simultaneously. Graft survival is 72% at one-year and this is further improved if a kidney is transplanted simultaneously. The overall goal of pancreas transplantation is to prevent the typical diabetic secondary complications: neuropathy, retinopathy, and cardiovascular disease. The overall goal of pancreas transplantation is to prevent the typical diabetic secondary complications: neuropathy, retinopathy, and cardiovascular disease.

Immunologic Analysis HLA Tissue Typing HLA Tissue Typing Cytoscreen Cytoscreen Cross Match Cross Match

Questions?