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Objectives

Transplantation Immunology

Laura Stacy March 22, 2006

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

Introduction The Immunology of Allogeneic Transplantation

Recognition of Alloantigens Activation of Alloreactive T Cells and Rejection

Outline

Introduction

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

Effector Mechanisms of Allograft Rejection

Hyperacute Rejection Acute Rejection Chronic Rejection

Xenogeneic Transplantation Blood Transfusion Bone Marrow Transplantation

Graft vs. Host Disease

Immunologic Analysis

Terms

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

First- and Second-set Allograft Rejection FirstSecond-

Figure 16.1

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The Immunology of Allogeneic Transplantation

Alloantigens elicit both cell-mediated and cellhumoral 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) co-

Recognition of Alloantigens

Direct Presentation

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

Indirect Presentation

Donor MHC is processed and presented by recipient APC Basically, donor MHC molecule is handled like any other foreign antigen

Direct and Indirect Recognition

Molecular Basis of Direct Recognition

Figure 16-4 16-

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 recipient' (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

Damage graft by reactions similar to DTH

CD8+ cells activated by direct pathway kill nucleated cells in the graft CD8+ cells activated by the indirect pathway are self MHC-restricted MHC-

2

Effector Mechanisms of Allograft Rejection

Hyperacute Rejection Acute Rejection Chronic Rejection

Hyperacute Rejection

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

Hyperacute Rejection: the early days

Mediated by pre-existing IgM alloantibodies preAntibodies come from carbohydrate antigens expressed by bacteria in intestinal flora

ABO blood group antigens

Hyperacute Rejection: Today

Mediated by IgG antibodies directed against protein alloantigens Antibodies generally arise from

Past blood transfusion Multiple pregnancies Previous transplantation

Not really a problem anymore

Hyperacute Rejection

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 Incidence is high (30%) for the first 90 days

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

3

Acute Rejection

Heart Kidney Lung Liver

Chronic Rejection

Occurs in most solid organ transplants

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

Characterized by fibrosis and vascular abnormalities with loss of graft function over a prolonged period (Abbas 381)

Chronic Rejection

Types of Rejection

Acute Rejection: CD4 controlled CD8 Rejection:

mediated (8-11 days) (8-

Hyperacute Rejection: pre-existing Rejection: preantibodies to donor tissue (7 min)

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

Chronic Rejection: Mixed CD4 and antibody Rejection: ­ "DTH like" (3 m to 10 years) like" Xenograft Rejection: pre-existing antibodies Rejection: preto donor tissue (7 min)

Xenogeneic Transplantation

Most Common Transplantation -Blood TransfusionTransfusion-

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

Transfuse

Not transfused

4

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

Graft vs. Host Disease

Caused by the reaction of grafted mature T-cells Tin the marrow inoculum with alloantigens of the host Acute GVHD

Characterized by epithelial cell death in the skin, GI tract, and liver

Rescue procedure for hemopoietic reconstitution subsequent to cancer chemo- or chemoradio- therapy radio-

Chronic GVHD

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 endHeart Association of class III or IV, ejection fractions of <20%, maximal oxygen consumption of (VO2) <14 ml/kg/min, and expected 1-year life expectancy of <50%. 1-

Heart Transplantation

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

5

Transplantation

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

Pancreas Transplantation

Graft survival is 72% at one-year and this oneis 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.

Immunologic Analysis

HLA Tissue Typing Cytoscreen Cross Match

Questions?

6

Information

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