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Transplantation Immunology. Laura Stacy March 22, 2006. Objectives. Name the different types of grafts Distinguish among the first-set, second-set, and chronic rejection Differentiate between host vs. graft rejection Describe serologic tests used for transplantation

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transplantation immunology

Transplantation Immunology

Laura Stacy

March 22, 2006

objectives
Objectives
  • Name the different types of grafts
  • Distinguish among the first-set, second-set, and chronic 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
outline
Outline
  • Introduction
  • The Immunology of Allogeneic Transplantation
    • Recognition of Alloantigens
    • Activation of Alloreactive T Cells and Rejection
  • Effector Mechanisms of Allograft Rejection
    • Hyperacute Rejection
    • Acute Rejection
    • Chronic Rejection
  • Xenogeneic Transplantation
  • Blood Transfusion
  • Bone Marrow Transplantation
    • Graft vs. Host Disease
  • Immunologic Analysis
introduction
Introduction
  • A major limitation to the success of transplantation is the immune response of the recipient to the donor tissue. (Abbas pg 369)
terms
Terms
  • Autologous graft
  • Syngeneic graft
  • Allogeneic graft
  • Xenogeneic graft
  • Alloantigens
  • Xenoantigens
  • Alloreactive
  • xenoreactive
the immunology of allogeneic transplantation
The Immunology of Allogeneic Transplantation
  • 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 alloantigens
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
activation of alloreactive t cells and rejection of allografts
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)
  • 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+ 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
effector mechanisms of allograft rejection
Effector Mechanisms of Allograft Rejection
  • Hyperacute Rejection
  • Acute Rejection
  • Chronic Rejection
hyperacute rejection
Hyperacute Rejection
  • Characterized by thrombotic occlusion of the graft
  • Begins within minutes or hours after anastamosis
  • Pre-existing antibodies in the host circulation bind to donor endothelial antigens
  • Activates Complement Cascade
  • Xenograft Response
hyperacute rejection the early days
Hyperacute Rejection: the early days
  • Mediated by pre-existing IgM alloantibodies
  • Antibodies come from carbohydrate antigens expressed by bacteria in intestinal flora
    • ABO blood group antigens
  • Not really a problem anymore
hyperacute rejection today
Hyperacute Rejection: Today
  • Mediated by IgG antibodies directed against protein alloantigens
  • Antibodies generally arise from
    • Past blood transfusion
    • Multiple pregnancies
    • Previous transplantation
hyperacute rejection17
Hyperacute Rejection

1. Preformed Ab, 2. complement activation,

3. neutrophil margination, 4. inflammation,

5. Thrombosis formation

acute 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
acute rejection19
Acute Rejection
  • T-cell, macrophage and Ab mediated,
  • myocyte and endothelial damage,
  • Inflammation
chronic rejection
Chronic Rejection
  • Occurs in most solid organ transplants
    • Heart
    • Kidney
    • Lung
    • Liver
  • Characterized by fibrosis and vascular abnormalities with loss of graft function over a prolonged period (Abbas 381)
chronic rejection21
Chronic Rejection
  • Macrophage – T cell mediated
  • Concentric medial hyperplasia
  • Chronic DTH reaction
slide22

Types of Rejection

  • Acute Rejection: CD4 controlled CD8 mediated (8-11 days)
  • Hyperacute Rejection: pre-existing antibodies to donor tissue (7 min)
  • Chronic Rejection: Mixed CD4 and antibody – ”DTH like” (3 m to 10 years)
  • Xenograft Rejection: pre-existing antibodies to donor tissue (7 min)
xenogeneic transplantation
Xenogeneic Transplantation
  • A major barrier to xenogeneic transplantation is the presence of natural antibodies that cause hyperacute rejection. (Abbas pg 386)
slide25

Question

Why are antibodies normally formed in response to ABO blood groups?

  • Due to prior exposure to blood
  • Maternal exposure
  • Gut flora
  • Plant pollen
slide26

Question

Why are antibodies normally formed in response to ABO blood groups?

  • Prior exposure to blood
  • Maternal exposure
  • Gut flora
  • Plant pollen
bone marrow transplantation
Bone Marrow Transplantation
  • Rescue procedure for hemopoietic reconstitution subsequent to cancer chemo- or radio- therapy
graft vs host disease
Graft vs. Host Disease
  • Caused by the reaction of grafted mature T-cells in the marrow inoculum with alloantigens of the host
  • Acute GVHD
    • Characterized by epithelial cell death in the skin, GI tract, and liver
  • Chronic GVHD
    • Characterized by atrophy and fibrosis of one or more of these same target organs as well as the lungs
slide29

Heart Transplantation

  • 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%,
  • maximal oxygen consumption of (VO2) <14 ml/kg/min, and
  • expected 1-year life expectancy of <50%.
slide30

Heart Transplantation

  • Survival is 80% at five years but at five year 50% also have coronary vascular disease due to chronic rejection.
slide31

Transplantation

  • Kidney25,000 patients are waiting for kidney transplantation
  • savings in three years compared to the cost of three years of renal dialysis.
  • LiverOne-year survival exceeds 75% and five-year is 70%.
slide32

Pancreas Transplantation

  • 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.
immunologic analysis
Immunologic Analysis
  • HLA Tissue Typing
  • Cytoscreen
  • Cross Match