Transcript Transplantation Immunology

Transplantation
Immunology
Laura Stacy
March 22, 2006
Objectives
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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
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Introduction
The Immunology of Allogeneic Transplantation
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Effector Mechanisms of Allograft Rejection
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Hyperacute Rejection
Acute Rejection
Chronic Rejection
Xenogeneic Transplantation
Blood Transfusion
Bone Marrow Transplantation
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Recognition of Alloantigens
Activation of Alloreactive T Cells and Rejection
Graft vs. Host Disease
Immunologic Analysis
Introduction
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A major limitation to the success of
transplantation is the immune response of the
recipient to the donor tissue. (Abbas pg 369)
Terms
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Autologous graft
Syngeneic graft
Allogeneic graft
Xenogeneic graft
Alloantigens
Xenoantigens
Alloreactive
xenoreactive
First- and Second-set Allograft Rejection
Figure 16.1
The Immunology of Allogeneic
Transplantation
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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
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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
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Indirect Presentation
Donor MHC is processed and presented by recipient
APC
 Basically, donor MHC molecule is handled like any
other foreign antigen
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Molecular
Basis of
Direct
Recognition
Figure 16-4
Direct and Indirect Recognition
Figure 16-3
Activation of Alloreactive T cells and
Rejection of Allografts
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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)
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CD4
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CD4+ differentiate into cytokine producing
effector cells
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and
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CD8
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
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Hyperacute Rejection
Acute Rejection
Chronic Rejection
Hyperacute Rejection
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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
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Mediated by pre-existing IgM alloantibodies
Antibodies come from carbohydrate antigens
expressed by bacteria in intestinal flora
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ABO blood group antigens
Not really a problem anymore
Hyperacute Rejection: Today
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Mediated by IgG antibodies directed against
protein alloantigens
Antibodies generally arise from
Past blood transfusion
 Multiple pregnancies
 Previous transplantation
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Hyperacute Rejection
1. Preformed Ab, 2. complement activation,
3. neutrophil margination, 4. inflammation,
5. Thrombosis formation
Acute Rejection
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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 Rejection
1. T-cell, macrophage and Ab mediated,
2. myocyte and endothelial damage,
3. Inflammation
Chronic Rejection
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Occurs in most solid organ transplants
Heart
 Kidney
 Lung
 Liver
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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)
 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
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A major barrier to xenogeneic transplantation is
the presence of natural antibodies that cause
hyperacute rejection. (Abbas pg 386)
Most Common Transplantation
-Blood Transfusion-
Transfuse
Not 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
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Rescue procedure for hemopoietic
reconstitution subsequent to cancer chemo- or
radio- therapy
Graft vs. Host Disease
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Caused by the reaction of grafted mature T-cells
in the marrow inoculum with alloantigens of the
host
Acute GVHD
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Characterized by epithelial cell death in the skin, GI
tract, and liver
Chronic GVHD
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Characterized by atrophy and fibrosis of one or
more of these same target organs as well as the
lungs
Heart Transplantation
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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%.
Heart Transplantation
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Survival is 80% at five years but at five year
50% also have coronary vascular disease
due to chronic rejection.
Transplantation
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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
five-year is 70%.
Pancreas Transplantation
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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
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HLA Tissue Typing
Cytoscreen
Cross Match
Questions?