Download transplantation

Bo Gao, Ph.D.
Email: [email protected]
Tel: 54237379
DEPARTMENT OF IMMUNOLOGY
INSTITUTE FOR IMMUNOBIOLOGY
2010-6-28
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Transplantation
is a Dream?
• Dream of Paranoia
• Dream of excellent surgeon who
•
wants to excel himself.
Dream of excellent scientist who
believe nothing is impossible.
2
Can you imagine?
Can you imagine?
Can you imagine?
3
Contents:
Introduction
Immunologic Basis of Allograft Rejection
Classification and Effector Mechanisms of allograft
rejection
Prevention and Treatment of Allograft Rejection
Xenotransplantation
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Introduction
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Transplantation: the process of taking cells,
tissues, or organs called a graft (transplant),
from one part of individual and placing them
into another (usually different individual).
Donor: the individual who provides the
graft.
Recipient or host: the individual who
receives the graft.
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Inbred mouse strains - all genes are identical
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The cells of allograft will
express alloantigens which
are recognized as foreign
by the recipient.
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A xenograft is generally rapidly rejected by the recipient.
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Experimental kidney transplantation -1912
Nobel Prize in Physiology or Medicine
1912
• Alexis Carrel (France)
• Work on vascular suture
and the transplantation of
blood vessels and organs
Great events in history of transplantation
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Medawar (1945): the graft reaction is an immunity
phenomenon
Nobel Prize in Physiology or Medicine
1960
• Peter Brian Medawar (1/2)
• 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
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Discovery of MHC
Nobel Prize in Physiology or Medicine
1980
• George D. Snell (1/3), Jean Dausset (1/3)
• Discoveries concerning genetically
determined structures on the cell surface
that regulate immunological reactions
– H-genes (histocompatibility genes), H-2 gene
– Human leukocyte antigens (HLA) ----MHC
Great events in history of transplantation
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1954 First long-term successful RT(Twin)
Nobel Prize in Physiology or Medicine
1990
• Joseph E. Murray (1/2)
• 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
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Discovery of Immunosuppressant drug
Nobel Prize in Physiology or Medicine
1988
• Gertrude B. Elion (1/3) , George H. Hitchings (1/3)
• Discoveries of important principles for drug
treatment
– Immunosuppressant drug (The first cytotoxic drugs)
----- azathioprine
Great events in history of transplantation
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 Today, kidney, pancreas, heart, lung,
liver, bone marrow, and cornea
transplantations
are
performed
among non-identical individuals with
ever
increasing
frequency
and
success.
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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
ACCEPTED
Skin from an inbred mouse grafted onto the same strain of mouse
REJECTED
Skin from an inbred mouse grafted onto a different strain of mouse
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Immunological basis of graft rejection
• Grafts rejection is a kind of specific
immune response
– Specificity
– Immune memory
• Grafts rejection
– First set rejection
– Second set rejection
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Immunological basis of graft rejection
Primary rejection of
strain skin
e.g. 10 days
Transfer lymphocytes
from primed mouse
Lyc
Naïve mouse
Transplant rejection is due to an antigenspecific immune response with
immunological memory
6 months
Secondary rejection of
strain skin
e.g. 3 days
Primary rejection of
strain skin
e.g. 10 days
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Immunologic Basis of
Allograft Rejection
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I. Alloantigens
Major histocompatibility antigens
(MHC molecules)
Minor histocompatibility antigens
Other alloantigens
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1. Major histocompatibility antigens
Main antigens of grafts rejection
Difference of HLA types is the main
cause of human grafts rejection
Cause fast and strong rejection
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2. Minor histocompatibility antigens
Also cause grafts rejection, but slow
and weak
Mouse H-Y antigens encoded by Y
chromosome
HA-1～HA-5 linked with non-Y
chromosome
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3. Other alloantigens
Human ABO blood group antigens
Some tissue specific antigens
Skin＞kidney＞heart＞pancreas ＞liver
VEC antigen (vascular endothelial cell)
SK antigen
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Alloantigens elicit both cell-mediated and
humoral immune responses, eventually
leading to the disruption of grafts.
Why alloantigens can elicit strong rejection
reactions ?
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T cells of the recipient recognize the allogenetic
MHC molecules
Many T cells can recognize allogeneic MHC
molecules.
10-5-10-4 of specific T cells recognize conventional
antigens.
1%-10% of T cells recognize allogeneic MHC
molecules.
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T cells of the recipient recognize the allogeneic
MHC molecules
Direct Recognition
Indirect Recognition
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Direct Recognition
T cell recognizes an intact allogeneic MHC
molecule on graft.
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Indirect recognition
 Uptake and presentation of allogeneic donor MHC
molecules by recipient APC in “normal way”
 Recognition by T cells like conventional foreign
antigens
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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
Roles in rejection
Acute rejection
Chronic rejection
Degree of rejection
Vigorous
Weak
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As mentioned above, alloreactive T cells in
the recipient can be activated by both
pathways, and these T cells will migrate into
the graft.
What role
will these activated T
lymphocytes play in the rejection response?
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Role of CD4＋T cells in the rejection response
Activated CD4+T by direct and indirect recognition
CK secretion
MΦ activation and recruitment
Damage grafts by reactions that resemble
delayed-type hypersensitivity (DTH)
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Role of CD8＋T cells in the rejection response
Activated CD8+T by direct recognition can
directly Kill the graft cells, which express the
allogeneic calss I MHC molecules.
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Humoral immunity in rejection response
Important role in hyperacute rejection
(Preformed antibodies)
Complements activation
Antibody-dependent cellular cytotoxicity
(ADCC)
Opsonization
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Role of NK cells
• KIR can’t recognize allogeneic MHC on
graft
• CKs secreted by activated Th cells can
promote NK activation
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Classification and Effector
Mechanisms of Allograft
Rejection
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Classification of Allograft Rejection
Host versus graft reaction (HVGR)
Conventional organ transplantation
Graft versus host reaction (GVHR)
Bone marrow transplantation
Immune cells transplantation
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I. Host versus graft reaction (HVGR)
 Hyperacute rejection
 Acute rejection
 Chronic rejection
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1. Hyperacute rejection
Occurrence time
– Occurs within minutes to hours after host
blood vessels are anastomosed to graft
vessels
Pathology
– Thrombotic occlusion of the
vasculature
– Ischemia, denaturation, necrosis
graft
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1. Hyperacute rejection
Mechanisms
– Preformed antibodies
• Antibody against ABO blood type
antigen
• Antibody against VEC antigen
• Antibody against HLA antigen
– Complement activation
• Endothelial cell damage
– Platelets activation
• Thrombosis, vascular occlusion, ischemic
damage
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1. Hyperacute rejection
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1. Hyperacute rejection
 Hyperacute rejection of a kidney allograft with
endothelial damage, platelet and thrombin thrombi,
and early neutrophil infiltration in a glomerulus.
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2. Acute rejection
Occurrence time
 Occurs within days to 2 weeks after
transplantation, 80-90% of cases occur within 1
month.
Pathology
 Acute rejection is a process of vascular and
parenchymal injury mediated by T cells and
antibodies.
 CD4+ T cells , CD8+ T cells and antibodies may
contribute to acute rejection.
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2. Acute rejection
Mechanisms
Parenchymal cell damage
DTH-like reaction mediated by
CD4+Th1
Killing of graft cells by CD8+Tc
Vasculitis
Antibodies can also mediate acute rejection if
a graft recipient mounts a humoral immune
response to vessel wall antigens.
The antibodies that are produced bind to the
vessel wall and activate complement.
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2. Acute rejection
Acute rejection of a kidney with inflammatory cells
in the interstitium and between epithelial cells of the
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tubules.
3. Chronic rejection
Occurrence time
– Develops months or years after acute
rejection reactions have subsided
Pathology
– Fibrosis and vascular abnormalities with loss
of graft function
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3. Chronic rejection
Mechanisms
– Not clear
– Extension and results of cell necrosis in
acute rejection
– Chronic inflammation mediated by CD4+T
cell/MΦ
– Organ degeneration induced by non
immune factors
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1.Macrophage-T cell mediated
2. Chronic DTH reaction
injury of vessel wall
3. Proliferation of smooth muscle cell and luminal
occlusion
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Kidney Transplantation----Graft Rejection
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II.Graft versus host reaction (GVHR)
Graft versus host reaction (GVHR)
– Allogeneic
bone
marrow
transplantation
– Rejection to host alloantigens
– Mediated by immune competent cells
in bone marrow
Graft versus host disease (GVHD)
A disease caused by GVHR,
which can damage the host
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II.Graft versus host reaction (GVHR)
 Graft versus host
disease
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II.Graft versus host reaction (GVHR)
Conditions
Enough immune competent cells in
grafts
Immunocompromised host
Histocompatability
between host and graft
differences
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II.Graft versus host reaction (GVHR)
Bone marrow transplantation
Thymus transplantation
Spleen transplantation
Blood transfusion of neonate
 In most cases the reaction is
directed
against
minor
histocompatibility antigens of the host.
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1. Acute GVHD
Endothelial cell death in the skin, liver,
and gastrointestinal tract
Rash, jaundice, diarrhea,
gastrointestinal hemorrhage
Mediated by mature T cells in the grafts
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 Acute graft-versus-host reaction with
vivid palmar erythema
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2. Chronic GVHD
Fibrosis and atrophy of one or more of
the organs without evidence of acute
cell death.
Eventually complete dysfunction of
the affected organ and may be fatal.
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Prevention and Therapy of
Allograft Rejection
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• Tissue Typing
• Immunosuppressive Therapy
• Induction of Immune Tolerance
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I. Tissue Typing
• ABO and Rh blood typing
• Crossmatching (Preformed antibodies)
• HLA typing
– HLA-A and HLA-B
– HLA-DR
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II. Immunosuppressive Therapy
• Cyclosporine(CsA), FK506
– Inhibit NFAT transcription factor
• Azathioprine, Cyclophosphamide
– Block the proliferation of lymphocytes
• Ab against T cell surface molecules
– Anti-CD3 mAb----Deplete T cells
• Anti-inflammatory agents
– Corticosteroids----Block the synthesis and
secretion of cytokines
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Removal
of T cells from marrow graft
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III. Induction of Immune
Tolerance
• Inhibition of T cell activation
– Soluble MHC molecules
– CTLA4-Ig
– Anti-IL2R mAb
• Th2 cytokines
– Anti-TNF-α，Anti-IL-2，Anti-IFN-γ mAb
• Microchimerism
– The presence of a small number of cells of
donor, genetically distinct from those of the
host individual
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Part IV
Xenotransplantation
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• Lack of organs for transplantation
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From which animals are we able to
transplant organs
1. The Chimpanzee:
Its DNA sequence
differs from ours by
only 2%
2. The Baboon:
Its organs are too
small for a large
adult human
3. The Pig:
Surprisingly similar
to our anatomy and
physiology
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• Hyperacute xenograft rejection (HXR)
– Human anti-pig nature Abs reactive with
Galα1,3Gal
– Construct transgenic pigs expressing
human proteins that inhibit complement
activation
• Delayed xenograft rejection (DXR)
– Acute vascular rejection
– Incompletely understood
• T cell-mediated xenograft rejection
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