Chapter 19

Transplantation Immunology


 

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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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Conceptions

‡ Transplantation
‡ Grafts
‡ Donors
‡ Recipients or hosts
‡ Orthotopic transplantation
‡ Heterotopic transplantation


 

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_obel Prize in Physiology or Medicine
1912

‡ Alexis Carrel (France)

‡ Work on vascular suture
and the transplantation of
blood vessels and organs

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_obel Prize in Physiology or Medicine
1960

‡ Peter Brian Medawar (1/2)

‡ Discovery of acquired
immunological tolerance
å The graft reaction is an
immunity phenomenon
å 1950s, induced immunological
tolerance to skin allografts in
mice by neonatal injection of
allogeneic cells

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_obel Prize in Physiology or Medicine

1990
‡ Joseph E. Murray (1/2)
‡ Discoveries concerning
organ transplantation in the
treatment of human disease
å In 1954, the first successful
human kidney transplant was
performed between twins in
Boston.
å Transplants were possible in
unrelated people if drugs
were taken to suppress the
body's immune reaction

 


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 _obel 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
å H-genes (histocompatibility genes), H-
H-2 gene
å Human transplantation antigens (HLA) ----
----MHC
MHC

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_obel Prize in Physiology or Medicine
1988
‡ Gertrude B. Elion (1/3) , George H. Hitchings (1/3)
‡ Discoveries of important principles for drug
treatment
å Immunosuppressant drug (The first cytotoxic drugs)
----- azathioprine

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 Today, kidney, pancreas, heart,
lung, liver, bone marrow, and cornea
transplantations are performed
among non-
non-identical individuals with
ever increasing frequency and
success


 

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Classification of grafts
‡ Autologous grafts (Autografts)
å Grafts transplanted from one part of the body
to another in the same individual
‡ Syngeneic grafts (Isografts)
å Grafts transplanted between two genetically
identical individuals of the same species
‡ Allogeneic grafts (Allografts)
å Grafts transplanted between two genetically
different individuals of the same species
‡ Xenogeneic grafts (Xenografts)
å Grafts transplanted between individuals of
different species

 

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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

 Immunological basis of graft rejection

Primary rejection of
strain skin
e.g. 10 days
Transfer lymphocytes
from primed mouse  6 months

Secondary rejection of
strain skin
  
 e.g. 3 days

Primary rejection of
strain skin
Transplant rejection is due to an antigen-
e.g. 10 days
specific immune response with
immunological memory

 

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‡ Grafts rejection is a kind of specific
immune response
å Specificity
å Immune memory
‡ Grafts rejection
å First set rejection
å Second set rejection


 

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 Part one
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I. Transplantation antigens

‡ Major histocompatibility antigens

(MHC molecules)
‡ Minor histocompatibility antigens
‡ Other alloantigens


 

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1. Major histocompatibility antigens

‡ Main antigens of grafts rejection

‡ Cause fast and strong rejection
‡ Difference of HLA types is the main
cause of human grafts rejection


 

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2. Minor histocompatibility antigens

‡ Also cause grafts rejection, but slow

and weak
‡ Mouse H-
H-Y antigens encoded by Y
chromosome
‡ HA
HA--1ËHA
HA--5 linked with non
non--Y
chromosome


 

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3. Other alloantigens

‡ Human ABO blood group antigens

‡ Some tissue specific antigens
å Skin
Skinm
mkidney
kidneym
mheart
heartm
mpancreas mliver
å EC antigen
å SK antigen


 

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II. Mechanism of allograft
rejection
‡ Cell-
Cell-mediated Immunity
‡ Humoral Immunity
‡ Role of _K cells


 

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1. Cell-
Cell-mediated Immunity

‡ Recipient's T cell-
cell-mediated cellular
immune response against alloantigens
on grafts


 

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Molecular Mechanisms of
Allogeneic Recognition
ëT cells of the recipient recognize the
allogenetic MHC molecules
ëMany T cells can recognize allogenetic
MHC molecules
å 10-5-10-4 of specific T cells recognize
conventional antigens
å 1%
1%--10% of T cells recognize allogenetic
MHC molecules


 

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ëThe recipient· T cells recognize the
allogenetic MHC molecules

‡ Direct Recognition
‡ Indirect Recognition


 

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Direct Recognition

‡ Recognition of an intact allogenetic MHC

molecule displayed by donor APC in the
graft
‡ Cross recognition
å An allogenetic MHC molecule with a bound
peptide can mimic the determinant formed by a
self MHC molecule plus foreign peptide
å A cross-
cross-reaction of a normal TCR, which was
selected to recognize a self MHC molecules plus
foreign peptide, with an allogenetic MHC
molecule plus peptide

 

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‡ Cross recognition

 

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‡ Passenger leukocytes
å Donor APCs that exist in grafts, such as
MÕ
DC, MÕ
å Early phase of acute rejectionë
rejectionë
å Fast and strongë
strongë


 

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ëMany T cells can recognize
allogenetic MHC molecules

‡ Allogenetic MHC molecules (different residues)

‡ Allogenetic MHC molecules²
molecules²different peptides
‡ All allogenetic MHC molecules on donor APC
can be epitopes recognized by TCR


 

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Indirect recognition

‡ Uptake and presentation of allogeneic

donor MHC molecules by recipient
APC in ´normal wayµ
‡ Recognition by T cells like
conventional foreign antigens


 

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‡ Slow and weak
‡ Late phase of acute rejection and chronic
rejection
‡ Coordinated function with direct recognition in
early phase of acute rejection


 

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Difference between Direct Recognition
and Indirect Recognition
Direct Indirect
Recognition Recognition
Allogeneic MHC Intact allogeneic Peptide of allogeneic
molecule MHC molecule MHC molecule
APCs Recipient APCs are Recipient APCs
not necessary
Activated T cells CD4:T cells and/or CD4:T cells and/or
CD8:T cells CD8:T cells
Roles in rejection Acute rejection Chronic rejection

Degree of rejection igorous Weak


 

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Role of CD4:T cells and CD8:T cells

‡ Activated CD4+T by direct and indirect

recognition
å CK secretion
å MÕ activation and recruitment
‡ Activated CD8+T by direct recognition
å Kill the graft cells directly
‡ Activated CD8+T by indirect recognition
å Can not kill the graft cells directly


 

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 Role of CD4:T cells and CD8:T cells

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2. Humoral immunity
‡ Important role in hyperacute rejection
(Preformed antibodies)
å Complements activation
å ADCC
å Opsonization
‡ Enhancing antibodies
/Blocking antibodies


 

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3 .Role of _K cells

‡ KIR can·t recognize allogeneic MHC on

graft
‡ CKs secreted by activated Th cells can
promote _K activation


 

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 Mechanisms of graft rejection

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Rejection

 

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 Part two
 

  



 

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Classification of Allograft
Rejection

‡ Host versus graft reaction (HGR)

å Conventional organ transplantation
‡ Graft versus host reaction (GHR)
å Bone marrow transplantation
å Immune cells transplantation


 

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I. Host versus graft reaction
(HGR)
' Hyperacute rejection
‡ Acute rejection
‡ Chronic rejection


 

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1. Hyperacute rejection
‡ Occurrence time
å Occurs within minutes to hours after host
blood vessels are anastomosed to graft
vessels
‡ Pathology
å Thrombotic occlusion of the graft vasculature
å Ischemia, denaturation, necrosis


 

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‡ Mechanisms
å Preformed antibodies
‡ Antibody against ABO blood type antigen
‡ Antibody against EC antigen
‡ Antibody against HLA antigen


 

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 å Complement activation
‡ Endothelial cell damage
å Platelets activation
‡ Thrombosis, vascular occlusion, ischemic
damage


 

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‡ 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
å Occurs within days to 2 weeks after
transplantation, 80-
80-90% of cases occur
within 1 month
‡ Pathology
å Acute humoral rejection
‡ Acute vasculitis manifested mainly by
endothelial cell damage
å Acute cellular rejection
‡ Parenchymal cell necrosis along with
infiltration of lymphocytes and MÕ


 

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‡ Mechanisms
å asculitis
‡ IgG antibodies against alloantigens on
endothelial cell
‡ CDC
å Parenchymal cell damage
‡ Delayed hypersensitivity mediated by
CD4+Th1
‡ Killing of graft cells by CD8+Tc


 

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Acute rejection of a kidney with inflammatory cells in the
interstitium and between epithelial cells of the tubules

 

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3. Chronic rejection
‡ Occurrence time
å Develops months or years after acute
rejection reactions have subsided
‡ Pathology
å Fibrosis and vascular abnormalities with loss
of graft function


 

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‡ Mechanisms
å _ot clear
å Extension and results of cell necrosis in
acute rejection
å Chronic inflammation mediated by CD4+T
Õ
cell/MÕ
cell/M
å Organ degeneration induced by non
immune factors


 

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 Kidney Transplantation----Graft Rejection


 

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 Chronic rejection in a kidney allograft with arteriosclerosis


 

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II.Graft versus host reaction
(GHR)
‡ Graft versus host reaction (GHR)
å Allogenetic bone marrow transplantation
å Rejection to host alloantigens
å Mediated by immune competent cells in
bone marrow
‡ Graft versus host disease (GHD)
å A disease caused by GHR, which can
damage the host


 

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 ‡ Graft versus host disease


 

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 ‡ Graft versus host disease

 

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Conditions
‡ Enough immune competent cells in grafts
‡ Immunocompromised host
‡ Histocompatability differences between
host and graft


 

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‡ 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 GHD

‡ 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-
graft-versus
versus--host reaction with
vivid palmar erythema

 

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2. Chronic GHD

‡ Fibrosis and atrophy of one or more of

the organs
‡ Eventually complete dysfunction of the
affected organ


 

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‡ Early, chronic graft-
graft-versus
versus--host reaction with widespread,
almost confluent hyperpigmented lichenoid papules and
toxic epidermal necrosis-
necrosis-like appearance on knee
‡ Late, chronic graft-
graft-versus -host reaction with
hyperpigmented sclerotic plaques on the back


 

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 Both acute and chronic GHD are

commonly treated with intense
immunosuppresion
‡ Uncertain
‡ Fatal


 

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 Part three
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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
å HLA
HLA--A and HLA
HLA--B
å HLA
HLA--DR


 

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 ‡ Laws of transplantation

 

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II. Immunosuppressive Therapy
‡ Cyclosporine(CsA), FK506
å Inhibit _FAT transcription factor
‡ Azathioprine, Cyclophosphamide
å Block the proliferation of lymphocytes
‡ Ab against T cell surface molecules
å Anti
Anti--CD3 mAb
mAb----
----Deplete
Deplete T cells
‡ Anti
Anti--inflammatory agents
å Corticosteroids
Corticosteroids----
----Block
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
å Soluble MHC molecules
å CTLA4
CTLA4--Ig
å Anti
Anti--IL2R mAb
‡ Th2 cytokines
å Anti T_F-->'Anti
Anti--T_F Anti--IL
IL--2'Anti IF_--U mAb
Anti--IF_
‡ Microchimerism
å The presence of a small number of cells of
donor, genetically distinct from those of the
host individual

 

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 Part I
 


 

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‡ Lack of organs for transplantation
‡ Pig
Pig--human xenotransplantation
‡ Barrier


 

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 ‡ Hyperacute xenograft rejection (HXR)

å Human anti-
anti-pig nature Abs reactive with
Gal>1,3Gal
Gal>
å Construct transgenic pigs expressing
human proteins that inhibit complement
activation
‡ Delayed xenograft rejection (DXR)
å Acute vascular rejection
å Incompletely understood
‡ T cell-
cell-mediated xenograft rejection


 

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