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TISSUE TRANSPLANTATION
GOAL: Replacement of diseased, damaged or worn-out tissues
Can be life-saving
At the same time may provoke powerful immune responses
REQUIREMENTS
• Introduce transplants to allow normal functions
• Maintain the health of both the recipient and the
transplant
• The immune system of the recipient must be prevented
from mounting an adaptive immune respone against the
graft to avoid rejection
 inactivation of the immune system
TRANSPLANTATION IMMUNOLOGY
• THE ALLO-REACTIVE IMMUNE RESPONSE IS DIRECTED AGAINST
TRANSPLANTATION ANTIGENS
– Major transplantation antigens are encoded by classical MHC genes
– Minor transplantation antigens are encoded by any polymorphic
gene and are recognized as peptides in the context of MHC
– Blood group antigens are considered as tissue-specific
transplantation antigens
• T CELLS ARE EDUCATED IN THE PRESENCE OF SELF MHC
ALLOTYPES
• OTHER MHC ALLOTYPES ARE RECOGNIZED AS FOREIGN BY T
LYMPHOCYTES
• REJECTION OF INCOMPATIBLE TISSUE IS MEDIATED PRIMARILY BY
T LYMPHOCYTES
• NK CELLS AND ANTIBODY MEDIATED EFFECTOR FUNCTIONS ARE
ALSO INVOLVED
ORGAN, TISSUE OR CELL TRANSPLANT
AUTOLOGOUS
autograft
SYNGENIC
syngraft
Skin, muscle, stem cell, dendritic cell, cartilage
BLOOD TRANSFUSION
Bone marrow-derived haematopoietic cells
(HSC)
ALLOGENEIC
allograft
Kidney, cornea, liver, heart, lung
bone marrow-derived haematopoietic
cells (HSC)
GRAFT REJECTION IS THE RESULT OF SPECIFIC IMMUNE
RESPONSE
Primary rejection
mouse strain
10 days
6 months
Lymphocyte transfer
from immunized mouse
Secondary rejection
mouse strain
3 days - MEMORY
Naive mouse
Primary rejection
mouse strain
10 days
Rapid rejection of the transplant is mediated by a memory immune
response
Hyperacute rejection is caused by pre-existing
antibodies binding to the graft.
MECHANISMS OF TISSUE REJECTION
• HYPERACUTE REJECTION
– Xenograft or AB0 incompatible graft
– Natural IgM antibodies against carbohydrates
• Galα1-3Gal on xenograft endothelial cells
– Antibodies generated upon previous blood transfusion, pregnancy
or transplantation – MHC-specific antibodies bind to endothelial cells
• Mismatch of recipient serum with donors B and T cells
– Complement and clotting system
– NK cell – mediated IgG-dependent ADCC
– Necrotic tissue demage
• EARLY ACUTE REACTION – 2 – 5 days
– Previous sensitization of cytotoxic T cells
– IgG-dependent ADCC
– Necrotic tissue demage
• LATE ACUTE and CHRONIC REACTION – 7 – 21 days
– Th1 – mediated cellular immune response
– Delayed Type Hypersensitivity
• Fibrosis
• Proliferation of smooth muscle cells
• Atherosclerosis
– Activation of cytotoxic T lymphocytes
BLOOD GROUP AND HLA-SPECIFIC ANTIBODIES INDUCE HYPERACUTE
REJECTION THROUGH COMPLEMENT ACTIVATION
• THE TRANSFUSION REACTION IS MEDIATED BY ANTIBODIES
– Red blood cells do not express MHC class I or class II molecules
• A, B, 0 ANTIGENS are expressed by endothelial cells of blood vessels
(solid vascularized organs)
• ANTIBODIES to blood group antigens bind to blood vessels, activate
complement
– Type II hypersensitivity
– Hyperacute rejection – cannot be reversed, should be avoided
• Anti – HLA ANTIBODIES
– Arise from pregnancy, blood transfusion, previous transplant
– Cross match: test recipient’s serum to donor lymphocytes
•
•
•
•
Panel reactive antibody (PRA) – % of positive reactions
Complement activation
Flow cytometry – more sensitive
Separated T and B cells to detect MHC class I and MHC class II specific
antibodies
– Anti – MHC I react with both B and T lymphocytes
– Anti – MHC II react with B lymphocytes only
ORGAN, TISSUE OR CELL TRANSPLANTATION
ALLOGENEIC
Late Acute rejection: Both patients and the organ has
tissue damage that releases danger signals – INFLAMMATION
– ENHANCE MHC expression
The immune response is mediated by CD4 and CD8 T-cells
Effector mechanisms are identical to that of Type IV
hypersensitivity
Patients are prepared by administration of immunosuppressive
drugs or T-cell specific antibodies prior to transplantation
Transplant rejection
Host versus graft
HVG
Acute rejection of a kidney graft through the direct
pathway of allo-recognition.
Acute rejection takes days to develop
The rejected graft is swollen and has deep-red
areas of hemorrhage and gray areas of
necrotic tissue.
Alloreactive T-cells of the recipient or of the donor
Can be detected by Mixed Lymphocyte Reaction
(MLR)
PRESENTATION OF GRAFT - DERIVED PEPTIDES
TO RECIPIENT’S T CELLS
Recipient
T
Demaged,
apoptotic/necrotic tissue
cells and soluble proteins
(MHC)
Recipient
peptide
Donor
Graft
APC
Recipient
T
Donor
peptide
Donor Recipient
T
peptide
Recipient
Host
Recipient
Donor
APC
T
peptide
DIRECT PRESENTATION
INDIRECT PRESENTATION
Host Versus Graft reaction HVG
High percentage of T cells are activated
DEPLETION OF GRAFT – DERIVED PROFESSIONAL APC REDUCES
REJECTION
Indirect presentation
DC
B
MOLECULAR BASIS OF THE ALLO-RESPONSE
RECIPIENT T CELLS
ANTIGENS PRESENTED
BY ALLO- AND SELF APC
Allo-MHC + allo-peptide
Allo-MHC + allo-peptide
Allo-MHC + self-peptide
Allo-MHC + self peptide
Allo-MHC + any-peptide
Allo-MHC + any-peptide
Self-MHC + allo-peptide
Self-MHC + allo-peptide
Self-MHC + any-peptide
HIGH PERCENTAGE OF RECIPIENT’S T CELLS ARE RESPONDING
ACUTE REJECTION
KIDNEY TRANSPLANTATION
HEART TRANSPLANTATION
T CELLS
Plasma cells
Lymphocytes and plasma cells
around renal tubules. Occurs after
terminating immune suppression
(CSA)
T lymphocytes in the myocardium.
Labeled with anti-CD3 antibody
REJECTION IS PRIMARILY MEDIATED BY MHC-SPECIFIC T
LYMPHOCYTES BUT PLASMA CELLS ARE ALSO PRESENT
Chronic rejection – may take months
Targeted against the vasculature of the transplant
Results in the thickening of the vessel wall and narrowing of the
lumina
E: endothel
G: granulocyte
T: alloreactive T
M: macrophage
EL: elastic lamina
SMC: smooth muscle
Chronic rejection
Interstitial fibrosis and chronic
inflammation. Renal arteries are
fibrous and thickened. No treatment,
can occur months or years after
transplantation.
Interstitial fibrosis after chronic
rejection in transplanted kidney.
SHORTAGE OF TRANSPLANTABLE ORGANS
Animal organs – Xenogeneic transplantation
Xenograft
PRIMATES – danger of viral transmission
PIG – equivalant organs size – hyperacute rejection
„natural” anti-pig antibodies in human blood
recognize carbohydrates on pig endothelial cells
galactosyl α-1,3-galactosyl β-1,4-Nacetylglucosaminyl (Gal)
Activate complement – cell damage
Human decay acceleration factor (DAF) transgenic pig – several days
KO - α-1,3-galactosyl transferase – 6 months survival
BONE MARROW TRANSPLANTATION IS A SPECIAL CASE OF
ORGAN TRANSPLANTATION
Transplantation of the donor’s hematopoietic and immune
systems to the recipient
• Receipient’s immune response is inhibited
– γ-irradiation, drugs
– No rejection of the transplant
– No host versus graft rejection
• Donor bone marrow-derived mature T lymphocytes
recognize recipient’s tissues
– Graft versus host reaction - against all tissues
– Acute autoimmun reaction, can be fatal
– Elimination of mature T cells prevents GVH
– Methotrexate and cyclosporin A inhibit GVHD
– Elimination of mature T cells inhibits engraftment and
anti-leukemia effect – may cause rejection
DEFECTS OF HEMOTPOIETIC CELLS CAN BE
CORRECTED BY BONE MARROW TRANSPLANTATION
• Degree of HLA matching of the healthy donor and
the patient determines the success of
transplantation
– Reduces alloreactions against the graft HVG 
– Reduces graft versus host reaction GVH 
– Ensures efficient presentation of graft antigens by
graft APC in the thymus
– Positive selection of graft T lymphocytes on host
thymic epithelial cells will produce graft-derived T
cells – shared MHC
– The host’s immune system will be reconstituted by
donor-derived lymphocytes
ORGAN, TISSUE OR CELL TRANSPLANTATION
Pre-treatment
ALLOGENEIC
Bone marrow
Treat tumor
Correct deficiency
Cardiovascular diseases
Transplant rejection
Host versus graft
HVG
Graft versus Host
GVH
GVHD
CYCLOSPORIN (CSA) AND TACROLIMUS (FK506)
TCR/CD3
PLC
INAKTIV
PLC
Ca2+
calcineurin
calcineurin
PTP-ase
ACTIVE
P
NF-AT
NF-ATc
Dephosphorylation
NF-AT translocation to the nucleus
calcineurin
PTP-ase
calcineurin
PTP-ase
CsA
Blocked by CSA and FK506
FK506
cyclophilin A
isomerase
NF-ATn
FKBP12
isomerase
NF-ATn
TF
Gene activation, expression of
cytokines and activation molecules
Some more ways to block the rejectionof transplants
FTY720: Synthetic analogue of a fungal toxin called Myriocin.
Sphingoson-like structure
Agonist of the S1P receptor, alters T-cell recirculation, traps them in LNs
Peripheral T-cell number is decreased, but no major T-cell defect!
BONE MARROW TRANSPLANTATION
Special case of tissue transplantation
•Graft versus host reaction GVH
Graft-donor
T
Recipient
peptide
•chronic and systemic
• Mature T cells transplanted
with the bone marrow react
with recipient cells
• Elimination of donor T cells
can prevent GVHD
Recipient
APC
survive
•Graft versus host disease – GVHD
Recipient
peptide
Graft-donor
T
Graft Versus Host Reaction
•Elimination of donor T cells
decreases graft versus
leukemia effect
•Bone marrow transplantation
is used for correcting SCID
Figure 11.1 The rash characteristic of
GVHD often starts on the face.
Also involves palms and soles
Panel a: early GVHD in the skin. Lymphocytes are emerging from blood vessels (lower arrow) and
adhering to the basal layer of the epidermis (upper arrow). Panel b: the basal cells of the epidermis begin
to swell and vacuolate. ...
GVHD in the colon
Inflammatory cells have invaded the crypts of the intestine and destroyed the
normal architecture (arrow). Photograph kindly provided by Mark Shlomchik.