Introduce transplants to allow normal functions Maintain the health of both the recipient and the...
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• 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
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
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• 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
TRANSPLANTATION IMMUNOLOGY
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AUTOLOGOUS
ORGAN, TISSUE OR CELL TRANSPLANT
Skin, muscle, stem cell, dendritic cell, cartilage
BLOOD TRANSFUSION
Bone marrow-derived haematopoietic cells (HSC)
autograft syngraft
SYNGENIC ALLOGENEIC
Kidney, cornea, liver, heart, lung
bone marrow-derived haematopoietic cells (HSC)
allograft
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6 months
Rapid rejection of the transplant is mediated by a memory immune response
GRAFT REJECTION IS THE RESULT OF SPECIFIC IMMUNE RESPONSE
Lymphocyte transfer from immunized mouse
Primary rejectionmouse strain
10 days
Secondary rejectionmouse strain
3 days - MEMORY
Primary rejectionmouse strain
10 days
Naive mouse
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Hyperacute rejection is caused by pre-existing antibodies binding to the graft.
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• 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
MECHANISMS OF TISSUE REJECTION
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• 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
BLOOD GROUP AND HLA-SPECIFIC ANTIBODIES INDUCE HYPERACUTE REJECTION THROUGH COMPLEMENT ACTIVATION
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ORGAN, TISSUE OR CELL TRANSPLANTATION
ALLOGENEIC
Transplant rejectionHost versus graft
HVG
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 immunosuppressivedrugs or T-cell specific antibodies prior to transplantation
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The rejected graft is swollen and has deep-red areas of hemorrhage and gray areas of necrotic tissue.
Acute rejection of a kidney graft through the direct pathway of allo-recognition.
Acute rejection takes days to develop
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Alloreactive T-cells of the recipient or of the donor Can be detected by Mixed Lymphocyte Reaction(MLR)
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DonorGraft APC
RecipientT
RecipientT
Donor peptide
Recipient peptide
DIRECT PRESENTATION
RecipientHostAPC
RecipientT
RecipientT
Donor peptide
Donor peptide
INDIRECT PRESENTATION
PRESENTATION OF GRAFT - DERIVED PEPTIDES TO RECIPIENT’S T CELLS
DEPLETION OF GRAFT – DERIVED PROFESSIONAL APC REDUCES REJECTION
Host Versus Graft reaction HVGHigh percentage of T cells are activated
Demaged, apoptotic/necrotic tissue cells and soluble proteins
(MHC)
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Indirect presentation
DC B
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RECIPIENT T CELLSANTIGENS 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
MOLECULAR BASIS OF THE ALLO-RESPONSE
HIGH PERCENTAGE OF RECIPIENT’S T CELLS ARE RESPONDING
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Lymphocytes and plasma cells around renal tubules. Occurs after terminating immune suppression
(CSA)
ACUTE REJECTION
T lymphocytes in the myocardium. Labeled with anti-CD3 antibody
KIDNEY TRANSPLANTATION HEART TRANSPLANTATION
REJECTION IS PRIMARILY MEDIATED BY MHC-SPECIFIC T LYMPHOCYTES BUT PLASMA CELLS ARE ALSO PRESENT
Plasma cells
T CELLS
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Chronic rejection – may take months
Targeted against the vasculature of the transplantResults in the thickening of the vessel wall and narrowing of the lumina
E: endothel M: macrophageG: granulocyte EL: elastic laminaT: alloreactive T SMC: smooth muscle
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Interstitial fibrosis and chronic inflammation. Renal arteries are fibrous and thickened. No treatment, can occur months or years after transplantation.
Chronic rejection
Interstitial fibrosis after chronic rejection in transplanted kidney.
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SHORTAGE OF TRANSPLANTABLE ORGANSAnimal organs – Xenogeneic transplantation
Xenograft
PRIMATES – danger of viral transmission
PIG – equivalant organs size – hyperacute rejection„natural” anti-pig antibodies in human bloodrecognize carbohydrates on pig endothelial cellsgalactosyl α-1,3-galactosyl β-1,4-N-acetylglucosaminyl (Gal)Activate complement – cell damage
Human decay acceleration factor (DAF) transgenic pig – several days KO - α-1,3-galactosyl transferase – 6 months survival
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• 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
BONE MARROW TRANSPLANTATION IS A SPECIAL CASE OF ORGAN TRANSPLANTATION
Transplantation of the donor’s hematopoietic and immune systems to the recipient
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• 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
DEFECTS OF HEMOTPOIETIC CELLS CAN BE CORRECTED BY BONE MARROW TRANSPLANTATION
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ORGAN, TISSUE OR CELL TRANSPLANTATION
ALLOGENEIC
Bone marrow
Transplant rejectionHost versus graft
HVG
Graft versus HostGVH
GVHD
Pre-treatment
Treat tumorCorrect deficiency
Cardiovascular diseases
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TCR/CD3
calcineurin
NF-ATn
NF-ATc
CsA
FK506 FKBP12isomerase
cyclophilin Aisomerase
NF-AT
Ca2+
NF-ATn
TF
calcineurinPTP-ase
calcineurinPTP-ase calcineurin
PTP-ase
P
PLC PLC
CYCLOSPORIN (CSA) AND TACROLIMUS (FK506)
INAKTIVACTIVE
Dephosphorylation
NF-AT translocation to the nucleus
Gene activation, expression of cytokines and activation molecules
Blocked by CSA and FK506
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Some more ways to block the rejectionof transplants
FTY720: Synthetic analogue of a fungal toxin called Myriocin.
Sphingoson-like structureAgonist of the S1P receptor, alters T-cell recirculation, traps them in LNsPeripheral T-cell number is decreased, but no major T-cell defect!
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•Graft versus host reaction GVH
•Graft versus host disease – GVHD
•chronic and systemic
• Mature T cells transplanted with the bone marrow react
with recipient cells
• Elimination of donor T cells can prevent GVHD
•Elimination of donor T cells decreases graft versus
leukemia effect
•Bone marrow transplantation
is used for correcting SCID
BONE MARROW TRANSPLANTATIONSpecial case of tissue transplantation
Recipient APC
survive
Graft-donorT
Graft-donorT
Recipient peptide
Recipientpeptide
Graft Versus Host Reaction
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Figure 11.1 The rash characteristic of GVHD often starts on the face.
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. ...
Also involves palms and soles
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Inflammatory cells have invaded the crypts of the intestine and destroyed the normal architecture (arrow). Photograph kindly provided by Mark Shlomchik.
GVHD in the colon