• 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

• 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

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

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

Hyperacute rejection is caused by pre-existing antibodies binding to the graft.

• 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

• 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

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

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

Alloreactive T-cells of the recipient or of the donor Can be detected by Mixed Lymphocyte Reaction(MLR)

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)

Indirect presentation

DC B

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

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

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

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.

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

• 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

• 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

ORGAN, TISSUE OR CELL TRANSPLANTATION

ALLOGENEIC

Bone marrow

Transplant rejectionHost versus graft

HVG

Graft versus HostGVH

GVHD

Pre-treatment

Treat tumorCorrect deficiency

Cardiovascular diseases

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

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!

•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

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

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