ORGAN TRANSPLANTATION Replacement of diseased, demaged or worn-out organs.

ORGAN TRANSPLANTATIONReplacement of diseased, demaged or worn-out organs

REQUIREMENTS

*Introduce a transplant in a way that allows it to function normally.

*Maintain the health of both the recipient and the transplant.

*Prevent an adaptive immune reaction by the host, against the graft- done by non-specific immunosuppression.

(immunosuppressive drugs + antibodies)

ORGAN TRANSPLANTATION

Major tissues and organs transplanted

Thoracic organsheart lungheart/lung

Abdominal organskidneyliverpancreasintestine

Tissues, cells and fluidscorneaIslets of Langerhansbone marrowblood transfusionheart valvebone

Examples

History of transplantations

1905: First successful cornea transplant (Czech Republic)1950: First successful kidney transplant (Chicago, U.S.A)[9]

1966: First successful pancreas transplant (Minnesota, U.S.A.)1967: First successful liver transplant (Denver, U.S.A.)1967: First successful heart transplant (Cape Town, South Africa)1981: First successful heart/lung transplant (Stanford, U.S.A.)1983: First successful lung lobe transplant (Toronto, Canada)1998: First successful live-donor partial pancreas transplant (Minnesota, U.S.A.)1998: First successful hand transplant (Lyon, France)1999: First successful Tissue Engineered Bladder transplanted (Boston Children's Hospital, U.S.A.)2005: First successful ovarian transplant (Wadia hospital Mumbai, India)2005: First successful partial face transplant (France)2008: First successful complete full double arm transplant (Technical University of Munich, Germany)2008: First baby born from transplanted ovary by James Randerson2008: First successful transplantation of near total area (80%) of face, (including palate, nose, cheeks, and eyelid)  (Cleveland, USA)2010: First full facial transplant (Hospital Universitari Vall d'Hebron on July 26, 2010 in Barcelona, Spain.)2011: First double leg transplant (Valencia's Hospital La Fe, Spain)

Basic concepts in transplantation

Allotransplantation (Allo- meaning “other”) is the transplantation of cells, tissues or organs to a recipient from donor of the same species. The transplant is called allograft.

Alloreaction is directed against transplantation antigens.

Transplantation antigens can be:Major- encoded by classical MHC genesManor- any polymorphic genes encoding peptides, in the context of MHC Blood group antigens are considered as transplantation antigens

To prevent an alloreaction the patients are given a variety of immunosuppressive drugs and antibodies that prevent the activation and proliferation of T cells. The drugs are lowered to maintenance levels and are increased in case of rejection signs.

RECIPIENT T CELLSANTIGENS PRESENTED

BY ALLOGRAFT AND SELF APC

Foreign MHC + any peptide

Foreign MHC + any peptide

Foreign MHC + self peptide

Foreign MHC + any peptide

Foreign MHC + foreign peptide

Foreign MHC + foreign peptide

Self MHC + foreign peptide

Self MHC + foreign peptide

Self MHC + foreign MHC-derived peptide

MOLECULAR BASIS OF THE ALLO-RESPONSE

HIGH PERCENTAGE OF RECIPIENT’S T CELLS ARE RESPONDING

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

T cells are educated in the presence of self MHC allotypes, other allotypes are recognized as foreign.

Rejection is caused by genetic differences between transplant donor and recipient.

Rejection signs Cell mediated, delayed type (hypersensitivity type IV)

Highly polymorphic WBC antigens – HLA class I and II that are presenting peptides to T cells initiate an immune response with the potential to destroy the transplant.

Crossmatch tests- to match HLA type between donor and recipient.

Rejection of incompatible tissue is mediated primarily by lymphocytes but NK cells and antibody-mediated effector functions are also involved.

Hyper-acute rejection:

•Pre-existing antibodies against ABO or HLA antigens (previous pregnancy, transfusion, transplantation)

•Develops immediately •ADCC, complement•ABO incompatibility,

Acute rejection:

•Effector T cells responding to HLA differences between donor ad recipient•Direct pathway of allorecognition•Takes days to develop Can be reduced or prevented using immunosuppression and T cell antibodies.•CD8 and CD4 T cells respond to differences in HLA class I and II, respectively

Chronic rejection:

•Months or years after transplantation•Graft vasculature reactions, thickening Ischmeia, loss of function•Antibodies against HLA I and II classes, T cell mediated reaction (type IV)

*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 daysCauses failure of more than half the kidney and heart transplants

after 10 years. *Th1 – mediated cellular immune response*Delayed Type Hypersensitivity* Fibrosis* Proliferation of smooth muscle cells* Atherosclerosis

*Activation of cytotoxic T lymphocytes

MECHANISMS OF TISSUE REJECTION

Acute rejection

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

Interstitial fibrosis and chronic inflammation. Renal arteries are fibrous and thickened.

Chronic rejection

Swallen rejected graft with haemorraegic and necrotic tissue area.

BONE MARROW TRANSPLANTATION

*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*GVH- 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 benefits 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

- Liver

- Pancreas

- Pancreatic islet cells

- Cornea

- Kidney

- Heart/Lung

- Skin

Survival and mismatching

•Graft versus host reaction GVH

•Graft versus host disease – GVHD

•chronic and systemic

• Mature T cells transplanted with the bone marrow react

with donor cells

• Elimination of donor T cells can prevent GVHD

•Elimination of donor T cells increases the occurence of

graft rejection by donor T cells

•This is not a problem when bone marrow transplantation is

used for correcting SCID

BONE MARROW TRANSPLANTATIONSpecial case of tissue transplantation

Recipient APC

Graft-donorT

Graft-donorT

Recipient peptide

Recipientpeptide

Graft Versus Host reaction

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