Transcript 12th seminar 2013 Transplantations

ORGAN TRANSPLANTATION
Replacement of diseased, demaged or worn-out organs
ORGAN TRANSPLANTATION
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 nonspecific immunosuppression.
(immunosuppressive drugs + antibodies)
Major tissues and organs transplanted
Thoracic organs
heart
lung
heart/lung
Abdominal organs
kidney
liver
pancreas
intestine
Tissues, cells and fluids
cornea
Islets of Langerhans
bone marrow
blood transfusion
heart valve
bone
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 Randerson
2008: 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 genes
Manor- 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.
MOLECULAR BASIS OF THE ALLO-RESPONSE
RECIPIENT T CELLS
ANTIGENS 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
HIGH PERCENTAGE OF RECIPIENT’S T CELLS ARE RESPONDING
PRESENTATION OF GRAFT - DERIVED PEPTIDES
TO RECIPIENT’S T CELLS
Recipient
T
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
T cells are educated in the presence of self MHC allotypes, other allotypes are
recognized as foreign.
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 is caused by genetic differences between transplant donor and recipient.
Rejection of incompatible tissue is mediated primarily by lymphocytes but NK
cells and antibody-mediated effector functions are also involved.
Rejection signs  Cell mediated, delayed type (hypersensitivity type IV)
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)
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
Causes 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
Acute rejection
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
Interstitial fibrosis and chronic inflammation.
Renal arteries are fibrous and thickened.
Swallen rejected graft with
haemorraegic and necrotic tissue
area.
BONE MARROW TRANSPLANTATION
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
* 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
DEFECTS OF HEMOTPOIETIC CELLS CAN BE
CORRECTED BY BONE MARROW TRANSPLANTATION
*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
Survival and mismatching
- Liver
- Pancreas
- Pancreatic islet cells
- Cornea
- Kidney
- Heart/Lung
- Skin
BONE MARROW TRANSPLANTATION
Special case of tissue transplantation
•Graft versus host reaction GVH
Recipient
peptide
Graft-donor
T
•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
Recipient
APC
Recipient
peptide
Graft-donor
T
Graft Versus Host reaction
•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
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