Download organ transpalntation

PRINCIPALES OF ORGAN
TRANSPLANTATION
Prof D.Nazem Shams
Professor Of Surgical Oncology
OCMU
The field of organ transplantation has made
remarkable progress in a short period of time.
Transplantation has evolved to become the
treatment of choice for end-stage organ failure
resulting from almost any of a wide variety of
causes. Transplantation of the kidney, liver,
pancreas, intestine, heart, and lungs has now
become commonplace in all parts of the
world.
Definition:
Transplantation is the act of transferring an
organ, tissue, or cell from one place to
.another.
Types:
Broadly speaking, transplants are divided into
three categories based on the similarity
between the donor and the recipient:
1-Autotransplants
2-Allotransplants
3-Xenotransplants
.
1-Autotransplants involve the transfer of
tissue or organs from one part of an
individual to another part of the same
individual. They are the most common type
of transplants and include skin grafts and
vein grafts for bypasses.
NO immunosuppression is required
2-Allotransplants involve transfer from one
individual to a different individual of the
same species—the most common scenario
for most solid organ transplants performed
today.
Immunosuppression is required for allograft
recipients to prevent rejection.
3- Xenotransplants involve transfer across
species barriers. Currently, xenotransplants
are largely relegated to the laboratory, given
the complex, potent immunologic barriers
to success.
TRANSPLANT IMMUNOBIOLOGY:
The success of transplants today is due in
large part to control of the rejection process,
thanks to an ever-deepening understanding
of the immune process triggered by a
transplant.
Transplant Antigens:
The main antigens involved in triggering
rejection are coded for by a group of genes
known as the major histocompatibility
complex (MHC). In humans, the MHC
complex is known as the human leukocyte
antigen (HLA) system. It comprises a series
of genes located on chromosome 6.
HLA molecules can initiate rejection and graft
damage, via humoral or cellular mechanisms:
Humoral rejection mediated by recepient's AB.
(e.g. blood transfusion, previous transplant, or
pregnancy)
Cellular rejection is the more common type of
rejection after organ transplants. Mediated by T
lymphocytes, it results from their activation and
proliferation after exposure to donor MHC
molecules.
Complications Of Organ
Transplantation
1- Rejection
2-Malignancy
1-Clinical Rejection:
Graft rejection is a complex process involving
several components, including T lymphocytes
, B lymphocytes, macrophages, and cytokines, with
resultant local inflammatory injury and graft
damage.
Rejection can be classified into the following types
based on timing and pathogenesis: hyperacute,
acute, and chronic.
A-Hyperacute rejection:
This type of rejection, which usually occurs within
min after the transplanted organ is reperfused, is
because of the presence of preformed antibodies in
the recipient, antibodies that are specific to the
donor. These bind to the vascular endothelium in
the graft and activate the complement cascade,
leading to platelet activation and to diffuse
intravascular coagulation. The result is a swollen,
darkened graft, which undergoes ischemic
necrosis.
B-Acute rejection:
This used to be the most common type of rejection, but with
modern immunosuppression it is becoming less and less
common. Acute rejection is usually seen within days to a
few months posttransplant. It is predominantly a cellmediated process, with lymphocytes being the main cells
involved. With current immunosuppressive drugs, most
acute rejection episodes are generally asymptomatic. They
usually manifest with abnormal laboratory values (e.g.,
elevated creatinine in kidney transplant recipients, and
elevated transaminase levels in liver transplant recipients).
C-Chronic rejection:
This form of rejection occurs months to years
posttransplant. Now that shortterm graft survival
rates have improved so markedly, chronic
rejection is an increasingly common problem.
Histologically, the process is characterized by
atrophy, fibrosis, and arteriosclerosis. Both
immune and nonimmune mechanisms are likely
involved. Clinically, graft function slowly
deteriorates over months to years
CLINICAL IMMUNOSUPPRESSION:
The success of modern transplantation is in
large part because of the successful
development of effective
immunosuppressive agents.
Two types of immunosuppression are used
in transplantation: Induction and
Maintenance immunosuppresion.
1-Induction immunosuppression
refers to the drugs administered immediately
posttransplant to induce
immunosuppression.
2-Maintenance immunosuppression
refers to the drugs administered to maintain
immunosuppression once recipients have recovered from
the operative procedure. Individual drugs can be
categorized as either biologic or nonbiologic agents.
Biologic agents (monoclonal and polyclonal antibodies)
consist of antibody preparations directed at various cells or
receptors involved in the rejection process; they are
generally used in induction (rather than maintenance)
protocols.
Nonbiologic agents (e.g. corticosteroids,azathioprine and
cyclosporines)form the mainstay of maintenance protocols.
2-Malignancy:
Transplant recipients are at increased risk for
developing certain types of de novo malignancies,
including nonmelanomatous skin cancers (3–7fold increased risk), lymphoproliferative disease
(2–3-fold increased risk), gynecologic and
urologic cancers, and Kaposi sarcoma. The risk
ranges from 1 percent among renal allograft
recipients to approximately 5–6 percent among
recipients of small bowel and multivisceral
transplants.
The most common malignancies in transplant
recipients are skin cancers. They tend to be located
on sun-exposed areas and are usually squamous or
basal cell carcinomas. Often they are multiple and
have an increased predilection to metastasize.
Diagnosis and treatment are the same as for the
general population.
Patients are encouraged to use sunscreen liberally
and avoid significant sun exposure.
Sources of organs for transpalntation:
The current Main Sources of organs for
transpalntation are:
1-Deceased (cadaver) donor (however the
recipient has to wait till this cadaver
becomes available)
2-Living donor transplantation (has medical,
ethical, financial, and psychosocial
problems).
The biggest problem facing transplant centers today
is the shortage of organ donors. Mechanisms that
might increase the number of available organs
include:
(1) optimizing the current donor pool (e.g., the use
of multiple organ donors or marginal donors);
(2) increasing the number of living-donor
transplants (e.g., the use of living unrelated
donors);
(3) using unconventional and controversial donor
sources (e.g., using deceased donors without
cardiac activity or anencephalic donors);
(4) performing xenotransplants.
New directions for organ
Transplantation:
STEM CELLS
,
CELL THERAPY
AND
TISSUE ENGINEEERING
Cell therapy can be defined as «The use of
living cells to restore, maintain or enhance
the function of tissues and organs».
The use of isolated, viable cells has emerged as
an experimental therapeutic tool in the past
decade, due to progress in cell biology and
particularly in techniques for the isolation and
culture of cells derived from several organs
and tissues
Cell-based therapy is one of the more recent
approaches in regenerative medicine that aims at
replacing or repairing organs and tissues. Different
cell types have been used, such as skeletal
myocytes, which have been injected into infarcted
cardiac scar tissue, or neuronal cells inoculated
into the brains of patients with nervous disorders.
Alternative approaches include extracorporeal
organ replacement for kidney and liver failure, the
potential transplantation of xenogenic organs and
cells and stem cell therapy.
Forms (types) of cell therapy:
1-Extracorporeal bioartificial organs used as
assistance devices.
2-Injections, implantations or transplantation
of cells.
1-Bioartificial Organs (Assistance
Devices):
Extracorporeal support systems most frequently
use a hollow fiber cartridge containing
immobilized cells with mass exchange
requiring either direct contact with perfused
blood or through a semi permeable membrane
separating cells from blood.
Howevr, although the bioartificial organs are an
attractive technology with therapeutic
potential, the limited availability of normal
human cells has prevented the technology
from being utilized in clinical settings
2-Injections, implantations or
transplantation of cells
Strategies (Methods) of Transplantation:
1-Transplantation into blood stream:
The reported problems with this method are :emboli,
cells carried to inappropriate sites, difficulties for
engraftment, and cells not in ideal environment.
2-Transplantation by grafting (Tissue
engineering):
It is ideal for cells from solid organs with less complication than
blood infusion. It requires implanting aggregated cells or, ideally,
cells on scaffolding [e.g., polylactide meshes.
Cell sourcing remains among the most critical
difficulties in the development of cell
therapies, whether for bioartificial organs or
for cell transplantation.
This proplem could be alleviated by use of stem
cells (this is called stem cell therapy),
especially probably in combination with
grafting methods, because the progenitor cells
can be cryopreserved, have dramatic expansion
potential, and have low or negligible
immunogenic antigens that can possibly be
managed with minimal need for
immunosuppressive drugs.
Why stem cell?
The following stem cell characterisics make
them good candidate for cell based
therapies:
1-potential to be harvested from patients.
2-High capacity of proliferation in culture.
3-Ease of manipulation to replace existing non
functioning genes via gene transfer
methods.
4-Ability to migrate to host’s target tissues.
Stem cells have 4 main properties:
1-Unspecialized.
2- Self renewal.
3-Potency :Stem cells are either:
Totipotent (e.g. fertilized ova).
Pleuripotent(e.g. ES cells, EC cells and EG cells , the last two are less desirable
for research).
Multipotent (e.g. tissue stem cells).
Unipotent (e.g. hepatocytes, skin and corneal stem cells).
4-Robust repopulation (functional, long term tissue reconstitution).
And moreover the flexibility in expressing these characteristics and serial
transplantability should be feasible
.Cells that fulfill all these criteria are called "actual stem cells." The cells that
possess these capabilities but do not express them are named "potential stem
cells." (Potten and Loeffler, 1990 and Dabeva et al., 2003).
Scientists primarily work with two kinds of stem cells
from animals (mouse) and humans: which are
embryonic stem cells and adult stem cells.
Scientists took about 20 years to learn how to grow human embryonic
stem cells in the laboratory following the development of conditions for
growing mouse stem cells.
Stem cell therapy
• means treatment in which stem cells are induced to
differentiate into the specific cell type required to repair
damaged tissues.
• Right now, only few diseases are treatable with stem cell
therapies because scientists can only regenerate few types of
tissues.
However, the success of the most established stem cellbased therapies (blood and skin transplants) gives hope
that someday stem cells will allow scientists to develop
therapies for a variety of diseases previously thought to
be incurable.
Stem cell therapy
• Only non-ESCs have been
used clinically so far. Bone
marrow cells were first used
successfully 4 decades ago, and
cord blood stem cells in the past
10–15 years. These cells have
been of benefit for blood
disorders such as leukemia,
multiple myeloma and
lymphoma; and disorders with
defective genes such as severe
combined immune deficiency.
• As yet, ESC has not been used clinically.
There are no current approved treatments or
human trials using embryonic stem cells.
ES cells, being totipotent cells, require specific
signals for correct differentiation - if injected
directly into the body; ES cells will differentiate
into many different types of cells, causing a
teratoma.
There are in fact only few and modest published
successes using animal models of disease.
Various potential therapeutic applications of human
embryonic stem cells (hES) (Habibullah, 2007).
Much of the work with stem cells is
preclinical, relying on results obtained from
mice or rats. In the following cases
(neurological disorders and cardiovascular
disease) phase I clinical trials are still
several years into the future (Panno, 2005).
Obstacles to stem cell therapy
There are many ways in which human stem cells
can be used in basic research and in clinical
research. However, there are many technical
hurdles and obstacles between the promise of
stem cells and the realization of these uses,
which will only be overcome by continued
intensive stem cell research.
Obstacles to stem cell therapy
These hurdles are:
A- For ESCs: There are three major
problems:
1-Ethical proplem (ethical issues): There are many
ethical dilemmas in stem cell and cloning research, and in
their use in therapy, concerning
- the isolation of cells,
- consent and donation,
- the destruction of potential life forms for the treatment of
It must beothers.
demonstrated that to alleviate human suffering
does not necessarily justify the use of any means to achieve
it.
Obstacles to stem cell therapy
These hurdles are:
A- For ESCs: There are three major
problems:
2- Immunological rejection problems (rejection).
3- Biological proplems: e.g. teratomas ,
chromosomal abnormalities and possible
contamination of the stem cells with retoviruses
and other animal pathogens
It must be demonstrated that to alleviate human suffering
does not necessarily justify the use of any means to achieve
it.
Obstacles to stem cell therapy
These hurdles are:
B- For Non–ESCs: There have been many technical
challenges that have been overcome in adult stem cell
research.
Some of the barriers include:
• the rare occurrence of adult stem cells among other differentiated
cells,
• difficulties in isolating and identifying the cells
• difficulties in growing adult stem cells in tissue culture
Obstacles to stem cell therapy
However
Tissue stem cells have been shown by the published evidence
to be a more promising alternative for patient treatments,
with a vast biomedical potential.
Tissue stem cells have proven success in the laboratory dish,
in animal models of disease, and in current clinical
treatments.
Tissue stem cells also avoid problems with tumor formation,
transplant rejection, and provide realistic excitement for
patient treatments.
The relative lack of success of embryonic stem cells should
be compared with the real success of tissue(adult) stem
cells. A wealth of scientific papers published over the
last few years document that tissue stem cells are a
much more promising source of stem cells for
regenerative medicine. Adult (tissue)stem cells actually
do show pluripotent capacity in generation of tissues,
meaning that they can generate most, if not all, tissues
of the body.
Tissue engineering
Tissue engineering is the process of creating living,
physiological 3D tissues and organs. The process starts
with a source of cells derived from a patient or from a
donor. The cells may be immature cells, in the stem cell
stage, or cells that are already capable of carrying out
tissue functions; often, a mixture of different cell types
(e.g., liver cells and blood vessel cells) and cell maturity
levels is needed. Many therapeutic applications of tissue
engineering involve disease processes that might be
prevented or treated if better drugs were available or if the
processes could be better understood .
Tissue engineering-based therapies may provide a
possible solution to alleviate the current shortage
of organ donors. In tissue engineering, biological
and engineering principles are combined to
produce cell-based substitutes with or without the
use of materials. One of the major obstacles in
engineering tissue constructs for clinical use is the
limit in available human cells. Stem cells isolated
from adults or developing embryos are a current
.source for cells for tissue engineering
In general, there are three main approaches to tissue
engineering:
(1) To use isolated cells or cell substitutes as cellular
replacement parts;
(2) To use acellular materials capable of inducing tissue
regeneration; and
(3) To use a combination of cells and materials (typically in
the form of scaffolds and this approach be categorized into
two categories:
Open and closed systems. These systems are distinguished
based on the exposure of the cells to the immune system
upon implantation
The materials used for tissue engineering are either synthetic
biodegradable materials (such as polylactic acid (PLA),
polyglycolic acid (PGA), poly lactic-glycolic acid (PLGA),
polypropylene fumarate, poly ethylene glycol (PEG) and
polyarylates) or natural materials such as collagen,
hydroxyapatite, calcium carbonate, and alginate. Natural
materials are typically more favorable to cell adherence,
whereas the properties of synthetic materials such as
degradation rate, mechanical properties, structure, and
porosity can be better controlled
Open tissue engineering systems
have been successfully used to create a number of biological substitutes
such as bone, cartilage, blood vessels, cardiac, smooth muscle,
pancreatic, liver, tooth, retina, and skin tissues. Several tissueengineered products are under clinical trials for FDA approval.
Engineered skin or wound dressing and cartilage are two of the most
advanced areas with regards to clinical potential. For example, a skin
substitute that consists of living human dermis cells in a natural
scaffold consisting of type I collagen already received FDA approval
to be used for a diabetic foot ulcer. In addition, various cartilage and
bone are also currently in clinical stages, and bladder and urologic
tissue are being tested in various stages of research (Levenberg et al.,
2006).
Closed tissue engineering systems have been •
used particularly for the treatment of diabetes,
liver failure, and Parkinson’s disease. This system
may prove to be especially useful in conjunction
with ES cells since the immobilization of ES cells
within closed systems may overcome the
immunological barrier that faces ES cell-based
therapies (Strauer and Kornowski, 2003).
Current approaches for tissue engineering using
tissue (postnatal) stem cells:
(A) Expansion of a population ex vivo prior to
transplantation into the host,
(B) Ex vivo recreation of a tissue or organ for
transplantation, and
C) Design of substances and/or devices for in vivo (
activation of stem cells, either local or distant, to
induce appropriate tissue repair