PRINCIPALES OF ORGAN TRANSPLANTATION

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PRINCIPALES OF ORGAN TRANSPLANTATION

• Prof D.Nazem Shams
• Professor Of Surgical Oncology
• OCMU

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• 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.
  

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Definition

• Transplantation is the act of transferring an
  organ, tissue, or cell from one place to
  another. .

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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
• .

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• 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

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• 2-Allotransplants involve transfer from one
  individual to a different individual of the same
  speciesthe most common scenario for most solid
  organ transplants performed today.
• Immunosuppression is required for allograft
  recipients to prevent rejection.

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• 3- Xenotransplants involve transfer across
  species barriers. Currently, xenotransplants are
  largely relegated to the laboratory, given the
  complex, potent immunologic barriers to success.

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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.

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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.

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• 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.

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Complications Of Organ Transplantation

• 1- Rejection
• 2-Malignancy

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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.

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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.

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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
  cell-mediated 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).

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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

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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.

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1-Induction immunosuppression

• refers to the drugs administered immediately
  posttransplant to induce immunosuppression.

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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,azathiopr
  ine and cyclosporines)form the mainstay of
  maintenance protocols.

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2-Malignancy

• Transplant recipients are at increased risk for
  developing certain types of de novo malignancies,
  including nonmelanomatous skin cancers (37-fold
  increased risk), lymphoproliferative disease
  (23-fold increased risk), gynecologic and
  urologic cancers, and Kaposi sarcoma. The risk
  ranges from 1 percent among renal allograft
  recipients to approximately 56 percent among
  recipients of small bowel and multivisceral
  transplants.

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• 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.

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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).

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• 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.

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New directions for organTransplantation

• STEM CELLS
• ,
• CELL THERAPY
• AND
• TISSUE ENGINEEERING

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• 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

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• 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.

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Forms (types) of cell therapy

• 1-Extracorporeal bioartificial organs used as
  assistance devices.
• 2-Injections, implantations or transplantation of
  cells.

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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.

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• 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

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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.

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• Cell sourcing remains among the most critical
  difficulties in the development of cell
  therapies, whether for bioartificial organs or
  for cell transplantation.

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• 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.

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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 hosts target tissues.
• 5-Ability to integrate into host tissues.

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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).

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• 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.
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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
cell-based 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.
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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 1015 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.

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• 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.

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Various potential therapeutic applications of
human embryonic stem cells (hES) (Habibullah,
2007).
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• 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).

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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.

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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 others.

It must be demonstrated that to alleviate human
suffering does not necessarily justify the use of
any means to achieve it.
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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.
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Obstacles to stem cell therapy
These hurdles are

• B- For NonESCs 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

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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.

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• 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.

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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 .

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• 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.

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• 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

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• 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

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• 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 tissue-engineered 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).

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• Closed tissue engineering systems have been used
  particularly for the treatment of diabetes, liver
  failure, and Parkinsons 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).

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• 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

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