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Transplantation

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... problems, organ failure, and death Liver, spleen, and bone marrow transplants all carry the risk of GVHD Cyclosporin A Xenotransplantation ... – PowerPoint PPT presentation

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Title: Transplantation


1
(No Transcript)
2
Transplantation
  • Definition to transfer (an organ or tissue) from
    one part or individual to another
    (Merriam-Webster)
  • May take place between different parts of the
    same organism (autografting), different organisms
    of the same species (allografting), or even
    different species (xenografting)

3
The Basics
  • Tissue from another source is grafted into a host
  • The host either recognizes the graft as self and
    accepts it, or recognizes it non-self and an
    immune response develops
  • The immune response destroys the graft and local
    vascular tissue (rejection)
  • http//www.novartis-transplant.com/medpro/
    symposia/immunology_of_TX.html

4
AutograftingAn example of graft acceptance
  • The transfer of self tissue from one body site to
    another in the same individual
  • Due to the genetic homology of the tissue, the
    immune system does not respond to it
  • Many uses
  • Skin grafts
  • Bone marrow transplantation
  • Stem cell transplantation
  • Synthetic implantation

5
Rejection
  • When the immune system of the host detects
    foreign graft tissue, it launches an attack,
    resulting in tissue rejection
  • Two Stages
  • Sensitization Stage
  • Effector Stage
  • Three Clinical Manifestations (more on this
    later)
  • Hyperacute
  • Acute
  • Chronic

6
Stage 1 Sensitization Stage
  • Antigen recognition by T-cells triggers
    lymphocyte proliferation
  • Antigen portions of the grafts HLA complex
    (MHC) are processed and presented
  • Minor histocompatibility complexes also play a
    role they dont need to match exactly, but
    multiple mismatches can trigger rejection
  • Important major HCs can be recognized directly
    by T-cells, minor HCs must be processed and
    presented by APCs

7
Stage 2 Effector Stage
  • The host immune system attacks the graft,
    destroying it with four methods (first two most
    important)
  • CTL-mediated cytotoxicity
  • Delayed-type hypersensitivity
  • Antibody-dependent cell-mediated cytotoxicity
  • Complement-mediated lysis

8
Clinical Transplantation
  • Many human diseases and disorders are caused by
    defects in organs and tissue
  • Transplanted organs can replace organs that are
    defective or damaged by disease.
  • Improved surgical technique has made many
    different types of tissue grafting possible

9
Clinical Transplantation
10
Milestones in Transplantation
  • 1682(!) bone from a dog is used to repair a
    human skull
  • 1881 earliest skin grafts (some using frog
    skin)
  • 1930 Karl Landsteiner awarded Nobel Prize for
    discovery of ABO blood groups
  • 1945 P.B. Medawar publishes a paper linking
    graft rejection and the immune system
  • 1954 first successful kidney transplant between
    identical twins
  • 1967 - first successful heart transplant
  • 1990 first living-donor lung transplant
  • 1992 a patient receives a baboon liver and
    survives for two months
  • 1995 An AIDS patient receives a bone marrow
    transplant from a chimpanzee
  • 2002 first liver transplant (between identical
    twins) performed without immunosuppresion

11
Hyperacute rejection
  • Takes place within 24 hours of transplantation
  • Serum antibodies react to foreign MHC, triggering
    the complement system
  • The inrush of neutrophils and the inflammation
    causes clot formation in the blood vessels
  • The graft dies without being vascularized

But where do those serum antibodies come from?
12
Acute rejectionA two-stage process
  • A good old fashioned immune response
  • Within two weeks of transplantation, macrophages
    and lymphocytes swarm the tissue, triggering
    cytotoxicity, complement activation, and graft
    cell lysis
  • The two week delay is indicative of the TH
    activation time

13
Chronic Rejection
  • Even if a graft escapes an immediate rejection
    responses, it can undergo rejection years later
  • Tissue typing and immunosuppressive drugs
    decrease the likelihood of chronic rejection, but
    they have a long way to go
  • If the rejection cannot be managed, another
    transplant may be necessary
  • Of course, due to the memory and specificity of
    the immune system, subsequent rejections occur
    even more quickly and vigorously

14
Zones of Immunological Privilege
  • Transplants into zones of immunological privilege
    have proven highly successful
  • For example, since there are few blood vessels in
    the cornea, there is a very low rate (about 20)
    of corneal graft rejection
  • There has even been some success transplanting
    fetal pig neural tissue into the brains of
    Parkinsons disease patients

15
Graft-versus-host disease
  • Lymphocytes from the donor are carried by the
    organ into the body of the graft recipient
  • If the recipient is immunocompromised, the
    foreign lymphocytes can attack his tissue,
    resulting in skin rashes, intestinal problems,
    organ failure, and death
  • Liver, spleen, and bone marrow transplants all
    carry the risk of GVHD

16
Barriers to Medical Transplant
  • Difficulties posed by the immune system
  • The necessity of MHC matching makes it harder to
    find compatible organs
  • Repeat graft recipients reject new organs faster
    and more vigorously with each new transplant
  • Shortage of available organs
  • Many transplantable organs can only be taken from
    cadavers
  • Organs must also be matched for size and
    condition
  • Solutions?

17
Immunosuppressive TherapyNon-specific
  • Drugs that interfere with the immune response
  • This attenuates the rejection of donor tissue
  • Decreased immune responsiveness increases
    susceptibility to pathogens and cancers
  • Current therapies involve using multiple drugs in
    low doses the goal of this is to minimize side
    effects while still preventing rejection
  • Many immunosuppressives are derived from
    fungiwhy?

Cyclosporin A
18
Immunosuppressive TherapySpecific
  • Treatments that produce an immunodeficiency
    specific to the donor alloantigens an
    artificial hole in the repertoire
  • Monoclonal antibodies can block T-cell activation
    and binding, extending the life of transplanted
    organs
  • Soluble fusion proteins can be made with block
    costimulatory signals necessary for T-cell
    activation

19
Xenotransplantation
  • Xenotransplantation the transfer of tissue from
    one species to another
  • Usually refers to the implantation of animal
    tissue in humans
  • Many different types of tissue may be
    transplanted
  • Using animals for organs would provide a vast new
    source of organs for humans

20
Clinical Aspects
  • Attempts at kidney, heart, liver, and bone marrow
    transplants from primates into humans have met
    with little success
  • The earliest xenotransplantation of a chimpanzee
    kidney into a human took place in 1964
  • In 1993, T.E. Starzl performed two liver
    transplants from baboons into patients suffering
    from liver failure (both died within 70 days)
  • Pigs have also been considered as a source of
    organs, especially kidneys

21
Problems with Xenotransplantation
  • Even with immunosuppression, the foreignness of
    animal tissue provokes a vigorous immune response
  • Viruses and diseases which have no ill effects in
    animals have the potential to cause serious
    illness in humans
  • Animal retroviruses may combine with human
    variants, producing dangerous new pathogens

22
Solutions?
  • Animals bred with human histocompatibility genes
    (transgenic animals) would have organs
    immunologically indistinguishable from human
    organs
  • Other transgenic organs might produce proteins
    that prevent destruction by the complement system

23
Summary
  • Graft antigens (in the form of MHC and bound
    ligands) are recognized by host lymphocytes (most
    importantly TH-cells)
  • The resulting cell-mediated response destroys the
    graft tissue, which undergoes necrosis
  • In future transplants, serum antibodies may
    trigger antibody-mediated (hyperacute) rejection
    specificity and memory
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