Transplantation

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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)

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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

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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

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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

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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

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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

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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

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Clinical Transplantation
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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

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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?
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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

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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

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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

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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

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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?

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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
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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

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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

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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

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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

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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

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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