Transcript Slide 1

IMMUNOLOGY
Bios 328
a textbook-based study of immunology
Spring 2003
http://www.lehigh.edu/~sk08/Courses/Bios328/mainpage.htm
Transplantation
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Definition: to transfer (an organ or
tissue) from one part or individual to
another (Merriam-Webster)
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May take place between different
parts of the same organism
(autografting), different organisms of
the same species (allografting), or
even different species (xenografting)
The Basics
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Tissue from another source is grafted into a
host
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The host either recognizes the graft as self
and accepts it, or recognizes it non-self and
an immune response develops
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The immune response destroys the graft and
local vascular tissue (rejection)
http://www.novartis-transplant.com/medpro/
symposia/immunology_of_TX.html
Autografting
An example of graft acceptance
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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:
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Skin grafts
Bone marrow transplantation
Stem cell transplantation
Synthetic implantation
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
Stage 1 – Sensitization Stage
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Antigen recognition by T-cells triggers
lymphocyte proliferation
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‘Antigen’ – portions of the graft’s HLA complex
(MHC) are processed and presented
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Minor histocompatibility complexes also play a
role – they don’t need to match exactly, but
multiple mismatches can trigger rejection
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Important: major HCs can be recognized
directly by T-cells, minor HCs must be
processed and presented by APCs
Stage 2 – Effector Stage
The host immune system
attacks the graft, destroying
it with four methods (first two
most important):
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CTL-mediated cytotoxicity
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Delayed-type hypersensitivity
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Antibody-dependent cellmediated cytotoxicity
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Complement-mediated lysis
Clinical Transplantation
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Many human diseases and disorders are
caused by defects in organs and tissue
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Transplanted organs can replace organs
that are defective or damaged by disease.
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Improved surgical technique has made
many different types of tissue grafting
possible
Clinical Transplantation
Milestones in Transplantation
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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
Hyperacute rejection
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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?
Acute rejection
A two-stage process
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A good old
fashioned immune
response
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Within two weeks of
transplantation,
macrophages and
lymphocytes swarm
the tissue, triggering
cytotoxicity,
complement
activation, and graft
cell lysis
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The two week delay
is indicative of the
TH activation time
Chronic Rejection
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Even if a graft escapes an immediate
rejection responses, it can undergo
rejection years later
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Tissue typing and immunosuppressive
drugs decrease the likelihood of
chronic rejection, but they have a
long way to go
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If the rejection cannot be managed,
another transplant may be necessary
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Of course, due to the memory and
specificity of the immune system,
subsequent rejections occur even
more quickly and vigorously
Zones of Immunological Privilege
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Transplants into zones of immunological privilege
have proven highly successful
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For example, since there are few blood vessels in
the cornea, there is a very low rate (about 20%)
of corneal graft rejection
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There has even been some success transplanting
fetal pig neural tissue into the brains of
Parkinson’s disease patients
Graft-versus-host disease
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Lymphocytes from the donor
are carried by the organ into
the body of the graft
recipient
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If the recipient is
immunocompromised, the
foreign lymphocytes can
attack his tissue, resulting in
skin rashes, intestinal
problems, organ failure, and
death
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Liver, spleen, and bone
marrow transplants all carry
the risk of GVHD
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?
Immunosuppressive Therapy
Non-specific
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Drugs that interfere with the
immune response
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This attenuates the
rejection of donor tissue
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Decreased immune
responsiveness increases
susceptibility to pathogens
and cancers
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Current therapies involve
using multiple drugs in low
doses: the goal of this is to
minimize side effects while
still preventing rejection
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Many immunosuppressives
are derived from
fungi…why?
Cyclosporin A
Immunosuppressive Therapy
Specific
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Treatments that produce an immunodeficiency specific to
the donor alloantigens – an artificial hole in the repertoire
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Monoclonal antibodies can block T-cell activation and
binding, extending the life of transplanted organs
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Soluble fusion proteins can be made with block
costimulatory signals necessary for T-cell activation
Xenotransplantation
Xenotransplantation – the transfer of tissue
from one species to another
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Usually refers to the implantation of animal
tissue in humans
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Many different types of tissue may be
transplanted
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Using animals for organs would provide a
vast new source of organs for humans
Clinical Aspects
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Attempts at kidney, heart, liver, and bone marrow
transplants from primates into humans have met
with little success
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The earliest xenotransplantation of a chimpanzee
kidney into a human took place in 1964
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In 1993, T.E. Starzl performed two liver transplants
from baboons into patients suffering from liver
failure (both died within 70 days)
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Pigs have also been considered as a source of
organs, especially kidneys
Problems with Xenotransplantation
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Even with immunosuppression, the
foreignness of animal tissue provokes a
vigorous immune response
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Viruses and diseases which have no ill
effects in animals have the potential to
cause serious illness in humans
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Animal retroviruses may combine with
human variants, producing dangerous
new pathogens
Solutions?
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Animals bred with human
histocompatibility genes (transgenic
animals) would have organs
immunologically indistinguishable
from human organs
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Other transgenic organs might
produce proteins that prevent
destruction by the complement
system
Summary
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Graft antigens (in the form of MHC and
bound ligands) are recognized by host
lymphocytes (most importantly TH-cells)
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The resulting cell-mediated response
destroys the graft tissue, which undergoes
necrosis
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In future transplants, serum antibodies may
trigger antibody-mediated (hyperacute)
rejection – specificity and memory