Ch. 17. Transplantation Immunology

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Ch. 17. Transplantation Immunology What is
graft rejection? How is graft rejection
controlled? What is the status of
transplantation? Barriers surgical availability
immune response
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First successful human kidney transplant-
1954 Many organs have been transplanted
successfully
Key insight came from blood group work (notion
of incompatibility) Medawar, 1940s- graft
rejection is immune reaction autografts are
accepted, allografts are not second grafts are
rejected more rapidly than the first
(memory) Discovery of MHC arose from transplant
work
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Current goals minimize graft rejection (demand
is high, availability of genetically identical
donors is low) Minimize rejection without
suppressing entire immune response
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Types of grafts Autograft- within same
individual Isograft- from genetically identical
donor Allograft- from genetically different
member of the same species Xenograft- from a
different species future transgenic species?
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Many antigens determine histocompatibility MHC
antigens produce most vigorous rejection response
Mouse haplotype b/b and k/k produce a b/k
offspring (inbred mouse strains) Offspring can
accept graft from either parent Neither parent
can accept graft from offspring
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Outbred populations Chance of match between
(full) siblings is about 25 How to determine
if donor and recipient are compatible? Blood
groups must match blood group antigens are also
found on endothelium of blood vessels (part
of donor tissue) Microcytotoxicity test
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p. 430
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Identity at MHC Class I and Class II is not
the whole story MHC differences may be
recognized directly by T cells
(alloreactivity) Other antigens must be presented
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Mechanisms of graft rejection Sensitization Dend
ritic cells in graft may act as APCs Host
effector cells can migrate Donor cells can
migrate to periphery and present graft antigens
there Other cells may act as APCs
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Varies with the graft Effector cells are usually
produced in the lymphoid tissue and then
circulate back to graft Skin- vasculature
restored gradually Kidney or heart-
immediately Some sites (e.g., eye) do not
encounter immune cells
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p. 453
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Clinical aspects of graft rejection Hyperacute-
within 24 hours graft is never
vascularized preexisting antibodies
(complement) Crossmatching to prevent
this Acute- within a few weeks TH cell
activation Chronic- a long time later humoral
and cell-mediated an intractable problem
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Immunosuppressive therapy Most drugs are
nonspecific Other rapidly-dividing cells are
affected (epithelial cells, bone marrow
cells) Mitotic inhibitors- azothiaprine,
methotrexate Corticosteroids- anti-inflammatory
More specific inhibitors cyclosporin A, FK506-
inhibit T cell activation Rapamycin- blocks TH
proliferation
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Cyclosporin A was the breakthrough Other drugs
are newer less toxic to kidneys effective at
lower doses TLI- total lymphoid
irradiation recipients lymphoid tissues are
irradiated before grafting bone marrow is not
repopulating cells seem to be more tolerant
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Immune therapy Monoclonal antibodies that block
T cell response To surface proteins high-affinit
y IL-2 receptor TCR-CD3 or accessory
molecules adhesion molecules looking for
anergy To cytokines To co-stimulatory
signal might target activated T cells more
specifically (TH and APC)
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• Clinical cases
• Kidney
• most common easier surgically than some
• the donor survives
• Transplant recipients are sensitized to further
• transplants

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II. Bone marrow Recipient is immunosuppressed
before graft Graft-vs-host disease is common
(50-70) TNF-? is a major player Possible
treatments immunosuppression donor T cell
depletion (partial some activity needed
against host T cells)
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III. Heart surgery is quite successful MHC
matching is often not feasible massive
immunosuppression transplants seem to be prone
to coronary disease IV. Lungs sometimes go
with heart transplants are still rare V. Liver-
parts have been grafted successfully resistant
to antibody mediated toxicity but not
GVHD relatively difficult surgery
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VI. Pancreas- functional parts (islet
cells) still rare VII. Skin- usually
autologous burn victims- tissue bank donors have
been used. immunosuppression is a problem
because a burn patient is vulnerable to infection
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VIII. Immunologically privileged sites Some
areas not infiltrated by immune cells cornea,
brain, uterus, testes thymus? What about
sequestering donor tissue from host immune
system? e.g., islet cells in semipermeable
membranes worked in mice
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VIII. Xenotransplantation- promising but
controversial Better to meet the
demand? Nonhuman primates- have not been
particularly successful, and not that common
anyway Transgenic pigs organs are similar size
and structure are being engineered to have human
antigens and/or immunosuppressive
capacities can be bred in large numbers and
under controlled conditions
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Drawbacks success of graft is not
proven appropriate use of these animals? risk
of spreading zoonoses (animal-borne diseases)
to human recipients? development of new
pathogens? should we be doing this?
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Why is the fetus not rejected? Protected
site Local immunosuppression uterine epithelium
and trophoblast secrete cytokines that
suppresses TH1 placenta secretes a substance
that depletes tryptophan T cell
starvation? tolerance of paternal MHC
antigens? Outer layer of placenta does not
express MHC Class I and Class II antigens