Ch. 17
Ch. 17. Transplantation Immunology
What is graft rejection?
How is graft rejection controlled?
What is the status of transplantation?
Barriers
surgical
availability
immune response
Ch. 17
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
Ch. 17
Current goals: minimize graft rejection
(demand is high, availability of genetically
identical donors is low)
Minimize rejection without suppressing entire
immune response
Ch. 17
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?
Ch. 17
p. 427
Ch. 17
p. 428
Ch. 17
p. 428
Ch. 17
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
Ch. 17
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
Ch. 17
p. 429
Ch. 17
Ch. 17
Ch. 17
p. 430
Ch. 17
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
Ch. 17
Mechanisms of graft rejection
Sensitization
Dendritic 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
Ch. 17
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
Ch. 17
p. 432
Ch. 17
p. 453
Ch. 17
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
Ch. 17
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
Ch. 17
Cyclosporin A was the breakthrough
Other drugs are newer
less toxic to kidneys
effective at lower doses
TLI- total lymphoid irradiation
recipient’s lymphoid tissues are irradiated
before grafting
bone marrow is not; repopulating cells seem
to be more tolerant
Ch. 17
p. 436
Ch. 17
Immune therapy
Monoclonal antibodies that block T cell response
To surface proteins
high-affinity 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)
Ch. 17
p. 438
Ch. 17
Ch. 17
p. 439
Ch. 17
p. 440
Ch. 17
Clinical cases
most common; easier surgically than some
the donor survives
Transplant recipients are sensitized to further
transplants
Ch. 17
II. Bone marrow
Recipient is immunosuppressed before graft
Graft-vs-host disease is common (50-70%)
TNF-β is a major player
Possible treatments
immunosuppression
donor T cell depletion (partial; some
activity needed against host T cells)
Ch. 17
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
Ch. 17
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
Ch. 17
p. 443
Ch. 17
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
Ch. 17
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
Ch. 17
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?
Ch. 17
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