Chapter 21

Transplantation

Transplantation biology has been a central area of investigation in immunology.

Much of the early studies involving the induction of tolerance were based on under-
standing how grafted tissue (transplants) was accepted or rejected. Transplantation
studies further the understanding of how the immune system works such as under-
standing how self-tolerance differs from acquired tolerance and indeed how both
processes are similar. T cells play a significant role in tissue transplant rejection. For
our discussion of transplantation we will focus on the immunological features that
lead to transplant rejection and the mechanisms of rejection. Finally we will exam-
ine graft versus host disease and see how this differs from the recipient rejecting a
tissue graft. There are different types of grafts and the recipient host will mount
different types of responses to the grafts depending on the origin of the graft.

Types of Grafts

An autograft is tissue grafted within the same individual e.g. skin excised from one
part of the body and used in a different location i.e. after serious burns. No rejec-
tion occurs.
Syngeneic grafts or isografts are types of tissue transplanted between individuals
that are genetically identical. The tissue is accepted. An allograft is tissue grafted
between unrelated individuals of the same species. The individuals are termed
allogeneic. There are allelic variants of specific genes present on the allograft.
Alloantigens will be expressed on the transplanted tissue. These will be seen as
foreign by the cells of the recipient (the basis for histoincompatibility) and an
immune response will be made. In this case the graft is accepted for a few days and
then it is rejected. This is known as first-set rejection. If tissue from the same
individual is grafted again the recipient rejects the graft in a rapid manner, known as
second-set rejection. The rejection is dependent on T cells and can be transferred by
adoptive means i.e. if cells from the recipient are transferred to a naive individual a

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similar rejection mediated by the adoptively transferred cells will occur. The
allograft is the most common type of tissue transplant used clinically. Rejection or
acceptance of tissue and organs is dependent on the effectiveness of immunosup-
pressive therapy to reduce the effects of T cells (both CD8 and CD4 positive) and as
a result prolong the acceptance (the retention) of the graft. Xenografts is transplan-
tation of tissue from individuals of different species. The genetic differences
between the individuals are pronounced. For example, a transplant from a pig to
human is a xenograft. Rejection of the tissue is rapid. T cells as well as antibodies
can mediate rejection.
Major histocompatibility antigens play a very significant role in graft acceptance
or rejection. The more similar the MHC antigens the more likely the tissue graft will
be accepted. The more different the MHC antigens, the higher the chance that tissue
will be rejected. This is known as the alloreactive response and is the result of the
recipient recognizing the foreign or non-self alloantigens on the graft. This is
because the recipient and the donor have differences in the histocompatibility anti-
gens or MHC. Both major and minor MHC antigens are responsible for the response
to foreign alloantigens. Recall from our discussions of the MHC antigens that an
individual inherits MHC haplotypes from both parents and these are co-­dominantly
expressed. In addition, the MHC are highly polymorphic along the ~20–40 gene
loci. Therefore when tissue typing is performed, ABO typing alone is not sufficient
to identify a histocompatible match. The MHC loci have to be matched as closely as
is possible for an outbred human population.
Alloantigens on grafted tissue can be seen by the host response in different ways.
First of all the region bearing the graft needs to be in direct route of lymphatic drain-
age, for the most serious consequence of rejection to occur. Note that the grafted
tissue may have with it T cells or antigen presenting cells (of donor origin)-these are
called passenger leukocytes. The APCs can migrate to lymphoid tissue and stimu-
late recipient T cells.
APCs from the recipient can also recognize and process alloantigens from
the graft.
Cytotoxic T cells (CD8) from the recipient can also mediate direct attack on the
alloantigens. Cytokines can induce cell activation reactivity to alloantigens.
Macrophages can also be nonspecifically activated leading to inflammation and tis-
sue damage.
Antibody in combination with complement fixation can also mediate hyperacute
rejection of tissue. This is particularly important when there might have been previ-
ous exposure to alloantigens from blood transfusions, individuals that have had
multiple pregnancies, or individuals that have had a previous transplant. Rejection
can occur within minutes of organ transplant-In this case because the organs trans-
planted are vascularized cells, antibodies and complement will have direct and
immediate access to the graft.
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Graft-Versus Host Disease

Unlike host versus-graft rejection, graft-versus host disease (GVHD) occurs when
cells from the donor contained within the graft, attack recipient tissue. The donor
cells recognize alloantigens on host tissue. Mature T cells play a significant role.
This is very important in bone marrow transplants (most of the T cells are contami-
nants). The effects of GVHD are intense inflammation, severe damage to the skin,
rashes, intestinal damage, diarrhea and pneumonitis. Very careful MHC typing for
histocompatibility is necessary. Depletion of mature T cells and treating transplant
patients with immunosuppressive drugs generally leads to improved outcomes.
The mixed lymphocyte response (MLR) is generally carried out to identify
alloreactive T cells. Both major and minor MHC antigens are important in GVHD. A
more reliable assay where the alloreactive T cells are enumerated is also used. The
types of tissue rejection that can occur include hyperacute rejection that can occur
within minutes of grafting the donor tissue. Acute rejection can occur within 6-8
days and chronic rejection can occur within a few months to years. Over time a
variety of causes will lead to damage of the graft. Toxicity to immunosuppressive
drugs such as cyclosporin A may develop. Thickening of the walls of blood vessels
in the graft, blocking of the blood vessels, scar tissue, deposition of immune com-
plexes, cell-mediated immune responses, cytokines such as TGF beta, IFN gamma
may also mediate chronic rejection. Experimentally, TNF alpha, RANTES, and
MCP play a role. Viral infections notably CMV infections can also accelerate rejec-
tion of a graft.
Regarding the tolerance of the fetus (technically an allograft), a number of
explanations have been proposed. However, there is still much that is unclear about
the repeated tolerance that develops. This is particularly significant in cases where
a woman has several children. Each time the fetus expresses paternally derived
alloantigens or nonself MHC proteins that are tolerated. The fetus occupies a
protective or privileged site and so due to immunosuppressive factors is not
recognized by maternal immune responses. Placental sequesteration of the fetus
from maternally reactive T cells protects the fetus.
Cyokine production by the uterine endothelium and trophoblast leads to a
suppression of THI responses. Fetal blood cells do make their way into maternal
circulation providing the opportunity for alloantigens to be detected.
lmmunosuppression of the recipient immune system can allow acceptance and
retention of allografts. Plasmapheresis can be performed to remove antibodies that
may cause acute rejection. Plasma is removed ex vivo and the washed cells returned
to the body. Tolerance can be induced to allografts by exposure of the recipient to
alloantigens in blood transfusions to tolerize the recipient to B and T cells. T cell
activation can be inhibited by immunosuppressive treatment or by lysis.
Corticosteroids lyse T cells through endogenous activation nucleases that cleave
DNA.  This is most effective for immature T cells (thymocytes). Cytokine gene
transcription and cytokine secretion can be blocked. Cytokines such as IL-1, IL-6,
TNF and chemokines can be blocked to prevent inflammation and to remove
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costimulators of T cell activation. Cyclosporin A is important clinically for

immunosuppression. It is a cyclic peptide produced as a natural metabolite of
fungus. The major action of cyclosporine A is to inhibit transcription of specific T
cell genes especially IL-2. Cyclosporin A binds to the active site of a ubiquitous
cellular protein known as cyclophilin that functions as an enzyme. This molecule
may be involved in the proper folding of a transcription factor. No IL-2 is produced
resulting in a profound effect on CMI activities as well as the activity of T helper
cells. Other cytokines are affected, and genes for c-myc for example are inhibited.
The result is that there is a lack of T cell growth, effector T cell activation, and a loss
in specific immunity. Side effects or toxicity can occur affecting the kidneys. Other
immunosuppressive drugs include FK506 (tacrolimus) or OKT3. Inhibition of
CD80/86 signaling by the binding to the drug CTLA4-Ig (belatacept) inhibits T cell
activation by rendering the T cells anergic when otherwise the cells would be
targeting transplanted tissue, targeting the tissue for rejection.

Selected References

Ferrara JLM, Levine JE, Reddy P, Holler E (2009) Graft-versus-host-disease. Lancet 373:1550–1561
Murphy K, Weaver C (2017) Janeway’s immunobiology, 9th edn. Garland Press, New York
Punt J, Stranford SA, Jones PP, Owen JA (2019) Kuby immunology, 8th edn. W.H. Freeman and
Company, New York. Chapter 20, Antigen-antibody interactions