both normal and neoplastic. Vaccines incorporating
such antigens have had little success, perhaps because
the antigens are expressed at some level in normal cells
and tend to induce tolerance that has to be overcome for
induction of effective antitumor immunity.
More recently, there has been interest in developing
personalized cancer vaccines tailored for each patient’s
are neoantigens generated by passenger mutations
affecting random cellular proteins, and the mutations
must be within peptides that can bind to the patient’s
sequencing technologies to determine all the mutations
in the protein-coding DNA sequences (exosomes) of
peptides that are most likely to bind to the HLA alleles
neoantigen peptides. This approach is promising, but it
also has significant challenges. The vaccines have to be
customized for each patient; effective CTLs have to be
generated by the vaccination (which has been difficult
under the selection pressure of the vaccine-induced
given to tumor-bearing patients, they have to overcome
the immune evasion mechanisms that tumors may have
Tumor-specific vaccines may be administered as a
CHAPTER 10 Immunology of Tumors and Transplantation 207
pathway of cross-presentation and will generate CTLs
vaccination used in combination with therapies to block
immune regulation will have added benefits.
Tumors caused by oncogenic viruses can be prevented by vaccinating against these viruses. Two such
vaccines that are proving to be remarkably effective are
against hepatitis B virus (the cause of a form of liver
These are prophylactic vaccines given to individuals
before they are infected, and thus prevent infections by
Some of the earliest attempts to replace damaged tissues
by transplantation were during World War II as a way
of treating pilots who had received severe skin burns
the transplanted tissues. Studies since the 1940s and
1950s established that graft rejection is mediated by the
adaptive immune system because it shows specificity
and memory and it is dependent on lymphocytes (Fig.
10.9). Much of the knowledge about the immunology
of transplantation came from experiments with inbred
strains of rodents, particularly mice. All members of an
inbred strain are genetically identical to one another and
one inbred strain are accepted and grafts from one strain
to another are rejected, firmly establishing rejection as a
rejection and showed that the products of many of these
genes are expressed in all tissues.
As mentioned in Chapter 3, the genes that contributed
the most to the rejection of grafts exchanged between
called the donor, and the individual in whom the graft
animals) are said to be syngeneic; animals (and grafts)
of one species that differ from other animals of the same
species are said to be allogeneic; and animals (and
grafts) of different species are xenogeneic. Allogeneic
immune system. The antigens that serve as the targets
of rejection are called alloantigens and xenoantigens,
the clinical situation, transplants are exchanged between
allogeneic individuals who are members of an outbred
immune responses to allografts.
Prior exposure to donor MHC molecules
leads to accelerated graft rejection
The ability to reject a graft rapidly can be
transferred to a naive individual by lymphocytes
Depletion or inactivation of T lymphocytes by drugs
or antibodies results in reduced graft rejection
Major histocompatibility complex.
208 CHAPTER 10 Immunology of Tumors and Transplantation
The antigens of allografts that serve as the principal
targets of rejection are proteins encoded in the MHC.
Homologous MHC genes and molecules are present
in all mammals; the human MHC is called the human
leukocyte antigen (HLA) complex. It took more than
20 years after the discovery of the MHC to show that
(see Chapter 3). Recall that every person expresses
six class I HLA alleles (one allele of HLA-A, -B, and
-C from each parent) and usually six or seven class II
HLA alleles (one allele of HLA-DQ and HLA-DP and
one or two of HLA-DR from each parent). MHC genes
are highly polymorphic, with over 12,000 HLA alleles
among all humans, encoding about 2800 HLA-A proteins, 3500 HLA-B proteins, 2500 HLA-C proteins, 1800
HLA-DRß proteins, 800 DQß proteins, and 700 DPß
proteins. Because of this tremendous polymorphism,
appear foreign to, each other. Because the genes in the
HLA locus are tightly linked, all the HLA genes from
each parent are inherited together, as a haplotype, in a
Mendelian pattern, and therefore the chance that two
siblings will have the same MHC alleles is 1 in 4.
The reaction to allogeneic MHC antigens on another individual’s cells is one of the strongest immune
responses known. T cell receptors (TCRs) for antigens
As a result of positive selection of developing T cells in
the thymus, mature T cells that have some affinity for self
MHC molecules survive, and many of these will have high
the allogeneic cells may look like self MHC molecules
example of an immunologic cross-reaction.
cells generated from prior infections, that are specific
for different foreign peptides bound to the same self
MHC molecule may cross-react with any one allogeneic MHC molecule, regardless of the bound peptide,
as long as the allogeneic MHC molecule resembles
complexes of self MHC plus foreign peptides. As a
result, many self MHC–restricted T cells specific for
selection in the thymus eliminates cells that strongly
recognize self MHC, but there is no mechanism for
selectively eliminating T cells whose TCRs have a high
affinity for allogeneic MHC molecules because these
molecules, every one of which may be recognized as
foreign by a graft recipient’s T cells. By contrast, in the
case of an infected cell, only a small fraction of the self
MHC molecules on the cell surface will carry a foreign
microbial peptide recognized by the host’s T cells. The
net result of these features of allorecognition is that the
frequency of alloreactive T cells in any individual is
about 1000-fold greater than the frequency of T cells
that recognize any one microbial antigen.
Although MHC proteins are the major antigens that
stimulate graft rejection, other polymorphic proteins
also may play a role in rejection. Non-MHC antigens
that differ in sequence between donor and recipient.
reactions against foreign MHC proteins.
Induction of Immune Responses Against
to draining lymph nodes, where they are recognized by
alloreactive T cells (Fig. 10.11). The dendritic cells that
present alloantigens also provide costimulators and can
stimulate helper T cells as well as alloreactive CTLs. The
effector T cells that are generated circulate back to the
transplant and mediate rejection.
cells, or they may recognize peptides derived from
donor MHC molecules bound to recipient MHC molecules on the surface of recipient APCs (Fig. 10.12).
These two pathways of presentation of graft antigens
have different features and names.
Self MHC molecule presents foreign
peptide to T cell selected to recognize
self MHC weakly, but may recognize
self MHC-foreign peptide complexes well
The self MHC-restricted T cell recognizes
the allogeneic MHC molecule whose
structure resembles a self MHC-foreign
The self MHC-restricted T cell recognizes
a structure formed by both the allogeneic
MHC molecule and the bound peptide
210 CHAPTER 10 Immunology of Tumors and Transplantation
Activation of T cells, generation
of effector T cells by direct and
Fig. 10.11 Immune response against transplants. Graft antigens that are expressed on donor dendritic
dendritic cells in the graft may migrate to secondary
lymphoid organs of the recipient. When naïve T cells
in the recipient recognize donor allogeneic MHC
molecules on these graft-derived dendritic cells,
the T cells are activated; this process is called direct
recognition (or direct presentation) of alloantigens.
Direct recognition stimulates the development of
alloreactive T cells (e.g., CTLs) that can then directly
recognize the allogeneic MHC molecules on cells of
the graft and destroy the graft.
and transported to draining lymph nodes. Here,
donor alloantigens are processed and presented by
self MHC molecules on the recipient APCs. This
process is called indirect recognition (or indirect
presentation) and is similar to the cross-presentation
of tumor antigens to CD8+ T cells, discussed earlier.
displayed by the recipient’s self MHC molecules on
the recipient’s APCs, so they cannot recognize and
kill cells in the graft (which, of course, express donor
MHC molecules). When graft alloantigens are recognized by the indirect pathway, the subsequent
rejection of the graft likely is mediated mainly by
alloreactive CD4+ T cells. These T cells may enter
the graft together with host APCs, recognize graft
antigens that are picked up and displayed by those
APCs, and secrete cytokines that injure the graft by
an inflammatory reaction. Indirect allorecognition
by host CD4+ T cells also contributes to stimulating
production of host antibodies that bind to graft MHC
molecules, as discussed later.
CHAPTER 10 Immunology of Tumors and Transplantation 211
We do not know the relative importance of the direct
chronic rejection, as described later.
T cell responses to allografts require costimulation,
but which stimuli in grafts enhance the expression of
costimulators on APCs is unclear. As with tumors, graft
cells may undergo necrosis, perhaps in the period of
ischemia before the transplant is done, and substances
released from the injured and dead cells activate APCs
by innate immune mechanisms. As we discuss later,
blocking costimulation is one therapeutic strategy for
The mixed lymphocyte reaction (MLR) is an in vitro
model of T cell recognition of alloantigens. In this model,
T cells from one individual are cultured with leukocytes
of another individual, and the responses of the T cells are
assayed. The magnitude of this response is proportional
exchanged between these individuals.
antibodies are helper T cell–dependent high-affinity
antibodies. In order to produce alloantibodies, recipient
B cells recognize donor alloantigens and then process
and present peptides derived from these antigens to
helper T cells (that may have been previously activated
by recipient dendritic cells presenting the same donor
of alloantigens, in this case by B lymphocytes.
Immune Mechanisms of Graft Rejection
Graft rejection is classified into hyperacute, acute, and
chronic, on the basis of clinical and pathologic features
(Fig. 10.13). This historical classification was devised by
clinicians based on rejection of kidney allografts, and it
has stood the test of time remarkably well. It also has
become apparent that each type of rejection is mediated
by a particular type of immune response.
process and present graft proteins other than allogeneic MHC molecules.
212 CHAPTER 10 Immunology of Tumors and Transplantation
vessels and ischemic necrosis of the graft. Hyperacute
rejection is mediated by circulating antibodies that are
specific for antigens on graft endothelial cells and that
are present before transplantation. These preformed
antibodies may be natural IgM antibodies specific for
blood group antigens (discussed later in this chapter), or
vascular endothelium and activate the complement and
clotting systems, leading to injury to the endothelium
and thrombus formation. Hyperacute rejection is not a
common problem in clinical transplantation, because
every donor and recipient are matched for blood type
and potential recipients are tested for antibodies against
the cells of the prospective donor. (The test for antibodies
is called a cross-match.) However, hyperacute rejection is
a major barrier to xenotransplantation, as discussed later.
• Acute rejection occurs within days or weeks after
transplantation and is the principal cause of early graft
may be CD8+ CTLs that directly destroy graft cells or
against cells in graft vessels, leading to vascular damage.
graft vessels is caused mainly by complement activation
by the classical pathway. Current immunosuppressive
be manifested as fibrosis of the graft and by gradual
T cells that react against graft alloantigens and secrete
in the graft. Alloantibodies may also contribute to
chronic rejection. Although treatments to prevent or
rejection is refractory to most of these therapies and is
becoming the principal cause of graft failure.
Prevention and Treatment of Graft Rejection
The mainstay of preventing and treating the rejection
of organ transplants is immunosuppression, using
drugs that deplete T cells or inhibit T cell activation
and effector functions (Fig. 10.14). The development
of immunosuppressive drugs launched the modern era
of organ transplantation because these drugs made it
feasible to transplant organs from donors that were not
HLA-matched with recipients, especially in situations
when such matching was impractical, such as transplantation of heart, lung, and liver.
the calcineurin inhibitors, including cyclosporine and
Another widely used drug is rapamycin, which inhibits
a kinase called mTOR (mammalian target of rapamycin)
calcineurin and mTOR inhibitors (see Fig. 10.14).
inhibit responses to more than the graft). Therefore,
infections, particularly by intracellular microbes, and the
The matching of donor and recipient HLA alleles by
tissue typing had an important role in minimizing graft
rejection before cyclosporine became available for clinical
use. Although MHC matching is critical for the success
other types of organ grafts (e.g., renal allografts), modern
immunosuppression is so effective that HLA matching is
of donors is limited and the recipients often are too sick to
wait for well-matched organs to become available.
The long-term goal of transplant immunologists is to
induce immunological tolerance specifically for the graft
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