352
U N I T 4
Infection and Immunity
Transplantation
Immunopathology
Transplantation is the process of taking cells, tissues, or
organs, called a
graft,
from one individual and placing
them into another individual. Sometimes grafts are trans-
planted from another site in the same individual. The indi-
vidual who provided the tissue is called the
donor,
and
the individual who receives the graft is called either the
recipient
or the
host.
Transplantation rejection is discussed
here because it involves several of the previously discussed
immunologic reactions. Amajor barrier to transplantation
is the process of rejection, in which the recipient’s immune
system recognizes the graft as foreign and attacks it.
The cell surface antigens that determine whether the tis-
sue of transplanted organs is recognized as foreign are the
MHC or
human leukocyte antigens
(HLA) that were dis-
cussed in Chapter 15. Transplanted tissue can be catego-
rized as an
autologous
graft if the donor and recipient are
the same person,
syngeneic
graft if the donor and recipient
are identical twins, and
allogeneic
(genetic variations of the
same gene within a given species) if the donor and recipi-
ent—whether related or not—share similar HLA types.
The molecules that are recognized as foreign on allografts
are called
alloantigens.
Donors of solid organ transplants
can be living or dead (cadaver) and related or nonrelated
(heterologous). Rejection of allografts is a response to
MHC molecules, which are so polymorphic that no two
individuals are likely to express the same MHC molecules,
unless they are identical twins. The likelihood of rejection
varies indirectly with the degree of MHC or HLA related-
ness between the donor and recipient.
Immune Recognition of Allografts
Rejection of allografts is a complex process that involves
cell-mediated immunity and circulating antibodies.
Although many cells may participate in the process of
acute transplant rejection, only the T lymphocytes seem
to be absolutely required.
1–3
The recipient’s T cells rec-
ognize allogeneic antigens in the graft by two pathways:
the direct and indirect recognition pathways.
2
In the
direct pathway,
T cells of the transplant recipi-
ent directly recognize donor MHC molecules of the
surface of antigen-presenting cells in the graft.
1,2
Both
the CD4
+
and CD8
+
cells of the transplant recipient are
involved in the reaction. Recipient CD8
+
T cells recog-
nize donor class I MHC molecules and differentiate into
mature CTLs that kill cells in the grafted tissue (see type
IV hypersensitivity reactions). The CD4
+
helper T-cell
subset is triggered into proliferation and differentiation
into T
H
1 effector cells by recognition of donor class II
MHC molecules. As with delayed hypersensitivity reac-
tions, cytokines secreted by activated CD4
+
cells cause
increased vascular permeability and local accumulation
and activation of macrophages, resulting in graft injury.
In the
indirect pathway,
recipient CD4
+
T cells recog-
nize donor MHC molecules after they have been picked
up, processed, and presented by the recipient’s own
antigen-presenting cells.
1,2
Thus, the indirect pathway is
similar to the physiologic processing and presentation of
other foreign antigens. This form of recognition mainly
activates DTH pathways of the type IV hypersensitivity
reactions. This indirect pathway is also involved in the
production of antibodies against graft alloantigens. If
the alloantigens are proteins, they are picked up by host
B cells and processed, and their peptides presented to
helper T cells, which then stimulate antibody responses.
2
Patterns and Mechanisms of Solid
Organ Graft Rejection
The basic patterns of transplant rejection have histori-
cally been classified based on the time course of the
response and the pathologic mechanisms involved.
1–3
Based on experience with kidney transplants, which have
been done for a longer time and more often than any
other organ, the patterns of response are called hyper-
acute, acute, and chronic. In actual practice, however,
there is often an overlap in features. The diagnosis is fur-
ther complicated by the effects of immunosuppressant
drugs or the possible recurrence of the original disease.
Hyperacute Rejection
Hyperacute rejection occurs almost immediately after
transplantation.
3
In kidney transplants, it can often be
seen at the time of surgery. As soon as blood flow from
the recipient to the donor kidney begins, it takes on a
cyanotic, mottled appearance. At other times, the reac-
tion may take hours or days to develop.
The hyperacute response is produced by existing
recipient antibodies to graft antigens that initiate a type
III, Arthus-type hypersensitivity reaction in the blood
vessels of the graft. These antibodies usually have devel-
oped in response to previous blood transfusions, preg-
nancies in which the mother makes antibodies to fetal
antigens, or infections with bacteria or viruses possess-
ing antigens that mimic MHC antigens.
Acute Rejection
Acute rejection may occur within the first few days to
weeks after transplantation, or it may occur suddenly
antibody complexes and are responsible
for vasculitis (as seen in systemic lupus
erythematosus or acute glomerulonephritis),
systemic immune complex disease (serum
sickness), and local immune complex disease
(Arthus reaction).
■■
Type IV cell-mediated hypersensitivity reactions
include direct cell cytotoxicity, in which sensitized
CD8
+
T cells kill antigen-bearing target cells, and
delayed-type hypersensitivity reactions, in which
presensitized CD4
+
T cells release cytokines that
damage and kill antigen-containing cells.
SUMMARY CONCEPTS
(continued)
