C h a p t e r 1 6
Disorders of the Immune Response
353
months or even years later, after the discontinuation
of immunosuppressants in the post-transplant period.
Before modern immunosuppression, acute rejection
would often begin several days to a few weeks after
transplantation. The delayed time of onset of acute rejec-
tion reflects the time it takes for the recipient’s immune
system to generate T cells and antibodies against the
graft.
1
In kidney transplantation it is characterized by
abrupt onset of kidney failure, which may be associated
with fever and graft tenderness.
Acute rejection most typically involves both cell-medi-
ated and humoral mechanisms of tissue damage. In acute
cell-mediated rejection the activated T cells cause direct
lysis of graft cells and recruit and activate inflammatory
cells that injure the graft. Acute antibody-mediated or
humoral mechanisms involve blood vessel damage and
intravascular thrombosis that leads to graft destruction.
Chronic Rejection
Chronic rejection develops insidiously over months and
years and may or may not be preceded by episodes of
acute rejection. In recent years, acute rejection has been
significantly controlled by immunosuppressive therapy,
and chronic rejection has emerged as an important
cause of graft rejection. In kidney transplantation there
are signs of progressive kidney failure.
The dominant lesion in chronic rejection is arte-
rial occlusion resulting from the proliferation of vas-
cular smooth muscle cells, with graft failure resulting
from ischemic damage. These arterial changes are
often referred to as graft vasculopathy or accelerated
graft arteriosis.
1
The actual mechanism of this type of
response is unclear but may include release of cytokines
that stimulate proliferation of vascular endothelial and
muscle cells; repair with fibrosis after repeated bouts of
acute antibody-mediated or cellular rejection; and toxic
effects of immunsuppressive drugs.
1
Transplantation of Hematopoietic Cells
Bone marrow transplantation is increasingly being
used as therapy for hematopoietic and some nonhema-
topoietic malignancies, aplastic anemia, and immuno-
deficiency disorders. Hematopoietic stem cells can be
collected from donor bone marrow or peripheral blood.
Stem cell aspiration from the bone marrow is the most
common form of allograft collection. Peripheral blood
offers a less-invasive method for obtaining stem cells.
Hematopoietic growth factors, such as granulocyte
colony-stimulating factor, often are used to induce stem
cells to move out of the bone marrow into the blood.
Before either bone marrow or peripheral blood stem
cells are infused, recipients receive pretreatment condi-
tioning regimens (e.g., total-body irradiation or treat-
ment with cytotoxic drugs) to destroy malignant cells
(e.g., in leukemia) and to create a graft bed. Rejection
of the allogeneic bone marrow transplant appears to
be mediated by a combination of reactive T cells and
natural killer (NK) cells that are resistant to radiation
therapy and chemotherapy.
2
Graft-Versus-Host Disease
Graft-versus-host-disease (GVHD) occurs when immu-
nologically competent cells or precursors are transplanted
into recipients who are immunologically compro-
mised.
17,18
Although GVHD occurs most often in persons
who have undergone allogeneic bone marrow transplan-
tation, it may also follow transplantation of organs rich
in lymphoid tissue (e.g., the liver) or follow transfusions
with nonirradiated blood.
2
Three basic requirements are
necessary for GVHD to develop: (1) the transplant must
have a functional cellular immune component, (2) the
recipient tissue must bear antigens foreign to the donor
tissue, and (3) recipient immunity must be compromised
to the point that it cannot destroy the transplanted
cells.
1,17,18
The primary agents of GVHD are the donor
immunocompetent T cells derived from the donor mar-
row and the recipient tissue that they recognize as foreign
and react against.
2
Graft-versus-host-disease results in
activation of both CD4
+
and CD8
+
T cells, ultimately gen-
erating type IV cell-mediated DTH and CTL reactions.
The greater the difference in tissue antigens between the
donor and recipient, the greater the likelihood of GVHD.
Graft-versus-host-disease can occur as an acute or
chronic reaction.
Acute GVHD
, which develops within
days to weeks after transplantation, involves the epithe-
lial cells of the skin, liver, and gastrointestinal tract.
2
The
organ most commonly affected in acute GVHD is the
skin. There is development of a pruritic, maculopapular
rash, which begins on the palms and soles and frequently
extends over the entire body, with subsequent desquama-
tion (sloughing off skin). Involvement of the gastrointesti-
nal tract usually parallels the development of skin and liver
involvement. Gastrointestinal symptoms include nausea,
bloody diarrhea, and abdominal pain. Graft-versus-host-
disease of the liver is heralded by painless jaundice, hyper-
bilirubinemia, and abnormal liver function test results.
Liver involvement can progress to development of veno-
occlusive disease, drug toxicity, viral infection, iron over-
load, extrahepatic biliary obstruction, sepsis, and coma.
19
Chronic GVHD
may follow acute GVHD or it may
develop insidiously. Persons in whom chronic GVHD
develops are profoundly immunocompromised, and
they develop skin lesions resembling systemic sclero-
sis (discussed in Chapter 44) and manifestations mim-
icking other autoimmune diseases. As a result of the
severely compromised immune system, recurrent and
life-threatening infections are common.
SUMMARY CONCEPTS
■■
Transplantation involves taking cells, tissues, or
organs, called a graft, from one individual (a donor)
and placing them into another individual (recipient).
A major barrier to transplantation is the process of
rejection in which the recipient’s immune system
recognizes the graft as foreign and attacks it.
(continued)
