Topic 21 Transplantation Immunology
Introduction
The immune response has evolved as a
way of discriminating between “self” and “non-self." Once “foreignness” has been established, the
immune response precedes toward its ultimate goal of destroying the foreign
material, be it a microorganism or its product, a substance present in the
environment, a drug, or a tumor cell.
The triggering of the immune system in response to such foreign
substance is, of course, of great survival value. In this section we discuss the process of rejection of
foreign organ grafts. This is, of course, a cell mediated immune response,
although antibodies also play a role in rejection. The transplantation of cells or organs from one individual
to another for therapeutic purposes has become commonplace. For example, transfusions of blood
are routine, and over 10,000 kidneys are transplanted per year worldwide with a
high degree of success. More
spectacular, and frequently widely publicized, transplantations of the
heart, lungs, and liver are becoming more common. If the operation nonetheless fails, it is not because the surgeon
lacks the necessary skill, but because of a immunological attack of the body
against the transplant. Since
individuals of the same species differ in their genetic constitution and
therefore differ also in the proteins and other constituents of their bodies, a
graft presents a set of foreign proteins to the recipient, which the
recipient’s immune system recognizes as antigens. The immune system mounts a response against them. In this section we will also, learn why grafts
are rejected, and what are the mechanisms are involved. Bone marrow grafts give rise to a condition called
graft-versus-host disease, which is also discussed. Finally we will look at the clinical aspects
of transplantation.
Objectives
On completion of this section and
the required reading, you should be able to:
n show that the cell mediated response to
transplants is the same as the immune response to any other foreign antigen;
n describe four types of grafts;
n distinguish among the first set rejection,
the second set rejection and chronic rejection;
n differentiate between a host versus graft
reaction and graft versus host reaction;
n compare the contribution of Class I and Class
II MHC to graft rejection;
n comment on which T cells are responsible
for graft rejection;
n describe serologic tissue typing;
n describe the mixed lymphocyte reactions
and why you would want to use the MLR in tissue typing;
n rank the success rate for transplants of
different tissues and organs.
Required Reading
Please refer to the Textbook Key for
the appropriate reading for this section.
P Key Words
|
• allogtraft • alloreactivity • autograft • chronic
rejection • Class
I MHC • Class
II MHC • first
set rejection • graft • grafting • Graft
vs host reaction |
• mixed
lymphocyte reaction • privileged
sites • privileged
tissues • second
set rejection • syngraft • transplant • transplantation • transplantation
immunity • xenograft |
P Key Concepts
n Transplantation rejection is
immunologically mediated
n Foreign organ grafts are rapidly rejected
by untreated recipients as a result of the recognition of MHC class I and class
II molecules on the graft by T cells
n Both T cells, and circulation antibodies
are induced against allografts or xenografts.
While antibodies are responsible for rejection of erythrocytes, T cells
are mainly responsible for the rejection of most other tissue.
n The degree of histocompatibility between
donor and recipient can be determined serologically or by mixed lymphocyte
reaction.
n Drugs that inhibit the immune responses
such as cyclosporine permit prolonged allograft survival and have made
transplantation of kidneys, heart, skin, and liver practical and effective
procedures.
n During pregnancy, the fetus protects
itself against maternal immune responses by means of local immunosuppresive
mechanisms active in placenta and uterus.
DID YOU KNOW?
Grafts that are not rejected -Privileged Sites
Certain areas of the body, such as the anterior chamber of the eye,
the cornea, and the brain, lack effective lymphatic drainage. Although antigen derived from grafts made in
these sites may reach lymphoid tissues, cytotoxic effector cells cannot reach the
graft, and these grafts survive relatively well. For this reason, corneal allografting is a successful procedure.
Sperm
Allogeneic sperm, of course, can successfully and repeatedly
penetrate the female reproductive tract without usually provoking a significant
immune response. Seminal plasma is
immunosuppresive, and sperm exposed to this fluid are nonimmunogenic, even
after washing. Prostatic fluid, one of
the immunosuppresive components of seminal plasma, also inhibits complement.
Pregnancy
Because the fetus possesses antigens derived from its father, it is
an allograft within the mother.
Nevertheless, the fetus is consistently successful in establishing and
maintaining itself through pregnancy, in spite of great histocompatibility
difference. The uterus is not a
privileged site, since grafts of other tissues, such as skin, made in the
uterine wall are readily rejected.
Under some circumstances, the mother makes antibodies against fetal
blood group antigens, and these can destroy fetal red blood cells either in
utero, as in humans, or following ingestion of colostrum, as occurs in other
mammals.
The immunological destruction of the fetus is prevented by the
combined activities of several immunosuppressive mechanisms. First MHC molecules are not expressed on
preimplantation embryos or oocytes.
Once the placenta forms, the fetus is protected from the mother’s immune
system by the trophoblasts (that part of the placenta in closest contact with
maternal tissue). Cells within the
trophoblasts do express MHC class I molecules, but these are not the highly
polymorphic class Ia molecules. Instead
the cells make HLA-G, nonpolymorphic class Ib molecule. This molecule, found only in the
trophoblasts, fails to trigger a T cell response and protects cells against NK
cell mediated lysis. As might be
expected, trophoblsts cells do not express MHC class II molecules. Another major cell-membrane structure found
on trophoblasts cells is CD46, also known as membrane cofactor protein. This molecule inhibits complement activation
and so prevent complement-mediated cell lysis.
In addition CD55 (decay accelerating factor) is incorporated in the
trophoblasts at the fetomaternal interface and so protects it against
complement attack. Cytokines such as
IFN- , which usually enhance MHC expression, have no effect on trophoblasts
cells. Nevertheless, in some mouse
strains, up to 95% of pregnant animals make antibodies against the fetal
MHC. In other strains none of the
mothers makes these antibodies. These
antibodies develop only at the end of a second pregnancy and are not
cytotoxic. Up to 40% of women make
antibodies to fetal MHC molecules after giving birth. Notwithstanding this, the presence of these antibodies has no
apparent effect on the course of the pregnancy.
Second, the fetus is a source of locally active immunosuppressive
factors, including the hormones estradiol and progesterone and possibly also
chorionic gonadotropin. The major
protein in fetal serum, -fetoprotein,
may be immuno- suppressive because of its ability to stimulate suppressor cell
function. Some pregnancy-associated
glycoproteins and a trophoblasts-derived interferon (IFN- ) have
immunosuppressive properties. Amniotic
fluid is rich in immunosuppressive phospholipids.
Third, blocking antibodies may be produced in response to fetal
antigens. These coat placental cells,
masking antigens and thus presenting their destruction by maternal T
cells. These antibodies can be eluted
from the placenta and shown to suppress other cell-mediated immune reactions
against paternal antigens, such as graft rejection. Absence of this blocking antibody accounts for some cases of
recurrent abortion in women.
Nevertheless, it can be shown that totally immunodeficient mice can have
successful pregnancies.
It must not be assumed from the foregoing list of immunosuppressive
factors that the pregnant female is grossly immunosuppressed. In fact, the immunosupression generated by
the fetus is very local in nature.
Pregnant animals have only minor deficiencies in cell-mediated immune
reactivity to nonfetal antigens, showing for example, a slight delay in the
rejection of skin grafts or transient unreactivity to the tuberculin skin
test. NK cell activity is also
suppressed during pregnancy.
Nevertheless a local immune response to fetal antigens stimulates
placental function. Thus hybrid
placentas are larger than placentas of inbred animals, and females tolerant to
paternal antigens have smaller placentas than intolerant females. Other studies show that mothers sensitized
to paternal MHC molecules have better fetal survival. This effect is due to the stimulatory effect of maternal IL-3 and
GM-CSF on trophoblasts growth.
I. R.Tizard. Immunology an
Introduction. 4th
edition. Sanders College Publishing,
Harcourt Brace College Publishers, 1995
Review Questions
1. Textbook Study Questions
Review questions at the end of the
Chapter 23. The answers with
explanations are available at the end of the textbook.
2. Multiple Choice Questions
1. Transplanted cells are
mainly destroyed by
A) B cells
B) macrophages
C) neutrophils
D) T cells
E) eosinophils
2. The fetus can be
considered a(n)
A) allograft
B) xenograft
C) heterograft
D) isograft
E) antigraft
3. The most common
serologic test used for the detection of HLA antigens on lymphocytes is
A) the complement fixation test
B) double gel diffusion
C) complement-dependent
cytotoxicity test
D) mixed lymphocyte reaction
E) radioimmunoassay
4. The MHC complex contains
the following except:
A) genes that encode
transplantation antigens
B) genes that encode
immunoglobulins
C) genes that regulate immune
responsiveness
D) genes that encode some
components of complement
E) genes that encode class I
and class II antigens
5. The major targets of
cytotoxic T cells within kidney allograft are
A) neutrophils
B) macrophages
C) vascular endothelial cells
D) glamerular cells
E) proximal tube cells
3. Definitions/Short Answer Questions
1. What is the difference
between autograft and syngraft? Give examples of both.
2. How do we know that the
immune system is involved in allograft rejection?
3. Are antibodies or T cells
the main mediators of rejection?
4. Compare and contrast the
first set rejection and the second set rejection.
5. What does the second set
rejection suggest about the similarity of transplantation antigens?
6. What conditions could lead
to a graft vs host response (GvHR)?
7. Even though class II
antigens are found mainly on immune cells, they can still contribute to graft
rejection. How?
8. What may be the biologic
significance of alloreactivity?
9. Describe serologic tissue
typing.
10. Describe the MLR (mixed
lymphocyte reaction). Why is this test done in addition to serologic tissue
typing?
11. Differentiate between
privileged sites and privileged tissues.
Where to Go from Here
Once you have completed the review,
take some time and complete the objectives. If you are having trouble with any
of the concepts, contact your instructor. Also, refer to your Instructor and
Assignment Information for assignments and due dates.
When you are confident that you can
complete the objectives, proceed to the next topic.