The HLA
System
Everyone has
distinguishing physical characteristics inherited from their
parents. Some, such as eye and hair color, are easily seen by
the naked eye. Others, such as fingerprints and blood type,
require more sophisticated technology to detect.
White blood cells
carry a distinguishing "fingerprint" on their surface called the
HLA system-the human leukocyte antigen system. (Leukocyte means
white blood cell). These antigens are proteins that play a
critical role in protecting the body against invading organisms
such as bacteria, viruses and other foreign matter.
At birth, certain
white blood cells called T-cells are programmed by the thymus
gland to identify all the antigens that belong in that person's
body. When a foreign antigen is encountered, e.g. antigens on
the cell surface of invading bacteria or viruses, the T-cells
summon the various components of the immune system to attack and
destroy the invading organism.
Similarly, when bone
marrow is transplanted from a donor into a BMT patient, the
patient's T-cells will examine the antigens on cells in the
donated marrow, and will launch an immune system attack if they
perceive the antigens to be "non-self". If the patient's immune
system destroys the donated bone marrow, graft-rejection results
and the BMT fails.
Alternatively (and
more commonly) the T-cells in the donor's bone marrow overpower
the patient's T-cells. They identify the patient's body as
"non-self" and orchestrate an immune system attack on the
patient's organs. This condition is called graft-versus- host
disease (GVHD). (The graft is the donated bone marrow, the host
is the patient). GVHD is usually not life-threatening. However,
it can be a very uncomfortable side effect of an allogeneic BMT,
and in severe cases can be lifethreatening.
The HLA fingerprint
on white blood cells is composed of a pair of antigens at
several sites or "loci" on the white blood cell-one each
inherited from the mother and the father. The antigens at three
of these sites-the HLA-A, HLA-B, and HLA-DR loci are known to
play an important role in determining whether graft-rejection
will occur and the severity of GVHD. Pairs of antigens are also
known to exist at other sites on white blood cells such as the
HLA-C,-E,-DP and DQ-loci. However, their importance in bone
marrow transplantation is not yet fully understood.
To date, 24
different possible antigens have been identified at the HLA-A
site, 52 at the HLA-B site, and 20 at the HLA-DR site. Since
each person has two antigens at each site, more than 600 million
combinations of HLA antigens are theoretically possible in the
general population! Fortunately, the antigens at the HLA-A,-B
and -DR loci are usually inherited as a set called a "haplotype"
from one or both parents, and certain types tend to occur
together, thus reducing the number of possible HLA combinations
known to occur in the general population.
In the figure above,
for example, one of the mother's haplotypes consists of the
antigens A-1, B-8, and DR-3; the other consists of the antigens
A-2, B-7 and DR-7. Children #1 and #4 have inherited the
mother's first haplotype, while children #2 and #3 have
inherited the second. Children #1, #2 and #4 have inherited the
father's first haplotype, while child #3 inherited the father's
second haplotype.
HLA-Matching
To minimize the risk
of graft rejection and graft-versus- host disease, a donor whose
HLA type matches that of the patient is best. The optimal donor
is often an identical twin. Not only will the twin have
inherited from the father and mother the same antigens at the
major loci (HLA-A,-B, and -DR) as the patient, but the antigens
at tissue antigen sites other than HLA sites that are more
difficult to detect or whose role in transplantation is unclear
will also match. The risk of either graft-rejection or severe
GVHD in BMTs using marrow from an identical twin is eliminated.
In other cases, the
best bone marrow donor will be a sibling who is not an identical
twin, but whose HLA-A, -B, and -DR antigens match those of the
patient. In the figure on page 36, for example, Child #1 and
Child #4 are a "perfect" HLA match, having each inherited one
identical haplotype from their father and one identical
haplotype from their mother. There may, however, be some mis-match
at other less significant or well understood non-HLA loci which
can cause mild to severe graft-versus-host disease post
transplant. The risk of developing severe GVHD in a transplant
using a matched sibling donor is approximately 20 percent, and
the risk of graft rejection is usually less than 1 percent.
Child #2 and Child
#3, on the other hand, each inherited an identical haplotype
from their mother, but different haplotypes from their father.
Were Child #2 or Child #3 to need a bone marrow transplant,
either an unrelated bone marrow donor with matching antigens at
the HLA-A, -B, and -DR loci would have to be found, or a
transplant using "mismatched" bone marrow from their sibling
would have tobe considered.
HLA-Typing
Tests
At least two tests
are used to determine whether a patient's and donor's HLA-types
match. The first is a blood test that can detect antigens at the
HLA-A, -B and -DR loci. Secondary tests, such as the mixed
lymphocyte culture (MLC) test, are used to assess whether or not
the patient's and donor's bone marrow interact adversely.
Newer tests such as
DNA typing will make HLA-typing more precise in the future. DNA
testing has already revealed that antigens once thought to be
identical may in fact have as many as 10 different variations or
"microvariants". The significance of all these variations is not
yet known, but they may explain the increased frequency and
intensity of GVHD and occurrence of graft rejection in BMTs
using mis-matched or unrelated donors.
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