Similar
to the fetus, donor organs and tumors are also
seen as foreign materials and attract the attention of cytotoxic T cells, or
killer T cells. These cells primarily attack the invaders by inducing two
molecules - granzyme and perforin. These molecules work together to cause the
self-destruction of cells in transplanted organs and produce inflammation that
could lead to further destruction.
Dr.
Horuzsko uses an analogy involving a gun
barrel and bullet to explain the roles of the two effector molecules. Similar
to a barrel, the perforin creates a path that targets the cell and the granzyme
B acts as the bullet that shoots through. In certain patients, whose immune
system maybe insufficient, granzymes may act alone. Cells that are rendered
dead as a result of such an attack
may trigger inflammation and granzymes themselves trigger inflammation
directly, thereby, hurting the organ.
Around
15 percent of patients who have undergone kidney transplants will experience
cytotoxic T cell attack within 5 years of the transplant. This
may happen despite the best efforts to match donors and recipient and use of
drugs to suppress the immune response. Dr. Horuzsko and his team have been able
to understand partly, the role of HLA-G dimer in tackling the immune molecules
and overcome the cytotoxic T cells that produce these molecules.
The Study
To
understand the impact of HLA-G dimer, the research team measured the plasma
level of 40 patients whose organs were rejected and 90 patients who were doing
well. Significantly higher levels of HLA-G dimer were found in patients doing
well, without any clear picture of demographic factors like age or race
indicating naturally higher levels of the molecule.
Genetic analysis also confirmed that HLA-G dimer directly
down-regulated the expression
of the granzyme B gene. Activation of the killer T cells and granzyme B by
HLA-G dimer were considerably restricted in a transgenic mouse developed by the
team that expresses human LILRB1, which is considered the primary receptor for
HLA-G.
When
the cytotoxic T-cells of healthy individuals, contained in a dish, were
activated by a lectin known to attract the attention of the immune system,
almost half of the resulting killer cells were found positive for granzyme B.
When the blood cells of healthy volunteers were penetrated with HLA-G dimer, it
was noted that granzyme B was downregulated and the killer T cells present were
less capable of their targeted kills. The
team found an increased number of HLA-G dimer receptors on the killer cells.
This suggests that granzymes and perforin aimed at the new organ did not act
and the protective nature of HLA-G as gauged by the research team is accurate.
'Humanized' Mouse
Model
The
research team developed a 'humanized' mouse, a living model of a human
transplant with the immune system of one person
being given cells from another. On using this mouse model, Dr. Horuzsko
mentioned,
"It provides an environment
that is much closer to what we see in a patient."
Similar
to patients with naturally high levels of HLA-G, giving HLA-G dimer also
interferes with the killer instincts of T cells.
"It's more evidence this mechanism is working in a real situation,"
says Dr. Horuzsko.
In
a transplant, where the match is less than ideal, white blood cells, an initial
indicator of immune response, show up as early as when a new organ is
transplanted in the operating room. Typically, this might happen over the
course of a week or so as the recipient's immune system naturally produces what
Dr. Horuzsko refers to as an 'orchestra' of immune cells, where the cytotoxic T
cells are the most powerful players. He says,
"It's a very dynamic process."
Future of Humanized
Models in Transplants
In
the future these humanized models could be used as an
additional test for compatibility of donor and recipient, says
Dr. Horuzsko. They could help in determining the type and volume of drugs that
would work best for individual patients.
"We
are talking about a living test of organ compatibility. This is the future of personalized medicine" he remarks,
observing that higher levels of HLA-G dimer and less response to the donor
organ would mean less medicine and better outcomes.
Observations of the
Research Team
Presently
the therapies used to help in evading organ rejection include enhancing the
recipient-donor match and prescribing drugs to suppress the immune response,
which can make patients susceptible to infections and cancer.
The dimer, though very
powerful, is also vulnerable and could break apart easily,
Dr. Hurzsko mentions. Speaking of the tasks that need to be completed before
clinical trials commence, he says,
"We
need to generate a stable, unbreakable HLA-G dimer."
Naturally
high levels of HLA-G may not increase an individual's risk of developing cancer
but would reduce the immune system's ability to fight cancer, if developed.
Small tumors do not attract the attention of HLA-G dimer.
Following
a
kidney
transplant, HLA-G levels would increase in most patients not
necessarily to protect the transplanted organ, but as a natural balance to the
immune response which boosts as a reaction to the presence of foreign material.
Dr.
Horuzsko says that granzyme B, similar to HLA-G, remains idle in the body until
it is required to kill a virus picked up from dirt or bacteria on a sandwich.
HLA studies are already being used to help identify good, matching donors.
Reference : - Molecule silences barrel, bullet pointed at transplanted organ - (https://jagwire.augusta.edu/archives/60880)
Source: Medindia
