“Live life, pass it on” reads an
advertisement designed to increase potential organ donors. With more than 1,000
transplant waiting list patients dying per year in the UK, organ availability
and transplant success rates are key to serve a constantly increasing demand
for organ transplants.
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| Transplant centres across the world require more donors. Photo from Geralt |
Though transplantation was first
explored in 1902, it was not until 1954 that the first successful human kidney
transplant operation was performed. 50 years down the road, transplantation is
considered the best possible treatment for most individuals with organ failure.
Patients with severe kidney failure often prefer a single transplant procedure
to a four-hour dialysis treatment three times a week. In addition, over a
period of ten years, each successful kidney transplant patient saves the NHS (UK’s National Health Services) £24,100 ($49,355 CDN) per
year compared to dialysis
treatment.
A successful kidney transplant saves $49,355 CDN per year compared to dialysis
However, transplantation has
numerous challenges including organ rejection, infections, and cost. Organ
rejection is when the body’s immune system recognizes the donated organ as
“foreign” and attacks it. If the donated organ is continuously attacked, the
organ becomes non-functional. There are three categories of rejection based on
when the rejection occurs: hyperacute (within first few hours after
transplant), acute (within first year after transplant), and chronic (a year or
more after transplant). These organ rejection categories are believed to be
initiated by different aspects of the immune system such as the recipient’s
antibodies (proteins that recognize foreign objects) or white blood cells.
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| Organ rejection is one of the biggest risks of transplantation Photo from http://spacesick.blogspot.ca/2009/07/organ-rejection-shirt.html |
In order to minimize the potential for
rejection and increase transplant success, multiple protective measures are
taken. First, the donor must meet certain physical requirements. However, as
deceased donors are becoming older, more obese, and less likely to have
suffered trauma-related death (ie. died from organ failure), fewer organs are
considered suitable for donation. In addition, the patient and the donor must
be a closely matched by three immune components; the patient cannot have
antibodies that recognize the donor’s cells, and the patient’s blood and human
leukocyte antigen (HLA) type must be compatible with the donor. As a result,
even though organs are in high demand, 12% of suitable organs are not
transplanted due to a lack of compatible patients. Despite these protective
measures, the recipient’s immune system may still recognize the donated organ
as foreign and reject it. As a result, we have to resort to non-specific
immunosuppressants. This poses a problem as this also suppresses other
essential immune system functions, and causes the patient to be extremely
susceptible to infections.
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| Immunosuppressants have improved acute organ rejection rates, but not chronic rejection rates Photo from Stevepb |
Thanks to recent improvements in
immunosuppressive drugs, immunosuppressants have decreased acute organ
rejection rates, but chronic rejection still remains a significant problem. For
example, 93% - 97% of donated adult kidneys are still functioning well a year
after surgery, but this drops to below 75% after ten years. Not only do immunosuppressants become less
effective at decreasing the risk of organ rejection over time, but chronic use
of immunosuppressants has many challenges including patients’ reluctance to
continue taking drugs, risk of infection, and long-term monetary cost (around
£5,000 per year for each patient).
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| 93%-97% of patients survive one year following kidney transplantation |
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| ~75% of patients survive ten years following kidney transplantation |
Rather than improving current
immunosuppressive drugs that repress the entire immune system, a major goal of
transplantation research is to tailor the immune response to accept the newly
transplanted organ by persuading the immune system to tolerate donor organs
while still retaining its ability to respond to other disease-causing agents.
The ability to induce tolerance would counteract the risk of acute and chronic
rejection while eliminating the need for lifelong immunosuppressive therapy.
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| Tolerance is a major goal of transplantation research Photo from DasWortgewand |
A potential avenue for inducing
tolerance is through “mixed chimerism”, where the host and donor
bone-marrow-derived elements co-exist in the recipient. Mixed chimerism is
effective in transplantation because donor blood cells can migrate to the host
thymus and “teach” new T cells, a type of white blood cell, to ignore the
donated organ without using immunosuppressants. This ensures the new T cells
generated in the host are tolerant of elements from both the host and donor. An
additional benefit of mixed chimerism is that severe depletion of patient’s
bone marrow cells is not required unlike traditional transplantation
techniques. This is extremely advantageous because in retaining some of their
own own bone marrow cells, the recipient still has aspects of a working immune
system as a backup system in case the donor organ is rejected.
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| Mixed chimerism could be an effective because it "teaches" new white blood cells called T cells. Photo from Geralt |
One major barrier that we still have
to overcome is graft-vs-host disease (GVHD). GVHD is when the donor’s T cells
from the donor’s transplant migrate into the recipient’s tissues and attack the
“foreign” recipient’s body by recognizing HLA, which is contrary to organ
rejection that is initiated by the host’s immune system. It is typically
associated with stem cell or bone marrow transplant, but can also occur in some
organ transplants. GVHD can lead to acute or chronic and include symptoms such
as skin rash, muscle weakness, and selective damage to the liver and
gastrointestinal tract. Since transplants often occur without perfectly
matching HLA, balancing inducing tolerance via mixed chimerism while avoiding
GVHD remains a challenge.
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| Lung transplant rejection with H&E stain |
In general, most tolerance-inducing
methods have been based on blocking an essential aspect of white blood cell
activation known as co-stimulation. Co-stimulation ensures white blood cells
can become fully functional and replicate properly. Blocking this
co-stimulation essentially dampens the immune system and allows mixed chimerism
to occur. In animals, antibodies that target a particular co-stimulatory
pathway have been shown to allow mixed chimerism through reducing the immune
inflammatory response. However, translating this process into humans has been
challenging due to complications with blood clotting.
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| Xenotransplantation (using animal organs for transplantation) could become a possibility with mixed chimerism tolerance induction. Photo from Netalloy |
Overall, major leaps have been made
in making mixed chimerism tolerance induction safer and less toxic, so we can
expand its use in transplantation and beyond. In fact, if we are able to induce
tolerance, the possibility of xenotransplantation—using animal organs for
transplantation—would become a possibility. Despite the fact that
closely-related species are better
matched immunologically, the US Department of Health and Human Services
declared a moratorium on primate-to-human transplantation in 1999 due to the
potential risk of virus transmission. Today, xenotransplantation is focused on
pigs because of their organ size and physiologic similarity to humans, and
favourable breeding characteristics. Early research in xenotransplantation
focused on monkeys due to their similarity with humans. While pigs can be
slightly genetically modified to be more “human-like”, tolerance induction
remains a critical keystone to future xenotransplantation applications and the
key to solving our organ shortage dilemma.
References:
NHS Statistics obtained from http://www.odt.nhs.uk/national-organ-retrieval-service/statistics/