Problem: Increasing demand for organ transplant and high risk of tissue rejection in transplanted

organs

While these increasingly common transplants have the potential to

save lives, treatment does not stop there. Our bodies tend to attack
transplanted organs, often damaging them over time to the point of
needing another transplant — a temporary solution meaning more
time spent on a waiting list.

What is Tissue Rejection and Why

Does it Occur?
Tissue rejection, or transplant rejection, is a process in which a
transplant recipient’s immune system attacks the transplanted organ
or tissue.

Our bodies’ immune systems are supposed to protect us from

agents that may be harmful, like bacteria or viruses. The immune
cells in blood identify antigens on the surface of the substance that
identify it as foreign, triggering an attack, so when those antigens
are found on a new organ, the organ can be in jeopardy. With
modern developments in transplant medicine, doctors can better
match immune systems to lower the risks of rejection.

There are multiple types of rejection:

 Hyperacute rejection – occurs just a few minutes after a
transplant when the antigens are completely unmatched. An
example would be a person being given the wrong blood type
during a blood transfusion. If the tissue is not removed right
away, the patient will usually die. This is now uncommon.

 Acute rejection – can quickly damage the transplanted organ,

but can also be treated with immunosuppressant drugs. The
risk is highest in the first three months but can occur even
years later. Most patients have an acute rejection of some sort.
  Chronic rejection – can take place over many years, slowly
damaging the transplanted organ. Even with
immunosuppressant drugs, chronic rejection can result in
eventual organ failure.

Immunosuppressant drugs are not without their own risks. They can
increase the risk of cancer or even lead to failure in a different
organ. While a necessary treatment to hold off the more severe risks
of transplant rejection, they tend to shorten the lifespan of
transplant recipients.

Organ Transplant Rejection Statistics

Historically, all tissue transplants have come with some level of
rejection. However, the risks are not equal across different types of
transplants.

 17% of kidney transplant recipients do not have a functioning

organ after three years, and only 54% still work after 10 years.

 25% of liver transplant recipients do not survive five years,

with 8,000 liver transplants performed in the U.S. alone each
year.

 12% of heart transplants fail in the first year, and the five-year

survival rate is 75 percent.

 Only about 50% of lung transplant recipients survive five

years.

Organ transplantation may be referred to as one of the greatest achievements in the history of
medicine. Short-, medium- and long-term results are excellent and, when compared with
patients who cannot receive a new organ, the impact on patient’s mortality, morbidity and
quality of life is tremendous. If we consider kidney transplantation as a paradigmatic
example, it currently represents the gold-standard for renal replacement therapy in patients
affected by end-stage renal disease. In fact, when compared with maintenance peritoneal or
hemodialysis, renal transplantation dramatically improves patient survival, quality of life, and
is cost-effective in terms of health care expenditures. According to a United States Renal
Data System report as of July 27, 2012, life expectancy from the time the dialysis is initiated
is approximately eight years for patients between the ages of 40 and 44, and 4.5 years for
those who are between 60 and 64 years of age. These figures are far surpassed by the
increased survival rates following kidney transplantation, which are 85%, 70%, and 44%
after 5, 10, and 20 years, respectively [13]. Similar data are reported by the European Renal
Association-European Dialysis and Transplantation Association (ERA-EDTA) Registry,
based on 2012 data, for which expected remaining life-times in years of
dialysis versus transplant patients in the age groups of 40–44 and 60–64 years are
11.5 vs 25.5 years, and 5.8 vs 12.3, respectively [14]. The main restriction of this modality is,
however, organ shortage. Based on “Organ Donation and Transplantation Activities Report in
2012,” released by Global Observatory on Donation and Transplantation (GODT) affiliated
to World Health Organization (WHO), the total number of 114,690 solid organs reported to
be transplanted in 2012 with just 1.8% of increase over 2011 and surprisingly less than 10%
of global needs [15]. Similarly, at the end of 2011, 96,574 patients were waiting for a kidney
in the USA, whereas only 16,813 kidney transplants were performed during the calendar
year. This corresponds to a cumulative probability to receive a renal graft at the first year
(from the time of registration on the waiting list) of only 9.65%. This figure increases at
3rd and 5th years to 21.65% and 36%, respectively—a rate that is not sufficient to satisfy the
demand for transplantable kidneys [13].
As these figures illustrate, the greatest challenge facing the field of organ transplantation is a
dramatic increase in the number of patients waiting for the organs in one hand, and the
limitation of available organs for transplantation, on the other hand.

Pigs and sheep both grow very fast, so from our estimates, it would take about 10
months or less. It depends on the organ, though. For pancreas islets, it might require
something like newborn piglets, whereas for something like a heart, you may have to
wait longer.
The organ was generated, useful and a perfect match. There’s no need for
immunosuppression or fear of organ rejection because it’s the patient’s own organ.

0
Solutions

Low organ transplant supply:

1.
Organ production outside the human body could address the shortage of organs for transplantation..
A new emerging technology proposes to use carrier animals for the development of human organs. In
this approach, induced pluripotent stem cells (iPSC) are injected in animal embryos to produce
chimeric animals that contain autologous human organs.

Induced pluripotent stem cells (iPSCs) are adult cells that have been genetically
reprogrammed to an embryonic stem cell–like state by being forced to express genes and
factors important for maintaining the defining properties of embryonic stem cells

iPSC are derived from skin or blood cells that have been reprogrammed
back into an embryonic-like pluripotent state that enables the development
of an unlimited source of any type of human cell needed for therapeutic
purposes. For example, iPSC can be prodded into becoming beta islet cells
to treat diabetes, blood cells to create new blood free of cancer cells for a
leukemia patient, or neurons to treat neurological disorders.
Interspecies chimeras may provide patient-specific organs for transplantation. The patient’s stem cells
(e.g., iPSCs) are injected into farm animal embryos to produce a human-animal chimera bearing
needed organ for transplantation back into the patient’s body. The chimeric animals can be made by
inducing stem cells into the embryo through aggregation, blastocyst injection or in utero
transplantation

Induced pluripotent stem cells (iPSCs) offer the prospect of generating

patient-specific organs. Delivering autologous, and thus immune-matched,
organs to replace a patient’s own failing organs would eliminate the
detrimental effects of lifelong immunosuppression needed after most
allogeneic human transplants.

A chimera is an organism with cells from two genetically different individuals. The
easiest chimera to understand is somebody with a heart transplant or bone marrow
transplant: That patient has somebody else’s cells in their body. So they’re a chimera.
My ultimate goal is to make human organs, and for that, we’re first trying to make
animal chimeras.
2.
In 2006, scientists discovered a way to “reprogram” mature cells – adult
skin cells, for example – into stem cells that could, in principle, give rise
to any tissue or organ in the body. Many assumed it was only a matter of
time until this groundbreaking technique found its way into the clinic and
ushered in a regenerative medicine revolution.

Because the same patient would be both the donor and the recipient of
cells derived from these so-called induced pluripotent stem cells (iPSCs),
these cells would be seen as “self” by the immune system, the thinking
went, and not subject to the problems of rejection that plague
conventional transplants.
Do Stem Cells Contain the Solution?
Although tissue rejection has always seemed like an unavoidable
occurrence with transplants, stem cells may offer a solution. A
clinical trial under the direction of Dr. Gary Levy and Dr. Harold
Atkins of The Ottawa Hospital suggests it may be possible to
essentially “trick” a body into accepting transplanted organs, without
the dangerous immune response that leads to rejection.

The new study is based on Atkins’ groundbreaking research into

treating multiple sclerosis with bone marrow-derived hematopoietic
stem cell (HSC) transplants. After the organ transplant, the doctors
plan to wipe out the patient’s immune system, then replace it with a
new immune system from the patients’ own stored HSCs. This
new immune system may then recognize a transplanted organ as
belonging in the body since it was there before the immune system
itself was formed — eliminating the need for immune-suppressing
drugs.

Although the trial is still in a limited phase, there are already

promising results. Three patients are no longer taking immune-
suppressing drugs. Levy describes them as immune tolerant.

One patient remained healthy for four and a half years, after
removing the drugs that used to be necessary to stop her immune
system from attacking her transplanted organ.
Heidary Rouchi, A, and M Mahdavi-Mazdeh. “Regenerative Medicine in Organ and Tissue
Transplantation: Shortly and Practically Achievable?.” International journal of organ transplantation
medicine vol. 6,3 (2015): 93-8.

Nagashima, Hiroshi & Matsunari, Hitomi. (2016). Growing human organs in pigs – a dream or reality?.
Theriogenology. 86. 10.1016/j.theriogenology.2016.04.056.