School of Applied Medical Sciences

Principles of Tissue Engineering

Organ Transplantation

By:

Abdallah Alashqar
Supervisor:

Dr. Hamdi Hamdi

German Jordanian University

Amman, Jordan
June 2015

Background and History

Organ transplantation is the act of moving an organ from the body of the donor to the patient
needing that organ.
Organ transplantation has a very wide and a bit old history; the first attempt of it goes
back to even before the invention of the first haemodialysis machine. Jaboulay was the first to
attempt it back in 1906. He attempted treating two patients with renal failure by transplanting
a goat kidney to the first patient and a pig kidney to the second patient. He joined the renal
vessels to the brachial vessels in both patients. Unfortunately, these transplants failed and both
patients died.[1]
It is true that the previous attempt was the first in the history of organ transplantation
and although it was done to treat humans, the donors in that attempt were animals. Thus the
truly first human to human organ transplantation attempt was done by the Ukrainian surgeon,
Yu Yu Voronoy in 1936, who performed the first in a series of six transplants to treat patients
suffering from renal failure secondary to mercury poisoning caused by attempts of committing
suicide by the victims. Unfortunately, all these transplants also failed.[1]
The limitations and problems that caused the failure of the aforementioned approaches to
transplant an organ can be summarized in 3 critical points; lack of suitable donor organs, problems related to surgical technique and problem of immune response.[1]
The early attempts used organs from animals or severely diseased humans until a realization
came of the excessive ischaemic injury and live donors organs began to be used. The second
major problem of surgical technique was related to joining vessels and kidney placement; this
could be overcome by a French solution in 1951 which involved placing the kidney extraperitoneally in an iliac fossa, where the external iliac vessels are easy to access and the bladder is
close by for anastomosis to the donor ureter.[1] The problem of immune response was and still
a very serious problem in such surgeries. Attempts to solve it included trying to control the
immune system using different methods. However, the first successful transplant came about
by avoiding an immune response alltogether by Joseph Murrays team when they performed a
kidney transplant between identical twins.[1][2]
As mentioned earlier, for a successful organ transplantation, a good number of healthy
donors is needed. This had been one of the main obstacles regarding organ transplantation.
The number of donors is very small compared to number of patients in waiting lists for organ
donation (especially kidney donors). A lot of patients die waiting for a donation or get removed
from the list after some time because they become too unfit for the operation.[1] This serious
problem will be addressed in details later in this report when talking about gaps and limitations
regarding organ transplantation.

Goals of the field

Organ transplantation surgeries have been very successful in the last years, thus promising to
be a considered as an efficient treatment for a wider range of diseases corresponding to a very
wide range of organs and tissues in the human body. Although there are other organs being
transplanted, currently most often transplanted organs are kidney, liver, pancreas, lung and
small intestine.[2] One of the goals is to widen this range of transplanted organs to a much
more complicated and difficult-to-deal-with organs.
Another important goal that needs to be addressed is to increase the number of donors and
fix the ratio of supply to demand regarding organ donation. This goal is being worked on by a
number of international health and research organizations and they have come up with some
interesting solutions that will be addressed later in this report.
One more goal is to improve the surgical technique and all technologies regarding this kind
on treatment including immunosuppression, organ preservation and other techniques that will
be discussed in the next section of this report.

Various Technologies that Made the Field Possible

Transplantation Tolerance and Immunosuppression
In organ transplantation, one of the major challenges is making the host body accept the new
transplanted organ and preventing it from attacking it. The field of immunosuppression and
transplantation tolerance is a very active field and open for research until now. In this subsection the techniques that are being used in addition to new approaches are going to be discussed.
Chemical immunosuppression is the ability to suppress the immune system sufficient to
permit engraftment of the transplant while at the same time not affecting other protective
immune responses.[1] The first chemical reagent that was successful in doing that was Azathioprine[1][4].
Currently, Immunosuppression is being performed using different chemical reagents that are
going to be discussed briefly in the following lines:
Ciclosporin
Ciclosporin has the ability of inhibiting T cell proliferation by blocking activation. Ciclosporin improved the results of kidney transplantation such that the vast majority of
kidney transplants survive 1 year. It also helps permitting successful liver, pancreas, heart
and lung transplantation.[1]

 Tacrolimus
Tacrolimus is very similar to ciclosporin but a bit more powerful. Tacrolimus binds
to calcineurin but on a different site than ciclosporin to achieve its effect. Tacrolimus
has also proved intestinal tansplant to be successfully undertaken. Both ciclosporin and
tacrolimus have some toxicities with a higher incidence of diabetes and neurotoxicity for
tacrolimus.[1]
Mycophenolic Acid (MPA)
MPA blocks the enzyme required for de novo synthesis of guanosine nucleotides; inosine
monophosphate dehydrogenase. By blockung guanosine synthesis by the lymphocytes,
DNA synthesis is blocked thus blocking lymphocyte proliferation. MPA is generally used
in combination with the drug classes: mTOR or CNIs. It has its main toxicity is in the
gastrointestinal tract.[1]

Now we are going to talk about tolerance which is a concept first introduced in 1953 when
Billingham et al showed that acceptance of skin graft from mice is a result of in-vetro injection of bone morrow cells from the same donor, while mice still rejected grafts from other
breeds.[13,14]
Tolerance is a very common and used term when talking about immune response and transplantation operations in general. It can be divided into three major types as follows:
True Tolerance
True tolerance is a term used to describe a situation where the transplant functions
normally for a considerable durable time and the subject or recipient has not taken any
immunosuppression reagents and there is no immune response that can be detected. In
other words, it is a permenant and specific immunological acceptance of the transplant
or allograft antigens without the use of any immunosuppression reagents.[5,6,7,8]
Operational Tolerance
The graft or transplant is not rejected and the recipient is not taking any immunosuppressants, but it could include some immune response towards the graft, but there is a
lack of any destructive response. This kind of tolerance usually is a result of elective or
non-elective immunosuppression withdrawal.[5,8]
Prope or Near Tolerance
As the name implies, this term is used to refer to the case when allograft functions
normally with normal histology but the patient receives minimal immunosuppression
reagents.

Tolerance induction is the modification of the host immune system to make it accept the new
transplanted organ without affecting its other functions as being competent and normally func4

tional. This method if performed successfully could guarantee the long-term survival of both
transplanted organ the patient.[5] In the coming lines, this is going to be discussed in a bit of
details.
Before we go so far and think of approaches to induce tolerance, lets look at an example
that is observed in our daily life. During pregnancy, the mothers immune system is being
tolerated to a whole new organism; the fetus. Furthermore, clinical cases have also shown that
tolerance could be achieved after cessation of immunosuppression reagents. However, in these
cases tolerance was a stochastic event.[9]
Tolerance also differs among different organs. For example, studies suggest that the liver is
more tolerated than heart, kidney and pancreas whereas other organs such as lung, skin and
intestine almost provoke or stimulate immunity.[9,10,11]
When studied deeply, it is noticeable that tolerance appears years after implantation; which
tells us that tolerance was achieved by a process rather than a sudden induction although there
are some exceptional cases. By looking on the studies, one can also see that there is no relationship to the recipients underlying renal disease. Furthermore, studies show a relationship with
patients age; donor age tends to be lower in patients that achieved tolerance in comparison
with general population.[9]
Although tolerance could be achieved in a good number of patients, more studies are needed
to know the exact factors affecting tolerance and immune response and to understand the
immune system more thoroughly. Furthermore, immunosuppressants withdrawal needs to be
studied to assess the best ways that would achieve long-term tolerance to transplanted organs.

Organ Preservation
A very important part of organ transplantation is organ preservation. The organs need to be
preserved in the best way so cells stay alive and active and no function of that organ is affected.
In this section the current approaches and methods used for organ preservation are going to be
discussed.
The two current approaches of organ preservation are static and dynamic approaches. The
main method for static preservation is simple static cold storage (SCS) while dynamic approaches include hypothermic machine perfusion (HMP) and other perfusion-based methods.[9]
SCS relies on cooling effects with the addition of some solutions that modify the inevitable cellular molecular changes positively. On the other hand, HMP depends on activating residual
metabolism with large dependency on energy generation which is synonymous with a need for
oxygen supply for aerobic metabolism delivered by vascular perfusion in mammalian systems.[9]

Relying on cooling methods is not always efficient, because sometimes the organ loses a part
of its function or has difficulty starting to function again after its function is stopped while it
is on ice. TransMedics, a new novel system that can preserve organs outside the body while
keeping them alive and fully functioning was developed in Europe. It proved efficiency and has
been approved for use in Europe while still under clinical trials in the US.[12]

The Gaps and Problems in the Field that Need to Be

Addressed
As mentioned earlier, the field of organ transplantation is a very critical field with a lot of
limitations and difficulties which makes at a very active and open field for further research and
studies.
One common problem is the very small numbers of organ donors compared to people on
waiting lists for donations. In other words; the huge gap between supply and demand regarding organ donations. Although in the last years number of live donors in the UK increased
drastically[1] the need for more donors is still there.
Another issue that needs to be further studied is the issue of immune response and tolerance
induction. Because transplantation tolerance has proved to be possible in many subjects and
recipients, it is very demanding to further study this field to be able to induce tolerance easily
and efficiently.

Future Outlook
Organ transplantation is a very active and developing field and thus has a very promising future.
Regarding supply and demand ratio, there has been a lot of campaigns around the globe;
especially in Europe to increase awareness about the necessity and importance of having more
live donors. These campaigns have proved effective by increasing the number of donors along
the past years and are expected to achieve more in the near future.
Another important aspect that has been discussed in this report is organ preservation. Currently, there are a lot of ongoing researches and studies to come up with new novel methods
to preserve organs more efficiently. One of the methods that are being developed is the TransMedics system that has been discussed earlier for the successes that it achieved and the wide
capabilities that it is open for.

References
[1] C. J. E. Watson and J. H. Dark, Organ transplantation: historical perspective and
current practice. British Journal of Anaesthesia, 2012.
[2] Merrill JP, Murray JE, Harrison JH, Guild WR. Successful homotransplantation of the
human kidney between identical twins. J Am Med Assoc 1956.
[3] WebMD website, Organ Transplant Overview. URL: http://www.webmd.com/a-to-zguides/organ-transplant-overview
[4] Calne RY. Inhibition of the rejection of renal homografts in dogs by purine analogues.
Transplant Bull 1961.
[5] R. F. Saidi and S. K. Hejazii Kenari, Clinical Transplantation and Tolerance: Are We
There Yet?, Int J Organ Transplant Med. 2014.
[6] Pearl JP, Preston E, Kirk AD. Tolerance: is it achievable in pediatric solid organ transplantation? Pediatr Clin North Am. 2003.
[7] Girlanda R, Kirk AD. Frontiers in nephrology: immune tolerance to allografts in humans.
J Am Soc Nephrol. 2007.
[8] Wiers G, Gras J, Bourdeaux C, et al. Monitoring tolerance after human liver transplantation. Transpl Immunol. 2007.
[9] Edgardo E. Guiberta Alexander Y. Petrenkob Cecilia L. Balabana Alexander Y. Somovb
Joaqun V. Rodrigueza* Barry J. Fullerc. Organ Preservation: Current Concepts and New
Strategies for the Next Decade, Transfusion Medicine and Hemotherapy, 2011.
[10] Hafez T, Fuller B: Applications: Organ preservation for transplantation; in Baust JG
(ed): Advances in Biopreservation. Owego, Cell Preservation Services, 2006.
[11] Elimadi A, Haddad PS: Cold preservation-warm reoxygenation increases hepatocyte
steady-state Ca++ and response to Ca++-mobilizing agonist. Am J Physiol Gastrointest
Liver Physiol 2001.
[12] CNN Article: New transplant technology keeps organs alive outside body. April 25,
2013 URL: http://edition.cnn.com/2013/04/25/health/live-organ-transplants/
[13] Stuber ML. Psychiatric issues in pediatric organ transplantation. Child Adolesc Psychiatr Clin N Am. 2010.
[14] Evans RW, Applegate WH, Briscoe DM, et al. Cost-related immunosuppressive medication nonadherence among kidney transplant recipients. Clin J Am Soc Nephrol. 2010.