Pancreatic islet cell transplantation

Abstract

Type 1 Diabetes mellitus is an autoimmune disease characterized by the destruction of insulin-producing beta cells in the pancreas. These patients become dependent on external insulin because they cannot produce insulin. However, in the long-term, exogenous insulin treatment does not prevent diabetic complications. In order to find an alternative diabetic treatment, clinical studies have demonstrated that pancreas transplantation or purified pancreatic islet transplantation could maintain control over blood sugar levels in Type 1 diabetes patients and were more effective treatment methods for these patients. Pancreatic islet transplantation is carried out with a smaller transplantation mass compared to complete pancreas transplantation. This also allows a more minor operation and transplantation of less immunologic tissue. Therefore, new methods aim to improve pancreatic islet transplantation.

Full text

doi: 10.5606/dsufnjt.2019.003
Demiroglu Science University Florence Nightingale Journal of Transplantation 2019;4(1-2):16-22
Pancreatic islet cell transplantation
Mine Ün1, Oytun Erbaş2
İletişim adresi: Mine Ün. İstanbul Aydın Üniversitesi Tıp Fakültesi, 34295 Sefaköy, Küçükçek mece, İstanbul, Türkiye.
e-posta: unmine13@gmail.com
ABSTRACT
Type 1 Diabetes mellitus is an autoimmune disease characterized by the destruction of insulin-producing beta cells in the pancreas. These patients
become dep endent on external in sulin because they cannot p roduce insulin. However, in the long -term, exogenous insu lin treatment does not preven t
diabetic complications. In order to find an alternative diabetic treatment, clinical studies have demonstrated that pancreas transplantation or purified
pancreatic isl et transplantation could maintain control over blood sugar levels in Type 1 diabetes patients and were more ef fective treatment methods
for these patients. Pancreatic islet transplantation is carried out with a smaller transplantation mass compared to complete pancreas transplantation.
This also allows a more minor operation and transplantation of less immunologic tissue. Therefore, new methods aim to improve pancreatic islet
transplantation.
Keywords: Beta cells, pancreatic islet transplantation, type 1 diabetes mellitus.
INSULIN HORMONE
Energy is the body’s most basic necessity in
order to maintain life. Through a hormone called
insulin produced by beta cells in the pancreas,
sugar (glucose) acquired from ingested food or
excreted to the blood from the stores in the liver
enters cells and is converted into the energy
required for the body.[1-3]
Blood sugar decreases when it enters cells.
That is, insulin is the main hormone to decrease
blood sugar. The beta cells of the pancreas
continually control blood sugar and release insulin
when the body needs it.[1- 3]
TYPE 1 DIABETES MELLITUS
The autoimmune disease in which the
pancreatic Langerhans islet beta cells are deemed
foreign and eliminated by the body’s defense
cells is called type 1 diabetes mellitus. In type 1
diabetes, destruction of beta cells renders the body
unable to produce insulin and becomes dependent
on external insulin intake.[4,5]
Type 1 diabetes is a disease of increasing
prevalence which reduces quality of life and life
expectancy and may threaten vital organs with
complications such as chronic hyperglycemia,
nephropathy, retinopathy, and neuropathy.[4-8]
In order to maintain blood sugar levels, patients
with type 1 diabetes require external insulin
intake. Banting and Best’s discovery of insulin
in the early 1920s was revolutionary. Diabetes,
which previously caused rapid mortality, became
preventable with this discovery.[7-10 ]
Insulin injection is used to delay or even
prevent the occurrence of complications such
as nephropathy, neuropathy, and retinopathy
in the short-term, however, in the long-term,
these patients may develop chronic diabetic
complications (nonhealing wounds, renal failure,
blindness, cardiovascular diseases, etc.) which
worsen over time.[4 ,5 ,7, 11]
Cite this article as:
Ün M, Erbaş O. Pancreatic islet cell transplantation. D J Tx Sci 2019;4(1-2):16-22.
1Istanbul Aydın University Medical Faculty, Istanbul, Turkey
2Department of Physiology, Demiroğlu Bilim University Faculty of Medicine, Istanbul, Turkey

17
Pancreatic islet cell transplantation
In other words, external insulin intake is
inadequate. Clinical studies have shown that
pancreas or purified pancreas islet transplantation
may ensure blood sugar control in type 1 diabetes
patients and are more effective treatment
methods.[12-14]
PANCREAS TRANSPLANT
Pancreas transplantation is the most effective
form of treatment in type 1 diabetes. However,
pancreas transplantation is a major surgical
procedure. It is also difficult to find a compatible
pancreas, and in order to prevent organ rejection,
recipients must use immunosuppressant’s for the
continuation of their lives, which has relatively
harmful effects. Therefore, pancreas transplantation
is only performed on end stage diabetic patients
who have developed type 1 diabetes-related renal
failure or other serious complications.[12, 14]
PANCREAS ISLET (BETA CELL)
TRANSPLANTATION
The best alternative to pancreas organ
transplantation in type 1 diabetes is pancreas islet
transplantation.[7,13,15]
Since Langerhans islets in the pancreas contain
insulin-producing beta cells, transplantation
of these islets alone is a relatively interesting
approach to type 1 diabetes. Islets account for
only 1-2% of the pancreas, and is therefore a
much smaller transplantation mass compared to
complete pancreas transplant. This allows for a
more minor surgical operation and transplantation
of less immunological tissue.[7,13,15 ]
Another advantage of islet transplant is that
healthy islets can be isolated from donor pancreas
even when the entire pancreas is unsuitable for
transplantation.[12,15 ]
ISLET TRANSPLANT STUDIES
For the first time in 1967, Paul Lacy developed
a new collagenase-based method for pancreas
islet isolation in rats. The method was further
modified by Dr. Camillo Ricordi, who worked
together with Lacy to successfully isolate islets in
in vitro and in vivo experiments.[16-29]
The first successful animal models for
successful islet transplantation was published in
the 1960s-1970s. Studies demonstrated how the
transplanted islets prevented diabetes in both
rodents and nonhuman primates.[19,20,28,29]
In the 1970s and 1980s, successful animal
models were attempted in humans. However,
since pancreas islets are structurally different in
humans compared to small animals (rats, guinea
pigs, etc.), methods used to isolate islet cells
in small cells were ineffective when applied in
humans. Therefore, these methods were aimed to
be adapted for humans.[21,28,29]
In the mid-1980s, the first human islet
transplantation was performed. Initial attempts
at islet transplantation had relatively low
success rates. According to studies, transplanted
islets were able to prevent diabetes after one
year of insulin synthesis in only one out of
10 patients.[7,21,22,28,29]
In the late 1990s, despite developments
with continuing transplants, only about 10% of
recipients were able to achieve normal blood
sugar (euglycemia).[7,22,28,29]
In later years, yearly islet transplantation
success rates leaped from 10 to 50% with
advancements in islet isolation and purification
techniques. In other words, at least half of patients
who underwent islet transplantation achieved
insulin independence in over a year.[7,21,22,28,29]
In following years, more successful islet
transplantations were performed. The most
important of these transplantations were
performed in 2000 by Dr. James Shapiro et al.[22]
at the Alberta University Diabetes Institute in
Edmonton, Canada. By using islets from multiple
donors, transplantation was conducted in seven
type 1 diabetes patients and all seven patients
achieved normal blood sugar levels without
exogenous insulin use over the period of one year.
In this manner, annual insulin independence rate
attained 100% with the Edmonton method.[22,28]
By introducing the world to the clinical
method to be known as the Edmonton protocol,
James Shapiro et al.[22] achieved a revolutionary
achievement in islet transplantation studies.[28]
This protocol was adapted by islet
transplantation centers worldwide and
greatly increased the success rates of islet
transplantation.[7,28]

D J Tx Sci18
HOW ARE ISLETS TRANSPLANTED?
The pancreas required for pancreas islet
transplant is obtained from persons who have
undergone brain death and islet cells are obtained
during a 6 to 8-hour long process of enzymatic
degradation of the pancreas and extraction of
beta cells. Currently, relatively pure islet cell
preparations can be obtained with collagenase
digestion of the pancreas, followed by the use
of Ficoll-Conray discontinuous gradient for the
separation of isolated islets.[13,28,29]
With many special drug combinations that
prevent organ rejection (sirolimus, tacrolimus,
daclizumab), isolated beta cells are transferred to
the liver through a catheter attached to the portal
vein (the main vessel that carries blood from the
intestines to the liver) under local anesthesia. The
islets of insulin that are transported to the liver
begin to secrete insulin to regulate blood sugar
(Figure 1).[7,28]
Although islet transplantation to the liver
(Edmonton method) may seem like it would have
long-term effect, studies by the same authors
showed that islets transplanted to the liver lost
function within the first few years, and most
patients require repeated injections after five
years.[ 7,2 3 ]
Studies have leaned towards comprehending
why islets lose function in the liver. After
administration to the portal vein, the islets reach
the liver and must adapt to it, however, they are
faced with negative conditions. Immediately after
administration to the vein, islets are exposed to
higher levels of drugs and nutrients such as glucose
in the portal system compared to the peripheral
circulation, causing loss of islet function.[24]
It should also be known that
immunosuppressant drugs used by the recipients
are another one of the main causes of function
loss in transplanted islets.[7,23,24]
DISADVANTAGES OF ISLET
TRANSPLANTATION
Although islet transplantation seems easy,
there are serious difficulties in isolating beta cells
from the pancreas without harming islets. In
addition, a considerable number of islets must be
transplanted in order to maintain blood glucose
levels for a long period of time. Since islets cannot
be extracted without completely harming all of
them, a single transplantation requires at least
two human donor pancreases. Furthermore, islet
transplantations must be repeated more than
once.[7,25,26]
Even if a large number of islets are successfully
transplanted, the recipient’s immune system
attacks the transplanted beta cells. Therefore,
the patient’s immune system must be suppressed.
Figure 1. Edmonton method. Beta cells isolated from the donor’s pancreas are injected to the recipient’s
portal vein. These cells settle in the liver and begin to produce insulin.[7]

19
Pancreatic islet cell transplantation
As in all transplantation procedures, recipients
are required to use immunosuppressants for
the rest of their life after islet transplantation.
High doses of immunosuppressive drugs are also
harmful (Figure 2).[7,27-29]
Therefore, it is necessary to develop new
methods to protect the transplanted islets from
prolonged destruction in the body and keep them
alive longer without the use of immunosuppressive
drugs which have the potential to cause serious
side effects in patients.[30]
NEW METHODS TO INCREASE ISLET
CELL LONGETIVITY
There have been significant developments in
islet transplantation over the last 10 years.[31-33 ]
It has been understood that one of the reasons
transplanted cells undergo rapid destruction
with the Edmonton method is that they are
transplanted to the liver, which contains high
levels of toxic drugs. Therefore, researchers have
studied alternative regions to transplant the islets.
Studies investigating transplantation into regions
such as arm muscle, spleen, renal capsule, and
bone marrow have found longer prolonged vitality
of the islets in these regions.[34-36]
In ongoing studies, it is aimed to transplant
islets without immunosuppressive drugs. In one
of the first methods developed to transplant
islets without immunosuppressive drugs, islets are
first encapsulated with materials to protect them
from external factors (encapsulation) and then
transplanted to recipients (Figure 3).[28,29,37]
These studies aim to protect the islets from
the recipient’s immune system by encapsulating
them with an encasement. However, this time,
the immune system develops tissue inflammation
against the encapsulation material. These
encapsulation studies on islet transplantation have
been unsuccessful.[28.29,37]
Researchers who realized they could not
protect the islets from the immune defense system
later attempted to transplant islets into regions
with the least amount of immune response. With
this purpose in mind, islet transplantation was
attempted in regions such as the brain, thymus,
and testes, rather than the liver. However, these
transplantations were also unsuccessful because
of the toxic molecules excreted by the molecules
of the tissue cells themselves. It was later thought
that it would be more reasonable to introduce the
corresponding molecules synthesized in these
tissues into the islets prior to transplantation by
gene transfer instead of transferring the islets to
these regions.[28,29,38]
After the idea of gene transplants to the islets,
the human gene TRAIL (TNF Related Apoptosis
Figure 2. Disadvantages of islet transplantation and methods of prevention.[27]

D J Tx Sci20
Figure 3. Encapsulation. Islets are transplanted to the
recipient after being encapsulated by materials capable of
protecting them from the recipient’s immune system.[28]
Inducing Ligand) came to mind. This gene has
the ability to suppress the immune system of
the recipient. With this aim, a large number
of islets were isolated from the pancreases of
rats. The TRAIL gene was transferred to islets
with adenovirus, which is a suitable vector for
gene transfer (Adenovirus is the most commonly
used gene vector in clinical gene therapy trials
today).[39 -48]
Later, two groups of rats with Streptozotocin-
induced type 1 diabetes were surgically
transplanted with islets with and without gene
transfer under their renal capsules. Rats with islet
transplantations without gene transfer had normal
blood sugar levels for a short period of time which
later reelevated. Increased blood sugar showed that
the transplanted islets were eventually rejected.
Islet transplantation after gene transfer, however,
maintained normal blood sugar levels for a longer
period of time compared to transplantation without
gene transfer. In addition, renal sections of rats
with gene-transferred islets showed a significantly
lower rate of immune cells compared to those
without gene transfer. This study demonstrated
that transferred genes protected the islets from
the recipient’s immune system and that none of
these rats were administered immunosuppressive
drugs.[43 -48] That study prevented gene-transferred
transplanted islets from being damaged by the
recipient’s immune system. This method only
provides protection to islets in the transplantation
region with gene transfer.[43-48]
In conclusion, studies on pancreas islet
transplantation are rapidly advancing and this
suggests that significant findings on this subject
will be discovered in the future.[43 -49]
Declaration of conflicting interests
The authors declared no conflicts of interest with
respect to the authorship and/or publication of this article.
Funding
The authors received no financial support for the
research and/or authorship of this article.
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