Hindawi Publishing Corporation
Journal of Transplantation
Volume 2011, Article ID 141898, 10 pages
Inductionof Protective GenesLeads to
IsletSurvival and Function
1Division of General Surgery, Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
2Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
3Center of Biotechnologies, Cardarelli Hospital, 80131 Napoli, Italy
Correspondence should be addressed to Hongjun Wang, email@example.com
Received 10 June 2011; Accepted 1 September 2011
Academic Editor: Antonello Pileggi
Copyright © 2011 Hongjun Wang et al.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Islet transplantation is the most valid approach to the treatment of type 1 diabetes. However, the function of transplanted islets is
often compromised since a large number of β cells undergo apoptosis induced by stressand the immune rejection response elicited
by the recipient after transplantation. Conventional treatment for islet transplantation is to administer immunosuppressive drugs
to the recipient to suppress the immune rejection response mounted against transplanted islets. Induction of protective genes in
the recipient (e.g., heme oxygenase-1 (HO-1), A20/tumor necrosis factor alpha inducible protein3 (tnfaip3), biliverdin reductase
(BVR), Bcl2, and others) or administration of one or more of the products of HO-1 to the donor, the islets themselves, and/or
the recipient offers an alternative or synergistic approach to improve islet graft survival and function. In this perspective, we
transplantation models and the prevention of onset of diabetes, with emphasis on HO-1, A20, and BVR. Such approaches are also
appealing to islet autotransplantation in patients with chronic pancreatitis after total pancreatectomy, a procedure that currently
only leads to 1/3 of transplanted patients being diabetes-free.
Type 1 diabetes (T1D) is caused by the death of insulin-
producing pancreatic β cells within the pancreas. Islet trans-
cose level in a physiological manner, holds the most promise
in treating patients with T1D . With the success of the
T1D patients with sustained and improved glycemic control
many problems with this procedure. First, nonimmune-
related stress during islet isolation and transplantation re-
sults in a significant number of islets undergoing apoptosis
immediately after transplantation. Thus, at least 2-3 donors
are needed per recipient to ensure survival of a sufficient islet
cell mass to achieve insulin independence [3–6]. Second,
those islets that survive need to sustain an allograft rejection
response and recurrence of autoimmunity mediated by
the recipients’ T cells, natural killer cells, monocytes, and
cytokines, otherwise additional islet/β cell death would
ensue . Both obstacles have significantly limited clinical
application of islet transplantation for the treatment of T1D.
Similarly, the effectiveness of autologous islet transplanta-
tion, a procedure currently implemented in the clinic to treat
patients suffering from chronic pancreatitis, is also impacted
by β cell apoptosis posttransplantation, that is, only 1/3 of
the patients are insulin-free after total pancreatectomy and
islet autotransplantation [8–10]. Donor islet quality plays
a critical role in determining the outcome of allo- and au-
totransplantation of islet grafts, with stress-induced β cell
apoptosis greatly contributing to failure of these procedures.
Thus, novel strategies that enable β cell resistance to stress
would prevent β cell apoptosis and reduce or even eliminate
immune rejection and recurrent autoimmunity thereby ben-
efiting clinical application of islet transplantation.
The etiology of T1D is complex and poorly understood.
Many factors including genetic susceptibility, environmental
factors, the immune system, and β cells themselves were
2 Journal of Transplantation
found to participate in the pathogenic process of this
disorder . A variety of pathogenic pathways including
CD8+cytolytic T-cell-mediated killing, cytokine exposure,
apoptosis caused by fatty acid synthase and fatty acid
synthase ligand can lead to immune-mediated destruction
of β cells during the onset of T1D , suggesting that
individual therapeutic strategies targeting one pathway may
not be sufficient to cure T1D [13, 14].
to stress through specific signaling cascades and transcrip-
tion factor regulation that when induced participate in pro-
moting cell survival  (Figure 1). Many protective genes
including HO-1, A20, B-cell lymphoma 2 (Bcl-2), Bcl-x, heat
shock proteins, biliverdin reductase (BVR), and antioxidant
enzymeshavebeenfoundtobe expressedin pancreatic islets,
and their expression leads to protection against apoptosis
and other injuries while their absence leads to a heightened
response to stress or in the case of HO-1, low fecundity, and
a shortened lifespan fraught with continuous inflammatory
sequelae throughout life , and in the case of A20 unfet-
HO-1 is the rate-limiting enzyme that degrades heme to
generate equal molar amounts of carbon monoxide (CO),
biliverdin, and iron . Biliverdin is rapidly converted into
bilirubin by biliverdin reductase, and iron is sequestered
into ferritin. HO-1 is a ubiquitous stress protein and can be
induced in many cell types by various stimuli . There
is increasing evidence indicating that induction of HO-1
provides cellular protection against transplant rejection [20,
21], hypertension , hyperoxia , acute pleurisy ,
ischemia reperfusion injury , and endotoxic shock .
HO-1 is intimately involved in the inflammatory, apoptotic,
and proliferative properties of the cell in response to a given
stress. The anti-inflammatory properties ascribed to HO-1
are an important means of protection and survival. Mice
deficient in HO-1 develop a chronic inflammatory state that
progresses with age. The first HO-1 deficient human died of
case of human HO-1 deficiency was reported recently in a
tiple organ dysfunction as well as hemolysis, inflammation,
nephritis, and resistance to therapy . There is evidence
that each product of HO-1, biliverdin/bilirubin, CO, or fer-
ritin accounts for its protective effects both when used alone
or in combination [29–32].
3. HO-1 IncreasesSurvivaland
More than half of the islet tissue is lost in both the syn-
geneic and the autoimmune transplantation settings at 2-3
days posttransplantation, which contributed to the primary
nonfunction of transplanted islets . Considering the
shortage of islet donors, prevention of β cell apoptosis will
effectively reduce the number of donors required for each
transplant and increase the success rate for this procedure.
Early islet/β cell apoptosis after transplantation is typi-
cally induced by nonimmune-mediated stressors including
prolonged hypoxia during the revascularization process,
nutrition deprivation, ischemia reperfusion injuries, and
proinflammatory and cytokine expression . HO-1 expres-
sion is observed in islets under stress conditions, such as
during islet isolation prior to transplantation or cytokine
treatment with IL-1β and IFNγ . Induction of HO-1
pharmacologically or via gene transfer protects islets from
stress-induced apoptosis in both the in vitro and the in
vivo settings. In vitro, several studies have showed that HO-
1 induction in β cell lines, primary murine, or human
islets protects against apoptosis induced by TNF-α and
cyclohexamide (CHX), interleukin-1β (IL-1β), and Fas [34–
36]. Transduction of HO-1 with a TAT protein transduction
domain (TAT/PTD), an 11-aa cell penetrating peptide from
the human immunodeficiency virus TAT protein, into islets,
improves islet viability in culture. HO-1 has been also shown
to prevent β-cell apoptosis via p38 MAPK activation and the
NF-κB pathway in this study .
In addition to the in vitro experiments described above,
Pileggi et al. showed that induction of HO-1 pharmaco-
logically with cobalt protoporphyrin (CoPP) in recipients
results in improved islet function in a marginal mass islet
transplantation model in rodents, that is, fewer islets are
required to achieve normoglycemia when transplanted into
a syngeneic recipient that have been rendered diabetic by
streptozotocin (STZ) treatment . In addition, a short
course of CoPP administration to recipients leads to long-
term survival of DBA/2 (H-2d) islets in 30% of diabetic
C57BL/6 (H-2b) recipients . Most importantly, tolerance
to transplanted islets is achieved as long-term graft-bearing
animals rejected third-party islets while accepting a second-
set donor-specific graft permanently, without additional
treatment. It seems that induction of HO-1 leads to a donor-
specific hyporesponsiveness in the CoPP-treated animals.
Additionally, there is greatly reduced class II expression and
a transient and powerful immunosuppression observed with
reduced lymphocyte proliferative responses and increased
proportions of T regulatory cells with decreased mononu-
clear cell infiltration into the graft [38, 39].
Another critical finding in the Pileggi study is that
preconditioning of islets with hemin to induce HO-1
activity leads to improved graft survival in untreated recip-
ients. Moreover, islet preconditioning provides additional
advantages in HO-1-induced recipients that results in an
increased proportion of long-term survival of transplanted
islet allografts in recipients. Encouraged by this study, we
tested whether HO-1 induction, or CO administration, to
the islet donor, would sustain survival and function of
transplanted islet allografts. Such an approach would avoid
the toxicity associated with recipient treatment. Our data
(20mg/kg CoPP, 24hr before isolation) or administering
CO (250ppm for 1hr) only to the donor leads to long-
term survival of DBA/2 (H-2d) islets in diabetic B6AF1
(H-2b,k/d) recipients, which are then antigen specifically
tolerant. In essence, by using CO, we were mimicking the
effects of HO-1 itself with one of its products. Several
Journal of Transplantation3
• BCL family
proinflammatory and proapoptotic genes that are strongly
induced in islets after transplantation in the untreated
situation were significantly suppressed after administering
CO to the donor. These included TNF-α, inducible nitric
oxide synthase (iNOS), monocyte chemoattractant protein-
1 (MCP-1), granzyme B, and Fas/Fas ligand, all of which
contribute to the pathogenesis and rejection of transplanted
islets. Moreover, donor treatment is correlated with less infil-
tration of recipient macrophages into the transplanted islets
. We tested further whether CO conferred protection
by suppressing Toll-like receptor 4 (TLR4) upregulation in
pancreatic β cells. TLR4 is normally activated in islets during
the isolation procedure, and its activation allows initiation of
inflammation, which leads to islet allograft rejection. Donor
treatment with CO suppresses TLR4 expression in freshly
isolated islets as well as in transplanted islets at various
times after transplantation. Islet allografts from TLR4-de-
ficient mice survive indefinitely in BALB/c recipients and
show significantly less inflammation after transplantation
compared with grafts from a control donor. Isolated islets
preinfected with a TLR4 dominant negative mutant virus
before transplantation demonstrated prolonged survival in
recipients. Despite the salutary effects of TLR4 suppression,
HO-1 expression is still needed in the recipient for islet
survival: TLR4-deficient islets were rejected promptly after
being transplanted into recipients in which HO-1 activity
was blocked . Our data suggest that TLR4 induction in
β cells is involved in β cell death and graft rejection after
transplantation. CO exposure protects islets from rejection
in part by blocking TLR4 upregulation in β cells.
There are at several mechanisms by which HO-1 func-
tions in the islet allogeneic transplantation model. First,
HO-1 induction leads to a decreased inflammatory response
in transplanted islets as compared to islets harvested from
untreated donors. Inflammation not only contributes to
β apoptosis but also heightens the alloaggressive immune
response; thus, suppression of inflammation can lead to
fewer cell deaths and a lesser immune rejection response.
Second, the diminution of free radicals by HO-1 and its
products should impart salutary effects as islet cells express
lower levels of antioxidant genes than most other tissues of
the body and are extremely sensitive to oxidative damages
. Third, HO-1 induction in the recipient increases
the number/function of T regulatory cells, which generate
a favorable microenvironment to transplanted islets and
eventually contribute to the survival of those islets. Last but
not least, HO-1 induction leads to the generation of bil-
of CO, which can amplify the protective effects of HO-1
as CO is anti-inflammatory and antiapoptotic and the bile
pigments are strong antioxidants and BVR can function
to quell the inflammatory response . Emerging data
clearly demonstrate that BVR can regulate the inflammatory
response through distinct intracellular signaling activity
leading to increases in the anti-inflammatory cytokine IL-10
Functionof anIslet Xenograft
The success of islet allogeneic transplantation is limited
by the number of organ donors. Xenogenic donors (e.g.,
pig) offer potential unlimited sources of islets, and islet
xenotransplantation is an alternative option for patients
with T1D. However, despite a number of widely recognized
advantages, the clinical application of porcine islet xeno-
transplantation has been hindered by a potent recipient
xenospecific immune response and by the lack of a tolerable
immunosuppressive strategy to overcome this barrier since
cellular immune responses to xenogeneic cells are less clear
and poorly understood [44–46]. A key for immunologic
rejection in xenotransplantation is the damage to the graft
due to chemotactic movement and infiltration of leukocytes
into the graft . The protective effects of HO-1 in the
islet xenotransplantation model have been investigated by
several groups, and improved survival and function of
islet xenograft was observed when HO-1 was induced. For
example, in a rat to mouse islet transplantation model,
incubation of rat islets with CoPP before transplantation
leads to a much better glucose-induced insulin secretion,
longer graft survival time (14.63 ± 1.19 day versus 9.88 ±
2.17 days in control group), and less lymphocyte infiltration
into the graft . These results were confirmed by another
group in which HO-1 was induced in male Sprague Dawley
4 Journal of Transplantation
donor rats before islet isolation and transplanting the islets
into C57BL/6 mice rendered diabetic by streptozotocin.
Again, improved graft survival was observed . In both
studies, less lymphocyte infiltration and elevated IL-10
expression were observed in HO-1-induced islet xenografts,
a phenomenon also observed in other models of HO-1
tions as a negative immunomodulatory factor and par-
ticipates actively during inflammation, tumor immune re-
sponses, and the transplantation immune response. It pro-
motes activation and differentiation of B cells, mediates
humoral immunity, and inhibits proinflammatory cytokine
expression and mononuclear cell expression of MHC II
molecules and costimulatory molecules, as well as cytokine
synthesis [50, 51]. Many of the observed protective effects of
HO-1 in the xenotransplantation model might be mediated
by IL-10 as HO-1 generates CO, which downregulated
iNOS and upregulates IL-10  and leads to protection to
the Onset of Diabetes
The pathophysiology of T1D is characterized by dysfunction
and death of insulin-producing β cells in the pancreatic
islets of Langerhans. At an early stage of disease onset,
progressive mononuclear cells invade the islets and cause
insulitis, a process that lasts for several weeks to months
infiltration leads to the generation of reactive oxygen species
γ, and TNF-α in pancreatic β cells. Elevated intracellular
levels of ROS, including superoxide, hydrogen peroxide, and
nitric oxide, leads to apoptotic and necrosis of β cells .
Increased proinflammatory cytokines contribute to insulitis
. The autoimmune nonobese diabetic (NOD) mouse
resulting from autoreactive T-cell-mediated destruction of β
cells is a useful and powerful model by which to study the
development of T1D due to its similarity to human disease.
Similar to human diabetes, the NOD mice develop insulitis
that has been linked to activated macrophages and T cells
the secretion of soluble mediators, such as oxygen radicals,
NO, and cytokines . HO-1 has been shown to slow
progression to overt diabetes and interdict disease progress.
Li and colleagues reported that HO-1 induction in NOD
preserves the number of β cells via suppressing infiltration
of CD11c+cells. Increased phosphorylation of AKT, BcL-
XL, and RSK levels and decreases in superoxide and 3-
NT levels were observed in mice where HO-1 was induced
. The effect of HO-1 in preventing progression of overt
diabetes was confirmed by another study in which HO-1 was
induced in female NOD mice at 9 weeks of age with a single
intravenous injection of a recombinant adeno-associated
virus bearing the HO-1 gene (AAV-HO-1, 0.5 × 1010– 2.5 ×
1010viruses/mouse). HO-1 induction significantly reduced
destructive insulitis and the incidence of overt diabetes
examined over a 15-week period. HO-1-mediated protection
was associated with a lower type 1 T-helper-cell-mediated
demonstrated that splenocytes isolated from AAV-HO-1
treated mice were less diabetogenic. However, no differences
in CD4+CD25+T regulatory cell infiltrates between saline-
treated and the AAV-HO-1 treated group was observed .
In both studies discussed above, the protective effects of HO-
1 could be substituted for with bilirubin and/or CO.
Huang et al. confirmed the protective effect of HO-1 in
preventing the onset of diabetes by generation of transgenic
NOD mice in which the HO-1 transgene was driven by an
insulin promoter (Plns-mHO-1) . Although the overall
expression level of HO-1 in transgenic islets was lower than
difference in insulitis and a lower incidence of diabetes
were observed in the transgenic mice. Onset of diabetes was
significantly delayed in the mHO-1-transgenic NOD mice,
that is, spontaneous diabetes developed after 15 weeks of
age in the mHO-1-transgenic NOD mouse compared to
12 weeks in age-matched controls. Diabetic incidence at 30
weeks of age was also significantly reduced (33.3% in the
transgenic mice compared to 66.7% in controls). Moreover,
islets from transgenic mice survived significantly longer than
those harvested from wild-type donors when transplanted
into new onset spontaneous diabetic female NOD recipients,
although permanent protection from recurrence of diabetes
was not achieved in this model . The mHO-1-transgenic
tation. Preservation of islet architecture and intact insulin-
secreting islets were observed within the pancreas .
However, local expression of HO-1 did not alter systemic
or local lymphocyte and dendritic cell development in NOD
HO-1 was shown to inhibit maturation of dendritic cells and
regulate the function of Th1 and Treg cells . Conclusions
from these studies were that the anti-inflammatory and
antioxidant properties of HO-1 and its products interfered
with the onset of diabetes in NOD mice.
The islets of Langerhans are equipped with a HO-CO
pathway which constitutes a regulatory system of physiologic
importance for the stimulation of insulin and glucagon
release . HO-1 expression and activity are reduced in
patients with T2D compared to healthy individuals .
Overexpression of HO-1 activates the insulin-signaling path-
way and has been shown to have unique and long-lasting
antidiabetic effects in the rodent model of insulin resis-
tance [62–64]. Moreover, HO-1 attenuates the oxidative
sitivity and glucose metabolism in the STZ-induced T1D
mouse model . Induction of HO-1 by hemin increases
plasma insulin level and enhances insulin sensitivity and
improves glucose tolerance. The antidiabetic effects of hem-
in lasted for 2 months after termination of therapy and
were accompanied by enhanced HO-1 expression and HO-1
activity of the soleus muscle, along with potentiation
of plasma antioxidants including bilirubin, ferritin, and
superoxide dismutase with elevation of the total antioxidant
Journal of Transplantation5
capacity. Hemin blocked C-Jun NH2-terminal kinase (JNK),
a substance known to inhibit insulin biosynthesis, and sup-
pressed markers/mediators of oxidative stress including 8-
isoprostane, NF-κB, and activating protein (AP-1 and AP-2)
attenuated pancreatic histopathological lesions including
and mononuclear cell infiltration . Thus, it seems that
hemin-induced HO-1 can enhance the function of β cells
HO-1 and its products are also protective against
diabetes-related complications. Human HO-1 cDNA trans-
ferred into diabetic rats restored mitochondrial ADP/ATP
and deoxynucleotide carriers . Elevated HO-1 was asso-
ciated with a significant increase in the phosphorylation of
AKT and levels of Bcl-XL proteins. The cytoprotective mech-
anisms of HO-1 against oxidative stress involve an increase
in the number of macrophages and antiapoptotic proteins
as well as cytochrome c oxidase activity in this model .
Moreover, exogenous administration of the CO releasing
molecule-3 (CORM)-3 and bilirubin prevents endothelial
cell sloughing in diabetic rats, likely via a decrease in oxida-
tive stress which represents a novel approach to prophylactic
vascular protection in diabetics [64, 67, 68]. In addition to
functioning as a positive modulator of glucose-stimulated
insulin release, CO increases the propagation of Ca2+signals
with coordinating effects on the β cell rhythmicity .
7.A20 andIslet Survivaland Function
A20, also known as the TNF-α-induced protein 3
(TNFAIP3), is a zinc-ring finger protein that was first iden-
tified as a cytokine-induced gene in human umbilical vein
endothelial cells . As a negative regulator of nuclear
factor kappa B (NF-κB) activation, A20 is recognized as a
central and ubiquitous regulator of inflammation and as a
potent antiapoptotic gene in certain cell types, including β
cells [71–73]. A20 offers a potential therapeutic target for the
treatment of diseases where apoptosis and/or the inflamma-
thus, it is an ideal cytoprotective gene therapy candidate for
T1D . Overexpression of A20 by means of adenovirus-
mediated gene transfer protects islets from IL-1β/INF-γ
and Fas-induced apoptosis [75–77]. Transplantation of a
suboptimal number of islets overexpressing A20 resulted in
a cure in a high percentage of recipients compared to control
islets. A20-expressing islets preserved functional β cell mass
and are protected from cell death. The cytoprotective effect
of A20 against apoptosis correlates with and is dependent
on the abrogation of cytokine-induced NO production due
to transcriptional blockade of iNOS induction; these data
demonstrate a dual antiapoptotic and antiinflammatory
function for A20 in β cells.
The breakdown of heme continues with biliverdin as it
is rapidly converted to bilirubin by BVR. BVR has, in
recent years, evolved into a complex enzyme with additional
functions including signal transduction and transcription
factor activity. We include it here as many of the effects of
HO-1 might be attributed in part to the additional functions
for BVR resulting from the presence of biliverdin. A direct
by Miralem et al. showing an attenuated HO-1 response to
superoxide anion and arsenite in cells where BVR expression
had been silenced . BVR is a unique enzyme because it
has been categorized to possess numerous biological func-
tions. The reductase activity leads to the protective effects
shown by biliverdin/bilirubin in a variety of experimental
models of organ transplantation, endotoxic shock, and vas-
sponding signal transduction and more recently nuclear tar-
geting and ability to regulate gene expression and the inflam-
matory response. Indeed, recent studies by us show that
BVR is present on the cell surface and in this location binds
cascade leading to activation of Akt that in turn increases
IL-10 expression . The rapid conversion of biliverdin
into bilirubin by BVR likely explains the beneficial effects
observed with exogenous biliverdin administration. Indeed
the signalling and transcriptional activity of BVR in addition
to generating increased bilirubin may act synergistically and
explain the mechanism of biliverdin-induced protection.
Modulation of BVR itself directly regulates the inflammatory
response and, in vivo, can prevent acute liver injury .
In addition to its anti-inflammatory effects, BVR mod-
ulates glucose uptake and insulin resistance by decreasing
glucose transport and metabolism in competition with the
insulin receptor substrate-1 (IRS-1) for phosphorylation
by insulin receptor kinase (IRK). This leads to a reduced
binding with PI3K and accelerated degradation of IRS .
Therefore, therapeutic molecules designed to suppress the
kinase activity of BVR may play an important role in the
reversal of diabetes.
As previously discussed, islet allografts suffer a gradual
and apoptosis as well as activation of the humoral immune
response. Although intraportal infusion represents the most
frequent procedure in the clinic for human islet transplant,
a high percentage of islets are destroyed at a very early
posttransplant stage because of the instant blood-mediated
inflammatory response [80, 81]. Bilirubin administration
reduced apoptosis and improved insulin secretion in an in
vitro model in INS-1 cells when challenged with nonspecific
inflammation induced by cytokines. Moreover, bilirubin
administration led to improved glucose control and protec-
tion of islets grafts in a syngeneic rat model of intraportal
islet transplantation by inhibiting the production of IL-
1β, TNF-α, ICAM-1, and MCP-1, as well as infiltration of
Kupffer cells .
Bilirubin administration to the donor, and even more so
to cultured islets, without further treatment of the recipient
isolated islets from bilirubin-treated donors led to a strong
expression of the protective genes HO-1 and bcl-2 and a
clear suppression of the proapoptotic and proinflammatory
6 Journal of Transplantation
genes caspase-3, caspase-8, and MCP-1 [83, 84]. This pro-
tective effect of bilirubin leads to reduced β-cell destruction
after transplantation, reduced macrophages infiltration, and
decreased expression of MCP-1, BID, caspase-3, -8, and -9,
TNF-α, iNOS, Fas, TRAIL-R, and CXCL10 in the graft after
allogeneic transplantation . The therapeutic potential of
bilirubin is further corroborated by data reported in Gunn
rats (genetically predisposed to high bilirubin levels) ren-
dered diabetic by streptozotocin administration in which the
typical hyperbilirubinemia represents a “natural” protection
to oxidative stress .
Bilirubin administration to recipients clearly improves
graft survival by inducing immune tolerance via de novo
generation of T regulatory cells. Bilirubin was no longer
protective when CD4+CD25+Treg cells were depleted from
recipients prior to transplantation suggesting that Tregs were
critical in the ability of bilirubin to protect . Moreover,
as previously shown in kidney and heart transplantation
models, dual therapy by combining CO and biliverdin en-
hanced long-term graft survival . Interestingly, a recent
study in a rodent model of type 2 diabetes describes the
protective effects of biliverdin administered orally .
Biliverdin inhibited β-cell injury caused by oxidative stress
and resulted in glucose tolerance and improved function.
Biliverdin has been shown to increase the insulin content,
reduce Bax, and enhance Pdx1 expression in diabetic mice
compared to control . Similar effects in T1D models
which would be a significant turning point for potential
clinical use have not yet been tested.
9.Other ProtectiveGenes/Factorsthat Can
IncreaseIslet Survivaland Function
There are many other protective genes that have been shown
to protect pancreatic β cells. Mancarella et al. reported
that exposing human islets to the nonpeptidyl low molec-
ular weight radical scavenger IAC [bis(1-hydroxy-2,2,6,6-
tetramethyl-4-piperidiny) decanedioate dihydrochloride] on
isolated human islet cells protected them from isolation and
culture-induced oxidative stress . Enhancing expression
of suppressor of cytokine signaling 1 (SOCS1) in isolated rat
islets prior to transplantation protected them from apoptotic
loss and prolonged survival . Transduction of NOD
islets with the antioxidative gene thioredoxin (TRX, reactive
NOD mice . Anthocyanins from Chinese Bayberry pro-
tects β cells against hydrogen-peroxide-induced necrosis and
apoptosis via upregulation of HO-1 . Adenoviral trans-
fection of human islets with human X-linked inhibitor of
apoptosis provided protection from inflammatory cytokines
and improved their viability and function [2, 93–104].
Due to the complex nature of the pathogenesis of diabetes,
interfering with antigenic recognition and/or cell death,
imparting tolerance, immunoregulation, and cell protection
offera promising form of immunotherapy [3, 105]. Based on
the potent cytoprotective and immunoregulatory effects of
HO-1, A20, BVR, and other protective genes, targeting
strategies aimed to induce their expression or by adminis-
tering one or more of their products hold great promise in
protecting islet cells from apoptosis and may prove critical as
potential therapies for diabetes and other human diseases.
CORM: CO releasing molecule
TLR4:Toll-like receptor 4
iNOS: Inducible nitric oxide synthase
MCP-1: Monocyte chemoattractant protein-1.
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