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The size of the global nutrition market rivals other lucrative world markets for food and beverage products.  The global snack foods market is forecasted to reach $334 billion by 2015 according to a report by market research firm Global Industry Analysts (GIA). Obesity is one of the biggest public health issues in many countries around the world.  In 2006, the number of overweight people in the world overtook the number of malnourished, underweight people for the first time.
Diabetes affects more than 285 million people globally according to estimates by the International Diabetes Federation (IDF) and IDF Diabetes Atlas.
With more of the world going gray and staying that way longer, consumers and healthcare providers are turning to functional foods and beverages to help prevent and manage the physical and mental effects of old age. Education Initiatives – Companies, organizations and governments should work together to raise awareness about the link between good nutrition and living a healthy, long life.  School health curriculums should strive to educate students on nutrition and the benefits of healthy eating habits in an engaging, memorable manner. 12:26 pm March 4, 2010 By Julian Horsey A new Glucowizzard a grain of rice sized implant may mean less pain for diabetes suffers by monitoring there blood sugar levels day and night. This data is then collected via  photovoltaic cells flashing light pulses through the skin to a wristband worn by the patient. The system would help patients monitor their blood glucose levels without the need to prick their skin every time.
I wish this would be available sooner I know 3 diabetics tthat are supposed to be monitoring their blood sugars but they don’t.
From 1980 to 2014, the number of adults in the United States aged 18a€“79 with newly diagnosed diabetes more than tripled from 493,000 in 1980 to more than 1.4 million in 2014.
Data Source: Centers for Disease Control and Prevention (CDC), National Center for Health Statistics, Division of Health Interview Statistics, data from the National Health Interview Survey. We intend to do this within local communities, with partnerships and just through word of mouth.
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DNA Immunotherapies for Type 1 DiabetesAlice Li1 and Alan Escher2[1] Loma Linda University, Loma Linda, California, USA[2] SEKRIS Biomedical Inc., Redlands, California, USA1. Education efforts should encompass the health benefits of positive lifestyle habits that go beyond food and nutrition to include exercise, the avoidance of smoking and excessive alcohol consumption and other fundamental aspects of health and well-being. Multinational companies can contribute to these efforts by leveraging their extensive distribution networks and sophisticated logistics capabilities to help deliver food items and agricultural inputs to remote locations. From 1991 to 2009, the number of new cases of diabetes increased sharply from 573,000 to more than 1.7 million.
Data computed by personnel in the Division of Diabetes Translation, National Center for Chronic Disease Prevention and Health Promotion, CDC. We intend for these key elements of sustainable lifestyle change to become pervasive within communities, and within the lives of all of us affected by the disease. The table summarizes plasmid DNA based immunotherapies under two categories: Gene therapies and DNA vaccines. They go to the Dr and get the fasting test done and think that is good enough but they don’t know what their sugar is like on a day to day basis. However, from 2009 to 2014, the number of new cases decreased significantly to approximately 1.4 million. Plasmid DNA immunotherapy for type 1 diabetes can be divided into two categories: DNA vaccines and gene therapies. Furthermore, similar to other autoimmune diseases, allergies and asthma, the incidence of type 1 diabetes is on the increase at an alarming rate in industrialized countries for unknown reasons. Plasmid DNA can be delivered using different routes, for example, the intradermal and intramuscular routes. Information released by the American Diabetes Association shows 23% and 21% increased rates of type 1 and 2 diabetes, respectively, from 2001 to 2009.
The increase in incidence of type 1 diabetes is especially apparent in young children and has generated an urgent need for novel treatments that can safely control diabetes-causing inflammation, and alleviate the need for administration of exogenous insulin.
Indeed, type 1 diabetes has been treated for almost a century in the same fundamental manner using daily insulin injections. DNA vaccine immunotherapiesPlasmid DNA vaccine-based immunotherapy is a promising therapeutic field for treatment of type 1 diabetes. Although it is a life-saving treatment and one of the most remarkable accomplishments of medicine, administration of exogenous insulin is still not a cure because it does not address the underlying autoimmunity that targets insulin-secreting beta cells. Because it is currently impossible to mimic regulation of physiological insulin levels faithfully, many type 1 diabetic individuals receiving standard of care are exposed to acute and chronic complications that cause increased morbidity and mortality.
Nevertheless, although beneficial effects were observed, it is clear that efficacy must be significantly improved.
As a result, there have been intense efforts to develop immunotherapies that can eliminate or at least alleviate the need for exogenous insulin. Improving efficacy will be likely dependent on the ability to modulate both the innate immune system, through activation of tolerogenic antigen-presenting cells like dendritic cells, and the adaptive immune system, through activation of various populations of regulatory cells. In this case the goal is to arrest pathological autoimmunity that destroys beta cells so that the cells can regain function, and possibly proliferate and regenerate. DNA vaccines are particularly well positioned to achieve this goal because plasmid DNA is information-based, and can encode molecules that affect the immune system in different manners. The challenge is to identify which combination of functions should be delivered together with a pancreatic autoantigen to treat disease with maximum efficacy and safety.Several beta cell autoantigens have been tested in mice for induction of immune tolerance by DNA vaccines and will be discussed in this section.
The first path relies on different forms of systemic suppression of inflammation that inhibit effector T lymphocytes in a non-specific manner.
Immune mechanisms associated with the therapeutic effects of DNA vaccines can be complex because of the variety of cells that can process the information encoded by plasmid DNA. Serious side effects associated with the use of systemic immunotherapies are increased risks of cancer and infection resulting from the decreased activity of effector cells involved in beneficial destructive immune responses against cancer cells and pathogens. These side effects have been observed with broadly acting immunosuppressants used to prevent organ transplant rejection, which have been also investigated for treating type 1 diabetes [1, 2]. Insulin DNA vaccinesThus far, the only DNA vaccine that has been tested in both preclinical and clinical trials is a plasmid DNA construct coding for intracellular proinsulin, which is a partially processed non-functional form of insulin.
Serious side effects can also be seen, albeit to a lesser degree, with more specific agents like antibodies that target specific molecules involved in inflammation [3, 4]. Insulin is not only the hormone produced by beta-cells that controls carbohydrate and fat metabolism in the body, it is also a main target autoantigen in autoimmune diabetes and the presence of anti-insulin autoantibodies can be an indication of disease initiation [59]. DNA vaccines coding for different forms of insulin have been investigated for type 1 diabetes immunotherapy since the late 1990’s. This path is thought to be safer because it aims to induce a regulatory immune response that targets the inflamed islets. Here the goal is to manipulate endogenous immune mechanisms of homeostasis that can re-establish some form of tolerance to the chosen autoantigen, as well as to other neighboring beta cell autoantigens through a mechanism known as “by-stander suppression” [5]. The DNA vaccine induced insulin B-chain specific CD4+ T regulatory cells that secreted interleukin-4, and locally reduced autoreactive activity of cytotoxic T lymphocytes in the pancreatic draining lymph nodes.
Accordingly, it is anticipated that pathological autoimmunity and inflammation of islets can be stopped in an organ-specific manner that does not impair the immune system. Further work showed that co-delivery of interleukin-4 was required to prevent diabetes onset in male nonobese diabetic mice [61]. In this chapter, we will review how plasmid deoxyribonucleic acid (DNA) has been used as an immunotherapeutic vector platform to treat type 1 diabetes through each immunotherapeutic path. Two isoforms of insulin are synthesized in rodent animals, insulin I in islets and insulin II in both islets and thymus while humans have only one form of insulin. For the purpose of this review, we have called the first path “gene-based immunotherapy”, meaning that plasmid DNA does not encode a known autoantigen, and the second path “DNA vaccine immunotherapy” meaning that a beta cell autoantigen is encoded by plasmid DNA (Figure 1). The pancreatic beta cells synthesize proinsulin before converting it to functional insulin. In other words, gene-based immunotherapy relies on the inherent function of a product encoded by plasmid DNA that can in turn affect cell function. In that regard, intranasal delivery of plasmid DNA encoding mouse proinsulin II together with injection of an anti-CD154 (also named CD40 ligand) antibody to prevent T cell activation was reported to prevent type 1 diabetes in nonobese diabetic mice [62]. In contrast, DNA vaccine immunotherapy relies on the tolerogenic immune response induced directly by the autoantigen after its processing by immune cells.
Delivery of 300 microgram DNA and 50 microgram antibody over a 2-week interval at 4 weeks of age synergistically prevented diabetes, reducing disease incidence from 100% diabetic down to 0% in 40-week old mice. As we shall see, some DNA vaccine immunotherapies have also a gene-based immunotherapy component that acts as a molecular adjuvant to promote tolerogenic immune responses. Nevertheless, in all cases synthesis of the molecule encoded by plasmid DNA, which is almost always a protein, starts after delivery of the plasmid DNA and its uptake by cells. However, delivery of the DNA vaccine alone did not reduce diabetes incidence, even though it could induce T regulatory cells and reduce insulitis.

Plasmid DNA has several notable advantages compared to other vectors and therapeutic molecules. Another report has shown that co-delivery of 50 microgram plasmid DNA encoding human proinsulin together with 100 microgram insulin peptide twice over a 2-week interval could prevent diabetes until 24 weeks of age in 6 week old nonobese diabetic mice. For example, it consists of relatively low molecular weight circles of double stranded DNA that can be readily isolated from bacteria in a generic and cost-effective manner. In addition, plasmid DNA permits rapid turnaround when developing new candidate products, refrigeration-free storage, and synthesis over time of a chosen antigen in its native conformation.
Results also indicated induction of CD4+CD25- islet specific T regulatory cells producing transforming growth factor-beta only in the co-immunization group.In another study, a DNA vaccine encoding proinsulin and pancreatic regenerating (Reg) III protein resulted in a significant reduction of hyperglycemia and diabetes incidence with increased serum insulin in a streptozotocin- induced mice model [64]. Furthermore, plasmid DNA can be given in repeat doses within short periods of time without inducing an immune response to vector and other side effects.
Cytotoxic T lymphocyte antigen 4 (CTLA-4 or CD152) is a strong negative regulator of T cell activity and another example of an immunomodulator that can be co-delivered with an autoantigen. Although they may sometime have pro-inflammatory properties that can be detrimental to controlling inflammation, these particles have been used to induce immune tolerance with plasmid DNA.
For example, chitosan-DNA nanoparticles encoding an ovalbumin antigen are tolerogenic when delivered orally [9]. It was found that a single amino acid substitution in B7-1 (denoted B7-1wa) could abrogate specific binding to CD28 but not to CTLA-4.
Indeed, route of delivery can play a significant role in the type and strength of immune responses induced by DNA vaccines in animal models [10, 11]. In humans, two microgram of a DNA vaccine for treatment of melanoma delivered with gold particles into skin was found to be as efficacious as 1000 microgram injected intramuscularly [12]. These results illustrate the significant impact that choice of route and method of delivery of a DNA vaccine can have not only on efficacy, but also on cost of treatment. Other delivery routes like intravenous, nasal, and sublingual have also been investigated [13].
Post delivery, expression of coding sequences in plasmid DNA results in significant levels of protein production that may persist for six weeks and longer without serious side effects in human patients [14, 15]. DNA vaccines and other gene-based vaccines belong to a third generation of vaccines after live and attenuated whole organism vaccine and recombinant protein vaccines. These vaccines can be used to either prevent (prophylactic vaccine) or treat (therapeutic vaccine) disease depending on their potency, in which prevention is generally easier to achieve than treatment.
Recent reports of beneficial results in different clinical trials using delivery of autoantigens indicate that DNA vaccination is reaching a stage where we are likely to see accelerated development of a therapeutic future for vaccines targeting a variety of autoimmune diseases.
In the case of type 1 diabetes, early results using a DNA vaccine encoding insulin have shown promise in humans. In addition, DNA vaccines encoding human heat shock protein 60 and glutamic acid decarboxylase 65 have also shown efficacy in preclinical trials and are reviewed in this chapter.
In contrast to DNA vaccine immunotherapy, gene-based immunotherapy involves delivery of genetic material by a plasmid vector into a cell, tissue or organ with the aim of improving the clinical status using the function of the encoded product, instead of its properties as an antigen. Gene-based immunotherapy includes delivery of anti-inflammatory cytokines, chemokines, and other factors to modulate the activity of immune cells [16, 17].2. Gene-based immunotherapiesSeveral pre-clinical trials have used plasmid DNA-based gene therapies in experimental models of autoimmune type 1 diabetes.
These strategies involve plasmid DNA designed to weaken pre-existing beta-cell autoimmunity through delivery of anti-inflammatory cytokines, chemokines, and other immune cell manipulating agents. Cytokine gene therapiesCytokine gene therapies are strategies that use engineered plasmid DNA to produce therapeutic immune cytokines, which are a group of immune active molecules secreted by different cells of the body. Some of these cytokines are considered beneficial for the suppression of autoimmunity, and thus are applied to disease models to reduce clinical symptoms and improve therapeutic effects. Studies of animals with spontaneous autoimmune diabetes have revealed that an important group of autoreactive T cells that mediates islet beta-cell destruction belongs to the T helper-1 type effector cell subset, and produces cytokines like interleukin-2 and interferon-gamma. On the other hand, regulatory T cells that control effector cells can secrete interleukin-4, interleukin-10, and transforming growth factor-beta.
One of the earliest applications of cytokine-engineered plasmid DNA was gene-gun delivery of murine interleukin-4 to prevent spontaneous type 1 diabetes [18]. The plasmid DNA was delivered as three times two microgram within 4 weeks into 3-week-old nonobese diabetic mice, which is the animal model system closest to human type 1 diabetes. Type 1 diabetes incidence was reduced from 90% in controls to 20% at 34 weeks of age, and was associated with T helper-2 type immune responses in the periphery and pancreas of mice. Two other reports have shown that systemic delivery of plasmid DNA constructs coding for interleukin-4 can prevent insulitis, which is an inflammatory sign of immune cell infiltrating pancreatic islets in nonobese diabetic mice [19, 20]. For example, a report indicates that intramuscular electroporation delivery of 50 µg plasmid DNA encoding interleukin-4 accelerated spontaneous type 1 diabetes in nonobese diabetic mice [21].In addition to interleukin-4, interleukin-10-encoded plasmid DNA alone was also tested for its diabetic suppressive effects. The plasmid DNA was delivered intramuscularly twice for a total of 200 microgram into 3 and 5 week old female nonobese diabetic mice [22]. Although the severity of insulitis at 13 weeks of age was not improved, the incidence of diabetes was markedly reduced to 50% at 35 week old compared to 90% with control mice. These results show that the progression of autoimmune disease in mice can effectively be suppressed by intramuscular DNA injection coding for anti-inflammatory cytokines alone. Another report investigating the immune effects of interleukin-10 DNA showed that systemic intramuscular administration of 200 microgram interleukin-10 plasmid DNA could alleviate blood glucose and insulitis in a streptozotocin induced diabetic mouse model up to day 28 post injection [24].
In this model, pancreatic interleukin-1b and tumor necrotic factor-alpha gene expression, serum interferon-gamma concentration, and the numbers of CD4+ and CD8+ lymphocytes were decreased on day 28. A similar interleukin-10 construct was modified by introducing nuclear factor kappa-B (NF-kB) binding sites into plasmid DNA to facilitate nuclear transport of the plasmid after delivery into the cell [25]. A single injection of 50 microgram of the plasmid using polyethylenimine as a gene carrier in 5 week old mice reduced the degree of insulitis and serum glucose levels in 100% of mice compared to 40% of the control mice at 32 weeks of age. These results illustrate how plasmid DNA can be easily modified in a generic manner to improve therapeutic efficacy.As mentioned previously, nanoparticle technology has been used to condense plasmid DNA into nanometer-size complexes to improve delivery. An interleukin-10 encoding plasmid DNA was assembled into a cationic nanoparticle complex, and a single dose of 50 microgram DNA was delivered intramuscularly into streptozotocin-induced diabetic mice [26]. Animals showed higher serum levels of interleukin-10, suppression of interferon-gamma level, reduction of islet insulitis, and lower blood glucose levels compared to those treated with interleukin-10 plasmid alone or the nanoparticle alone up to week 6 post injection.
Histology of muscle showed that nanoparticles were biocompatible and did not cause a chronic inflammatory response.
In addition to their use alone, delivery of both interleukin-4 and interleukin-10 DNA has also been investigated.
Combined delivery into nonobese diabetic mice of the two plasmid DNA constructs encoding interleukin-4 and interleukin-10 (25 µg each) was done intravenously using a degradable, cationic polymeric carrier, poly (alpha-(4-aminobutyl)-L-glycolic acid)[27]. Overexpression of the two cytokine messenger RNAs was confirmed in the liver of mice 5 days after delivery. Six weeks after injection, 75% of observed islets were intact compared with less than 3% in the control group, and development of diabetes was prevented in 75% of treated animals at 30 weeks of age, compared to 20% in control mice receiving plasmid DNA coding for a single cytokine or vector control alone.
The results indicated that the interleukin-4 and interleukin-10 plasmid DNAs had synergistic effects on the prevention of autoimmune diabetes.
A report from the same research group showed that a ‘chimeric’ plasmid expressing both of the interleukin-4 and interleukin-10 under controls of two CMV promoters could also reduce insulitis in the same system [28].More recently, a research group also reported packaging plasmid DNA constructs coding for interleukin-4 and interleukin-10 into cationic nanomicelles to prevent type 1 diabetes [29].
A single intramuscular dose of 50 microgram of the complex reduced levels of blood glucose and insulitis up to 6-week post delivery in 5-week-old streptozotocin-induced diabetic mouse. Notably, plasmid DNA coding for interleukin-4 and interleukin-10 has also been used as adjuvant to promote the therapeutic effect of DNA vaccines in a murine model for type 1 diabetes, which will describe later in this chapter in the ‘Glutamic Acid Decarboxylase DNA Vaccines’ section.In addition, a number of studies have reported that injection of plasmid DNA coding for cytokines normally considered pro-inflammatory can prevent diabetes. These results reflect the multifaceted role of cytokines on immune response [30], which could be dependent on dosage and time of administration. For example, administration of interleukin-18, also known as interferon-gamma inducing factor, can prevent diabetes in NOD mice [31, 32].
However, it was also shown that intramuscular electroporation of 2 x 100 microgram plasmid DNA coding for interleukin-18 into 4-6-week-old nonobese diabetic mice aggravates diabetes [33]. Another report showed that intraperitoneal administration of 30 microgram of plasmid DNA encoding interferon-gamma promotes insulitis in reovirus type-2 induced diabetic mice compared to controls [34].
This is in contrast with another report showing that injection of interleukin-12 induces interferon-gamma that prevents diabetes in NOD mice [35]. Together, these results suggest that there is risk associated with direct delivery of cytokines for the treatment of type 1 diabetes. This possibility is suggested by a phase I clinical trial where new onset patients with type 1 diabetes received a combination treatment of interleukin-2 and the immunosuppressant rapamycin. Chemokine gene therapiesChemokines are a family of small chemotactic cytokines secreted by cells [36]. Their name is derived from their ability to induce directed chemotaxis, or directed cell migration, in responsive cells.

Some chemokines are considered pro-inflammatory and can be induced during an immune response to recruit cells of the immune system to a site of infection, while others are considered homeostatic and are involved in controlling the migration of cells during normal tissue maintenance and inhibiting abnormal inflammation like pathological autoimmune response. Chemokines are involved in pathogenesis of autoimmune disease because they can selectively recruit various subsets of immune lymphocytes [37, 38].
Based on structural motifs near their N-terminal cysteine residue [C], chemokines are divided into four subfamilies, termed CXC, CX3C, C, and CC. The function of chemokines is modulated by the type of chemokine receptors they bind to as ligands on the surface of cells, and studies have shown that chemokines and chemokine receptors are involved in the pathogenesis of autoimmune diseases like type 1 diabetes. Chemokine gene therapies for type 1 diabetes use anti-inflammatory chemokines as well as inhibitors of pro-inflammatory chemokine binding.
It was found that, in type 1 diabetic adult patients, elevated levels of serum CXC ligand-10 are associated with high-risk of disease in latent diabetic subjects [39]. This finding was translated in animal models where blockade or neutralization of the CXC ligand-10 can prevent type 1 diabetes in nonobese diabetic mice [40].
In virus-induced diabetic mice, virus infection results in rapid and differential expression of CXC receptor-3 and CXC ligand-10, which plays a dominant role in programming the ensuing autoimmune disease [41]. The blockade of CXC ligand-10 by using anti CXC ligand-10 monoclonal antibodies successfully aborts severity of antigen-specific injury of pancreatic beta cells and abrogates type 1 diabetes. Mechanistically, the blockade impedes the expansion of peripheral antigen-specific T effector cells and hinders their migration into the pancreas.
A similar effect of the antibodies was confirmed in a cyclophosphamide accelerated model of type 1 diabetes [40]. Based on these reports, plasmid DNA encoding the CXC ligand-10 was constructed to induce production of anti-CXC ligand-10 antibodies in the host [42]. Intramuscular electroporation of 100 microgram of the plasmid DNA at 4 and 6 weeks of age induced synthesis of anti CXC ligand-10 antibodies in vivo, and suppressed the incidence of spontaneous diabetes which went from 75% in control mice down to 25% in treated mice at 30 weeks of age.
Although this treatment did not inhibit insulitis or alter the immunological response, it enhanced the proliferation of pancreatic beta cells and resulted in an increase of beta-cell mass.A subsequent report from the same research group showed that combining complete Freund’s adjuvant with plasmid DNA encoding the CXC ligand-10 could reverse diabetes [43]. Diabetes incidence was reduced from 70% in control mice to 20% in treated mice 10 weeks after plasmid DNA delivery.
In contrast, mice receiving complete Freund’s adjuvant and control plasmid DNA did not show disease reversal. In mice that were treated successfully, residual beta-cell mass was significantly increased, and some beta-cells were in a proliferative state. Although systemic cytokine profiles were unaffected, the frequency of regulatory T cells expressing CXC receptor-3 was significantly increased in local pancreatic lesions and possibly associated with the regulation of anti-islet autoimmunity. Another research group found that intra-pancreatic CC ligand-4 levels are increased in a model of diabetes protection by interleukin-4 treatment in female nonobese diabetic mice [44].
The protective effect of CC ligand-4 was confirmed by abrogation of diabetes suppression after injection of anti-CC ligand-4 antibodies [45]. These result led to studies using CC ligand-4-encoded plasmid DNA therapy which showed that gene-gun delivery of 1 microgram of the plasmid DNA protects against type 1 diabetes in NOD mice, with diabetes rates reduced from 75% in control mice to 30% at 35 weeks of age when treated weekly from week 3 to 14, and from 80% in control mice down to 30% when treated weekly from week 9 to 14 [45].
Data also indicated that plasmid DNA delivery could both prevent and treat type 1 diabetes. This protection was associated with a T helper-2-like response in the spleen and pancreas, decreased recruitment of activated CD8 T cells to islets accompanied by diminished CC receptor-5 expression on CD8 T cells, and increased regulatory T cell activity in the draining pancreatic lymph nodes.
To summarize, plasmid DNA encoding CC ligand-4 and CXC ligand-10 have been tested for their type 1 diabetic suppressive effects in spontaneous diabetic mouse models. Diabetes suppression is associated with decreased CD8 T lymphocyte activity and increased CD4 T regulatory cell activity. Other cell-manipulating gene therapiesSeveral immune cell populations have deficiencies in type 1 diabetes, such as CD4 T lymphocytes, CD8 T lymphocytes, B lymphocytes, dendritic cells, macrophages, and NK cells in both nonobese diabetic mice and human patients [46, 47]. The goal of cell-manipulating gene therapy is to increase the diabetic suppressive function of cells like T regulatory or T helper-2 lymphocytes, which are considered important not only for therapeutic purposes, but also for playing a determining role in the development of type 1 diabetes.As mentioned at the beginning of this chapter, type 1 diabetes is a T helper-1-mediated autoimmune disease and strategies suppressing the function of these cells can be expected to have an impact on disease progression. One of these strategies is the delivery of galectin-9, a carbohydrate-binding protein that regulates T helper-1 cells and induces their apoptosis through the galectin-9 receptor. Apoptosis, or programmed-cell-death, is a constantly ongoing process in steady state in vivo and helps maintain tissue and immune homeostasis.
Mice treated with plasmid DNA coding for galectin-9 were significantly protected from diabetes: intravenous delivery of 2 x 100 microgram bi-weekly protected 85% of mice from diabetes versus 55% in controls [48]. Splenocytes from treated mice were also less responsive to mitogenic stimulation than splenocytes from the control group. Data indicated that galectin-9 DNA may downregulate T helper-1 immune response in diabetic mice and could be used as a therapeutic agent in autoimmune diabetes.In contrast with galectin-9, decoy receptor 3 inhibits apoptosis. The membrane protein is a member of the tumor necrosis factor receptor superfamily, and regulates immune responses by neutralizing apoptotic signals transmitted through CD95 (Fas receptor), lymphotoxin beta-receptor, and death receptor 3 on target cells. As a result, transgenic expression of decoy receptor 3 in pancreatic beta cells protects nonobese diabetic mice from autoimmune diabetes [49].
When decoy receptor 3 is delivered systemically as plasmid DNA, it inhibits insulitis and diabetes by modulating immune responses. For example, four weekly intravenous injections of 100 microgram of plasmid DNA coding for decoy receptor 9 into nonobese diabetic mice was reported to reduce diabetes incidence from 90% in controls to 30% when treated at 4 weeks of age, 45% (started at 7 week old), and 70% (as Fc-fusion form, started at 12 week old) in 35-week-old female nonobese diabetic mice [50]. Treated mice showed less splenocyte proliferation and adoptive transfer of the cells ameliorated diabetes. Data also indicated that immune modulation by decoy receptor 3 may have been the result of differentiation and maturation of dendritic cells that subsequently regulated T effector differentiation and function.Cell migration is another process that plays a role in pancreatic beta cell destruction.
In this regard, plasmid DNA coding for CD44, which is a protein associated with cell migration and delivery of apoptotic signals by inflammatory cells, was investigated for the suppression of diabetes.
It was found that subcutaneous implants of a silicone tube filled with wound dressing sponge carrying CD44 encoded plasmid DNA could attenuate diabetes in a transfer model [51].
Diabetes was induced in male nonobese diabetic mice by transfer of diabetogenic splenocytes from female diabetic mice and was reduced from 90% in controls to 20-30% 12 weeks after two implants. Here the mechanism of treatment was not thought to be strictly a gene therapy effect, but rather induction of anti-CD44 antibodies that inhibited CD44 function. An increasing body of evidence points to a possible relationship between the central nervous system and diabetes [52]. For example, the pancreatic autoantigen glutamic acid decarboxylase is an enzyme responsible for synthesis of the neurotransmitter gamma-aminobutyric acid (GABA) in the peripheral and central nervous system.
Notably, at least two neurotransmitter-related peptides have been used successfully as plasmid DNA immunotherapies for type 1 diabetes. The first peptide is calcitonin gene-related peptide (CGRP), which has been found to play an important role in the regulation of T lymphocytes and in protecting cells from reactive oxygen species.
It was found that a single injection of 200 microgram plasmid DNA encoding the peptide delivered intramuscularly using electroporation could significantly ameliorate hyperglycemia and insulin deficiency [53]. The treatment decreased diabetes incidence from 73% in controls to 23% at 28 days post delivery in a streptozotocin-induced diabetic model. The gene transfer also significantly inhibited T cell proliferation and secretion of the T helper-1 cytokine interferon-gamma, increased the levels of the T helper-2 cytokine interleukin-10, but had no effect on interleukin-4 and transforming growth factor-beta secretion.
Therefore, calcitonin gene-related peptide gene transfer appears to ameliorate streptozotocin-induced diabetes through immune deviation.The second peptide is named vasoactive intestinal peptide (VIP) and functions as a neuromodulator and neurotransmitter [54]. The peptide is a potent vasodilator that regulates smooth muscle activity, epithelial cell secretion, and blood flow in the gastrointestinal tract.
Importantly, a body of evidence points to a significant role of vasoactive intestinal polypeptide in regulating immune responses.
The peptide acts as a potent endogenous anti-inflammatory molecule and promotes the activity of T regulatory cells, which makes it a promising candidate for the treatments of inflammatory and autoimmune diseases, such as septic shock, arthritis, multiple sclerosis, Crohn disease, and autoimmune diabetes [55, 56].
For example, a single intramuscular injection of 300 microgram of vasoactive intestinal polypeptide-encoding plasmid DNA significantly reduced the incidence of cyclophosphamide accelerated diabetes in female nonobese diabetic mice, from 70% in control to 30% on day 33 post delivery in 8-10-week-old mice [57]. Summary of Section 2Section 1 covers plasmid DNA encoding small protein molecules like cytokines, chemokines, peptides and other immune cell-manipulating agents with therapeutic effects on preclinical type 1 diabetes (Table 1). These approaches belong to systemic treatments and inevitably bear the risks associated with nonspecific immune suppression and chronic complications resulting from interference with the host immune system. Nonetheless, if used as adjuvants or supplements to pancreatic autoantigen-targeting therapies like DNA vaccines, these approaches could be used selectively in DNA-based combination therapies.

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