Vaccination with Empty Plasmid DNA or CpG Oligonucleotide Inhibits Diabetes in Nonobese Diabetic Mice: Modulation of Spontaneous 60-kDa Heat Shock Protein Autoimmunity

Quintana, Francisco J.; Rotem, Asaf; Carmi, Pnina; Cohen, Irun R.

doi:10.4049/jimmunol.165.11.6148

Cited by 139 publications

(101 citation statements)

References 36 publications

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“…However, this phenomenon is observed only when a relatively high dose of CpG oligonucleotides is used (29). In contrast, empty vectors containing the CpG motif ameliorated the clinical and histological severity of the autoimmune encephalomyelitis that is thought to be a Th1-mediated disease, as shown in previous studies by us (30) and others (31,32).…”

Section: Discussionmentioning

confidence: 84%

Nonviral Aβ DNA vaccine therapy against Alzheimer’s disease: Long-term effects and safety

Okura

Miyakoshi

Kohyama

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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It was recently demonstrated that amyloid ␤ (A␤) peptide vaccination was effective in reducing the A␤ burden in Alzheimer model mice. However, the clinical trial was halted because of the development of meningoencephalitis in some patients. To overcome this problem, anti-A␤ antibody therapy and other types of vaccination are now in trial. In this study, we have developed safe and effective nonviral A␤ DNA vaccines against Alzheimer's disease. We administered these vaccines to model (APP23) mice and evaluated A␤ burden reduction. Prophylactic treatments started before A␤ deposition reduced A␤ burden to 15.5% and 38.5% of that found in untreated mice at 7 and 18 months of age, respectively. Therapeutic treatment started after A␤ deposition reduced A␤ burden toϷ50% at the age of 18 months. Importantly, this therapy induced neither neuroinflammation nor T cell responses to A␤ peptide in both APP23 and wild-type B6 mice, even after long-term vaccination. Although it is reported that other anti-A␤ therapies have pharmacological and͞or technical difficulties, nonviral DNA vaccines are highly secure and easily controllable and are promising for the treatment of Alzheimer's disease. (4) and the passive transfer of anti-A␤ antibodies were also effective in reducing amyloid deposits (5). Moreover, vaccinated mice showed an improvement in memory loss (6, 7). Thus, A␤ peptide vaccine therapy has been shown to be effective in animal models, and human clinical trials were started with Betabloc (AN-1792), composed of synthetic A␤1-42 and QS21 as an adjuvant (8). However, the phase II clinical trial was halted because of the development of acute meningoencephalitis that appeared in 18 (6%) of 298 vaccinated patients (9). Importantly, it was later demonstrated by autopsy that there was a significant reduction of amyloid deposition and disappearance of degenerative axons in a treated patient (10). At the same time, T cell-dominant meningeal encephalitis was present in the cerebral cortex. These findings suggest that the vaccine therapy is a promising strategy for human Alzheimer's disease if excessive immune reactions are minimized to avoid unwanted neuroinflammation.Recently, it was reported that naked plasmid DNAs encoding proteins are taken into cells and produce the proteins in a small amount for a relatively long period when injected into the muscle or skin (11). Then, the proteins that are released in the extracellular space induce antibodies against the proteins (12, 13). Thus, gentle and quiet immune reactions could be obtained by DNA vaccine administration. In our and other's laboratories, immune therapies with DNA vaccines have been examined in autoimmune disease models (14-17) and have been found to be effective in preventing the diseases without the use of adjuvants. Here, we developed nonviral A␤ DNA vaccines and were able to reduce the amyloid burden in the cerebral cortex and hippocampus of Alzheimer's disease model (APP23) mice by vaccination. Importantly, the side effects, such as T cell proliferation and neuroin...

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Section: Discussionmentioning

confidence: 84%

Nonviral Aβ DNA vaccine therapy against Alzheimer’s disease: Long-term effects and safety

Okura

Miyakoshi

Kohyama

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…41 Islet function is routinely determined by static glucose stimulation where islets are sequentially incubated with 60 mg/dl glucose (basal level), then with 300 mg/dl glucose (stimulated level) and eventually with 60 mg/dl glucose (basal level) (basal-stimulated-basal). Since theophylline is a known potent secretagogue for insulin, we also co-cultured islets with glucose (300 mg/dl) and theophylline (180 mg/dl).…”

Section: Discussionmentioning

confidence: 99%

Adenovirus-based vascular endothelial growth factor gene delivery to human pancreatic islets

et al. 2004

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Islet transplantation is limited by islet graft failure due to poor revascularization, host immune rejection and nonspecific inflammatory response. Delivery of human vascular endothelial growth factor (hVEGF) gene to the islets is likely to promote islet revascularization and survival. We used a bicistronic adenoviral vector encoding hVEGF and CpG-free allele of green fluorescent protein (Adv-GFP-hVEGF) and introduced into human pancreatic islets by transfection. We found that transfection efficiency and apoptosis were dependent on the multiplicity of infection (MOI). Compared to Adv-GFP transfected and nontransfected islets, the levels of hVEGF secreted from Adv-GFP-hVEGF transfected islets were higher and exhibit a linear relationship between hVEGF expression and MOI (10-5000). Persistent, but low level expression of hVEGF from nontransfected islets was also observed. This may be due to expression of the endogenous hVEGF gene under hypoxic conditions. The levels of DNA fragmentation determined by ELISA of islet lysates were dependent on the MOI of Adv-GFP-hVEGF. On glucose challenge, insulin release from transfected islets was comparable to nontransfected islets. Immunohistochemical staining for hVEGF was very high in Adv-GFP-hVEGF transfected islets. Weak staining was also observed for hCD31 in both transfected and nontransfected islets. These findings suggest that Adv-GFP-hVEGF is a potential candidate for promoting islet revascularization.

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“…The conclusion that TLR9 is involved in preventing the development of potentially damaging autoreactive responses fits with the observations from mouse disease models. Treatment of mice with CpG to stimulate TLR9 has alleviated disease severity in colitis, arthritis, and diabetes (50)(51)(52)(53). In addition, lupus-related renal disease is exacerbated in TLR9-deficient autoimmune prone mice (20)(21)(22)(23), and recent reports suggest that TLR9 is required to prevent pathological responses that result from TLR7-mediated signaling (24,25).…”

Section: Discussionmentioning

confidence: 99%

A tolerogenic role for Toll-like receptor 9 is revealed by B-cell interaction with DNA complexes expressed on apoptotic cells

Miles

Heaney

Sibinska

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

122

124

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Intracellular protein complexes containing nucleic acids are common targets of autoantibodies in many autoimmune diseases. Central tolerance to these antigens is incomplete, yet nucleosomal DNA is expressed on the surface of cells dying by apoptosis. It is commonly believed that autoimmunity is prevented by the rapid uptake of apoptotic cells (ACs) by neighbors or professional phagocytes to which they deliver anti-inflammatory signals. Self-reactive, innate-like B cells contact and are selected by intracellular antigens expressed on ACs; however, how self-tolerance is maintained is not well understood. Here we report that IL-10 production by B cells, stimulated by contact with ACs, results from the engagement of Toll-like receptor 9 (TLR9) within the B cell after recognition of DNA-containing complexes on the surface of ACs. Until now, TLR9 ligation has been considered an inflammatory signal, but we have confirmed a hitherto unexpected immunoregulatory role by demonstrating the absence of the protective effect of ACs during experimental autoimmune encephalitis (EAE) in TLR9-deficient mice. Human circulating CD27 + B cells also respond to DNA-bearing ACs, but not to DNase-treated cells, by secreting IL-10. Chronic autoimmune disease may arise if this tolerance mechanism is not reimposed after episodes of inflammation, or if the regulatory B-cell response is subverted.

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Vaccination with Empty Plasmid DNA or CpG Oligonucleotide Inhibits Diabetes in Nonobese Diabetic Mice: Modulation of Spontaneous 60-kDa Heat Shock Protein Autoimmunity

Cited by 139 publications

References 36 publications

Nonviral Aβ DNA vaccine therapy against Alzheimer’s disease: Long-term effects and safety

Nonviral Aβ DNA vaccine therapy against Alzheimer’s disease: Long-term effects and safety

Adenovirus-based vascular endothelial growth factor gene delivery to human pancreatic islets

A tolerogenic role for Toll-like receptor 9 is revealed by B-cell interaction with DNA complexes expressed on apoptotic cells

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