Tolerizing DNA vaccines for autoimmune arthritis

Ho, Peggy P.; Higgins, Julian P T; Kidd, Brian; Tomooka, Beren; DiGennaro, Carla; Lee, Lowen Y.; Vegvar, Henry E. Neuman de; Steinman, Lawrence; Robinson, William H.

doi:10.1080/08916930601061603

Cited by 18 publications

(19 citation statements)

References 35 publications

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“…Although DNA immunization research has largely focused on eliciting protective immunity against a variety of infectious pathogens, the technology may prove to have important applications in autoimmune diseases such as MS [4,5]. Vaccination using naked DNA encoding self-Ag has been shown to protect and even reverse established disease in several autoimmune animal models for various diseases, including rheumatoid arthritis [6], insulin-dependent diabetes mellitus [7] and MS [8]. Notably, recent clinical trials in MS patients based on DNA vaccination with myelin basic protein (MBP) demonstrated that the therapy was safe and well tolerated, caused Ag-specific immune tolerance, and was associated with a reduction in MRI-measured disease activity [9,10].…”

Section: Introductionmentioning

confidence: 99%

Treatment with MOG-DNA vaccines induces CD4+CD25+FoxP3+ regulatory T cells and up-regulates genes with neuroprotective functions in experimental autoimmune encephalomyelitis

Fissolo

Costa

Nurtdinov

et al. 2012

J Neuroinflammation

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BackgroundDNA vaccines represent promising therapeutic strategies in autoimmune disorders such as multiple sclerosis (MS). However, the precise mechanisms by which DNA vaccines induce immune regulation remain largely unknown. Here, we aimed to expand previous knowledge existing on the mechanisms of action of DNA vaccines in the animal model of MS, experimental autoimmune encephalomyelitis (EAE), by treating EAE mice with a DNA vaccine encoding the myelin oligodendrocyte glycoprotein (MOG), and exploring the therapeutic effects on the disease-induced inflammatory and neurodegenerative changes.MethodsEAE was induced in C57BL6/J mice by immunization with MOG35-55 peptide. Mice were intramuscularly treated with a MOG-DNA vaccine or vehicle in prophylactic and therapeutic approaches. Histological studies were performed in central nervous system (CNS) tissue. Cytokine production and regulatory T cell (Treg) quantification were achieved by flow cytometry. Gene expression patterns were determined using microarrays, and the main findings were validated by real-time PCR.ResultsMOG-DNA treatment reduced the clinical and histopathological signs of EAE when administered in both prophylactic and therapeutic settings. Suppression of clinical EAE was associated with dampening of antigen (Ag)-specific proinflammatory Th1 and Th17 immune responses and, interestingly, expansion of Treg in the periphery and upregulation in the CNS of genes encoding neurotrophic factors and proteins involved in remyelination.ConclusionsThese results suggest for the first time that the beneficial effects of DNA vaccines in EAE are not limited to anti-inflammatory mechanisms, and DNA vaccines may also exert positive effects through hitherto unknown neuroprotective mechanisms.

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Section: Introductionmentioning

confidence: 99%

Treatment with MOG-DNA vaccines induces CD4+CD25+FoxP3+ regulatory T cells and up-regulates genes with neuroprotective functions in experimental autoimmune encephalomyelitis

Fissolo

Costa

Nurtdinov

et al. 2012

J Neuroinflammation

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“…Several studies have shown beneficial effects of statin administration on joint inflammation in the mouse CIA model [13-16]. However, these studies did not specifically address the effects of statin administration before arthritis induction, an issue that follows from our observational study [9].…”

Section: Introductionmentioning

confidence: 99%

“…However, these studies did not specifically address the effects of statin administration before arthritis induction, an issue that follows from our observational study [9]. Nonetheless, to relate our results to the animal studies indicated above [13-16], we also evaluated effects of statin administration after arthritis induction.…”

Section: Introductionmentioning

confidence: 99%

Statins accelerate the onset of collagen type II-induced arthritis in mice

et al. 2012

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IntroductionStatins (hydroxymethylglutaryl coenzyme A reductase inhibitors) are effective in reducing the risk of cardiovascular morbidity and mortality in patients with hyperlipidemia, hypertension, or type II diabetes. Next to their cholesterol-lowering activity, statins have immunomodulatory properties. Based on these properties, we hypothesized that statin use may eventually lead to dysregulation of immune responses, possibly resulting in autoimmunity. We have recently shown in an observational study that statin use was associated with an increased risk of developing rheumatoid arthritis. Our objective was to investigate whether a causal relationship could be established for this finding.MethodsThe mouse collagen type II (CII)-induced arthritis (CIA) model was used, with immunization, challenge, and euthanasia at days 0, 21, and 42, respectively. Statins were given orally before (day -28 until day 21) or after (day 21 until day 42) CIA induction. Atorvastatin (0.2 mg/day) or pravastatin (0.8 mg/day) was administered. Arthritis was recorded three times a week. Serum anti-CII autoantibodies and cytokines in supernatants from Concanavalin-A-stimulated lymph node cells and CII-stimulated spleen cells were measured.ResultsStatin administration accelerated arthritis onset and resulted in 100% arthritic animals, whereas only seven out of 12 nonstatin control animals developed arthritis. Atorvastatin administration after CIA induction resulted in earlier onset than atorvastatin administration before induction, or than pravastatin administration before or after induction. The arthritic score of animals given pravastatin before CIA induction was similar to that of the nonstatin controls, whereas the other groups that received statins showed higher arthritic scores. Atorvastatin administration, especially before CIA induction, increased anti-CII autoantibody production. IL-2 and IL-17 production by lymph node and spleen cells was higher in CIA animals than in PBS controls, but was not affected by statin administration. While IFNγ production was not affected by CIA induction, atorvastatin administration before CIA induction increased the production of this cytokine.ConclusionThese data support previous results from our observational studies, indicating a role for statins in the induction of autoimmunity.

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“…The reduced severity of CIA was associated with decreased proinflammatory cytokines as well as reduced spreading of the antibody response (the latter was tested by arthritis microarray analysis) (71). Interestingly, the effect of DNA vaccination was significantly increased by atorvastatin, one of the statin drugs previously shown to suppress the severity of EAE (71).…”

Section: Tolerogenic Gene Therapy For Arthritismentioning

confidence: 99%

“…Tolerizing DNA vaccines-Recently, the success of another gene therapy approach in arthritis was reported: the tolerizing DNA vaccine encoding CII leading to the downmodulation of established CIA (71). The reduced severity of CIA was associated with decreased proinflammatory cytokines as well as reduced spreading of the antibody response (the latter was tested by arthritis microarray analysis) (71).…”

Section: Tolerogenic Gene Therapy For Arthritismentioning

confidence: 99%

Antigen-Specific Tolerogenic and Immunomodulatory Strategies for the Treatment of Autoimmune Arthritis

Satpute

Durai

Moudgil

2008

Seminars in Arthritis and Rheumatism

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Objectives-To review various antigen-specific tolerogenic and immunomodulatory approaches for arthritis in animal models and patients in regard to their efficacy, mechanisms of action and limitations.Methods-We reviewed the published literature in Medline (PubMed) on the induction of antigenspecific tolerance and its effect on autoimmune arthritis, as well as the recent work on B cell-mediated tolerance from our laboratory. The prominent key words used in different combinations included arthritis, autoimmunity, immunotherapy, innate immunity, tolerance, treatment, and rheumatoid arthritis (RA). Although this search spanned the years 1975 to 2007, the majority of the short-listed articles belonged to the period 1990 to 2007. The relevant primary as well as cross-referenced articles were then collected from links within PubMed and reviewed.Results-Antigen-specific tolerance has been successful in the prevention and/or treatment of arthritis in animal models. The administration of soluble native antigen or an altered peptide ligand intravenously, orally, or nasally, and the delivery of the DNA encoding a particular antigen by gene therapy have been the mainstay of immunomodulation. Recently, the methods for in vitro-expansion of CD4+CD25+ regulatory T cells have been optimized. Furthermore, interleukin-17 has emerged as a promising new therapeutic target in arthritis. However, in RA patients, non-antigen-specific therapeutic approaches have been much more successful than antigen-specific tolerogenic regimens.Conclusion-An antigen-specific treatment against autoimmune arthritis is still elusive. However, insights into newly emerging mechanisms of disease pathogenesis provide hope for the development of effective and safe immunotherapeutic strategies in the near future.

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Tolerizing DNA vaccines for autoimmune arthritis

Cited by 18 publications

References 35 publications

Treatment with MOG-DNA vaccines induces CD4+CD25+FoxP3+ regulatory T cells and up-regulates genes with neuroprotective functions in experimental autoimmune encephalomyelitis

Treatment with MOG-DNA vaccines induces CD4+CD25+FoxP3+ regulatory T cells and up-regulates genes with neuroprotective functions in experimental autoimmune encephalomyelitis

Statins accelerate the onset of collagen type II-induced arthritis in mice

Antigen-Specific Tolerogenic and Immunomodulatory Strategies for the Treatment of Autoimmune Arthritis

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