Vaccination with DNA Encoding an Immunodominant Myelin Basic Protein Peptide Targeted to Fc of Immunoglobulin G Suppresses Experimental Autoimmune Encephalomyelitis

Lobell, Anna; Weissert, Robert; Storch, Maria K.; Svanholm, Cecilia; Graaf, Katrien L. de; Lassmann, H.; Andersson, Roland; Olsson, Tomas; Wigzell, Hans

doi:10.1084/jem.187.9.1543

Cited by 88 publications

(52 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Annealing temperatures were 55°C for Fc␥RI and GAPDH, 60°C for Fc␥RIIa and Fc␥RIIb, and 62°C for Fc␥RIII. The PCR reaction was stopped after 20,23,26,29,32,35,38,41, and 44 cycles at the very end of the extension phase (72°C), and 5-l samples were obtained.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Increased expression of Fcγ receptors II and III on macrophages of rheumatoid arthritis patients results in higher production of tumor necrosis factor α and matrix metalloproteinase

Blom¹,

Radstake²,

Holthuysen³

et al. 2003

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. To evaluate Fc␥ receptor (Fc␥R) expression on synovial macrophages from rheumatoid arthritis (RA) patients and to determine whether this expression correlates with the production of the proinflammatory cytokines tumor necrosis factor ␣ (TNF␣), interleukin-1␤ (IL-1␤), IL-12, and matrix metalloproteinase 1 (MMP-1). We also sought to determine whether mature macrophages from RA patients express aberrant levels of Fc␥RI, Fc␥RII, and Fc␥RIII, and to determine the production of inflammatory mediators after immune complex (IC) stimulation.Methods. Immunohistochemistry was performed on cryostat sections of synovial biopsy specimens obtained from 27 RA patients and 5 controls. Fc␥R I, II, and III were detected, as well as the proinflammatory mediators IL-1, TNF␣, IL-12, and MMP-1. Monocytes were isolated from the blood of 10 RA patients and 10 healthy controls and cultured for 7 days with macrophage colony-stimulating factor to obtain macrophages. Using fluorescence-activated cell sorting, the expression of Fc␥RI, Fc␥RII, and Fc␥RIII was determined. On day 7, macrophages were stimulated with heat-aggregated gamma globulins (HAGGs) for 24 hours. Production of cytokines was measured using enzyme-linked immunosorbent assay, and production of gelatinases/ collagenases was measured by degradation of fluorescent gelatin.Results. Immunohistochemistry showed higher Fc␥RII and Fc␥RIII expression in RA synovium than in controls. Fc␥RII and Fc␥RIII, but not Fc␥RI, were highly correlated with the number of synovial macrophages. Consistent with this, TNF␣ expression correlated positively with Fc␥RIII expression. Moreover, MMP-1 expression strongly correlated with Fc␥R I, II, and III expression. Mature macrophages from RA patients showed significantly enhanced expression of Fc␥RII and Fc␥RIII compared with controls. Twentyfour hours after stimulation of RA macrophages with HAGGs, significantly higher production of TNF␣ and gelatinase/collagenase was measured.Conclusion. RA synovium and mature RA macrophages express significantly elevated levels of Fc␥RII and Fc␥RIII, resulting in much higher production of TNF␣ and gelatinase/collagenase after IC stimulation. These data suggest that disturbed expression of Fc␥R on mature synovial macrophages is involved in the pathology of RA.

show abstract

Section: Methodsmentioning

confidence: 99%

“…The function of Fc␥RIIIb, which lacks an intracellular domain, is still unknown (18). Coordinate expression of Fc␥R has been implicated in various diseases involving ICs, such as diabetes (19), systemic lupus erythematosus (20,21), multiple sclerosis (22,23), autoimmune anemia (24,25), and RA (26).…”

mentioning

confidence: 99%

Increased expression of Fcγ receptors II and III on macrophages of rheumatoid arthritis patients results in higher production of tumor necrosis factor α and matrix metalloproteinase

Blom¹,

Radstake²,

Holthuysen³

et al. 2003

Arthritis & Rheumatism

View full text Add to dashboard Cite

show abstract

“…Indeed, initial reports have demonstrated that induction of experimental autoimmune encephalomyelitis can be prevented by immunizing rodents with pDNAs encoding a variable ␤-chain segment of an encephalogenic TCR (28) or with epitopes derived from autoantigens used to induce the disease process (29,30). However, the efficacy of pDNA immunization to suppress established autoimmunity was not examined in these studies.…”

mentioning

confidence: 88%

“…Of importance is that spontaneous GAD65-specific Th1 cell reactivity is first detected in 4-wk-old NOD mice and reaches maximal levels in animals 12 wk of age (5,6). Two recent experimental autoimmune encephalomyelitis studies have demonstrated that T cells are tolerized via anergy/deletion mechanisms, and autoimmunity is prevented by immunizing rodents with pDNAs encoding peptides derived from the autoantigens used to induce disease (29,30). In these studies, however, the animals lacked primed autoantigen-specific T cells at the time of pDNA immunization.…”

Section: Discussionmentioning

confidence: 99%

Antigen-Specific Mediated Suppression of β Cell Autoimmunity by Plasmid DNA Vaccination

Tisch

Wang

Weaver

et al. 2001

The Journal of Immunology

110

103

View full text Add to dashboard Cite

In this study, we have investigated the use of plasmid DNA (pDNA) vaccination to elicit Th2 effector cell function in an Ag-specific manner and in turn prevent insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. pDNA recombinants were engineered encoding a secreted fusion protein consisting of a fragment of glutamic acid decarboxylase 65 (GAD65) linked to IgGFc, and IL-4. Intramuscular injection of pDNA encoding GAD65-IgGFc and IL-4 effectively prevented diabetes in NOD mice treated at early or late preclinical stages of IDDM. This protection was GAD65-specific since NOD mice immunized with pDNA encoding hen egg lysozyme-IgGFc and IL-4 continued to develop diabetes. Furthermore, disease prevention correlated with suppression of insulitis and induction of GAD65-specific regulatory Th2 cells. Importantly, GAD65-specific immune deviation was dependent on pDNA-encoded IL-4. In fact, GAD65-specific Th1 cell reactivity was significantly enhanced in animals immunized with pDNA encoding only GAD65-IgGFc. Finally, NOD.IL4null mice treated with pDNA encoding GAD65-IgGFc and IL-4 continued to develop diabetes, indicating that endogenous IL-4 was also required for disease prevention. These results demonstrate that pDNA vaccination is an effective strategy to elicit β cell-specific Th2 regulatory cell function for the purpose of preventing IDDM even at a late stage of disease development.

show abstract

“…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)(15)(16)(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.…”

mentioning

confidence: 99%

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.

View full text Add to dashboard Cite

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...

show abstract

Vaccination with DNA Encoding an Immunodominant Myelin Basic Protein Peptide Targeted to Fc of Immunoglobulin G Suppresses Experimental Autoimmune Encephalomyelitis

Cited by 88 publications

References 25 publications

Increased expression of Fcγ receptors II and III on macrophages of rheumatoid arthritis patients results in higher production of tumor necrosis factor α and matrix metalloproteinase

Increased expression of Fcγ receptors II and III on macrophages of rheumatoid arthritis patients results in higher production of tumor necrosis factor α and matrix metalloproteinase

Antigen-Specific Mediated Suppression of β Cell Autoimmunity by Plasmid DNA Vaccination

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

Contact Info

Product

Resources

About