June 11, 2009
Novel DNA Vaccine Leads To Kidney Damage Prevention
DNA vaccination using lupus autoantigens and interleukin-10 (IL-10, a cytokine that plays an important role in regulating the immune system) has potential as a novel therapy to induce antigen specific tolerance and may help to prevent kidney damage in patients with systemic lupus erythematosus (SLE), according to a new study presented today at EULAR 2009, the Annual Congress of the European League Against Rheumatism in Copenhagen, Denmark.
SLE is a complex, chronic autoimmune disease that causes inflammation and damage to body tissues. Inflammation of the kidney can cause kidney failure, often a significant complication of SLE associated with the more severe forms of the disease, and the primary cause of disability that leads to other fatal complications in people with the condition.
In the study, one group of experimental mice was vaccinated with Sm (Smith antigens that are small nuclear ribonucleoproteins: snRNPs) lupus autoantigen in combination with IL-10 and another group vaccinated with the same antigen and IFN-gamma, both signaling molecules involved in the immune process. SLE was induced in the mice and the levels of antibodies against various lupus autoantibodies were analysed. The study found that levels of anti-Sm antibodies in the IL-10 vaccinated group were lower than those in the group vaccinated with IFN-gamma (p=0.026, statistically significant).
Interestingly, the prevalence and levels of other autoantibodies such as anti-Argonaute2 (Ago2)/Su and chromatin did not differ between the groups, indicating that the vaccination was Sm antigen-specific and successfully targeting particular antibodies. Significant proteinuria (a urinary condition which can indicate kidney damage) (>1.5+) was less common in the IL-10 vaccinated group compared with the IFN-gamma group, which may suggest a beneficial role for IL-10 vaccination in preventing kidney damage associated with SLE.
Dr Monica Vazquez del Mercado, Head of the Instituto de Investigaci³n en ReumatologÃa y del Sistema MÃºsculo Esquel©tico of the Universidad de Guadalajara, Mexico, corresponding author of the study, said: "Some autoantibodies are specific for SLE and are considered to be characteristic of the condition. The mechanisms that regulate the production of these antibodies are poorly understood, however, the results of our study have identified one possible way of influencing the pathway behind kidney damage in SLE."
Studies in human and mouse models of lupus have revealed that the major epitopes of the anti-Sm antibodies are present at specific locations (D1, D2 and B/BÃ´) of the Sm antigens. Researchers in this study prepared DNA vaccines of Sm D1, D2, B/BÃ´, B/BÃ´COOH, IFN-gamma and IL-10 using direct cloning techniques with pcDNA"3.1D/V5-His-TOPOÃ® and purified these using Qiagen Endo-Free Giga Prep Kit. Eight groups of 6 week-old female BALB/c mice (13/group) received intramuscular injections of 100 micrograms of the vaccination preparation at days 2 and 9. At day 16, mice were induced with experimental SLE.
Serum samples were collected at day 0 and then monthly for analysis of autoantibodies and immunoglobulin levels. Serum autoantibodies were tested by immunoprecipitation and ELISA. Proteinuria (excessive protein in the urine) was assessed monthly using MultistixÃ®. Kidney pathology and immune complex deposition were examined at 6 months.
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