Vaccination with a Novel Antigen-Specific Tolerizing DNA Vaccine Encoding CCOL2A1 Protects Rats from Experimental Rheumatoid Arthritis.

Abstract

Antigen-specific tolerizing DNA vaccines are one of the most promising strategies for rheumatoid arthritis (RA) treatment. They act by inducing potent immune tolerance instead of generalized immunosuppression. Recently, we developed a novel antigen-specific tolerizing DNA vaccine pcDNA-CCOL2A1 coding for chicken type II collagen (CCII) and confirmed its potent therapeutic efficacy in an established rat model of collagen-induced arthritis (CIA). Here we report the prophylactic vaccination efficacy of a single 300 μg/kg dose of pcDNA-CCOL2A1 against CIA incidence, severity, and onset. CCOL2A1 transcripts were detected in the blood of CIA rats 14-42 days after intramuscular injection by 300 μg/kg pcDNA-CCOL2A1. The expression of CCOL2A1 transcripts increased quickly on day 21, peaked at day 28, and then gradually decreased thereafter. Importantly, a single prophylactic vaccination of pcDNA-CCOL2A1 14 days before CIA establishment significantly reduced CIA incidence and severity, deferred its onset, and was as efficacious as the current gold standard drug, methotrexate. The marked effects on CIA incidence and severity closely corresponded to the expression of CCOL2A1. Furthermore, prophylactic vaccination with pcDNA-CCOL2A1 markedly decreased serum content of anti-type II collagen (CII) immunoglobulin G (IgG) antibodies, induced Th1-to-Th2 and Tc1-to-Tc2 shifts, and decreased the percentages of CD4+CD29+ and Th17 T cells. Prophylactic vaccination with pcDNA-CCOL2A1 also downregulated various Th1 cytokines, while upregulating both the Th2-type cytokine interleukin-10 and the Th3-type cytokine transforming growth factor β. Our results indicate that the pcDNA-CCOL2A1 DNA vaccine acts as a highly efficient inducer of specific immunotolerance that could be a promising option for RA treatment in the near future.