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Safety and immunogenicity of a novel therapeutic DNA vaccine encoding chicken type II collagen for rheumatoid arthritis in normal rats.

ABSTRACT: Current clinically available treatments for rheumatoid arthritis (RA) fail to cure the disease or unsatisfactorily halt disease progression. To overcome these limitations, the development of therapeutic DNA vaccines and boosters may offer new promising strategies. Because type II collagen (CII) as a critical autoantigen in RA and native chicken type II collagen (nCCII) has been used to effectively treat RA, we previously developed a novel therapeutic DNA vaccine encoding CCII (pcDNA-CCOL2A1) with efficacy comparable to that of the current "gold standard", methotrexate(MTX). Here, we systemically evaluated the safety and immunogenicity of the pcDNA-CCOL2A1 vaccine in normal Wistar rats. Group 1 received only a single intramuscular injection into the hind leg with pcDNA-CCOL2A1 at the maximum dosage of 3 mg/kg on day 0; Group 2 was injected with normal saline (NS) as a negative control. All rats were monitored daily for any systemic adverse events, reactions at the injection site, and changes in body weights. Plasma and tissues from all experimental rats were collected on day 14 for routine examinations of hematology and biochemistry parameters, anti-CII IgG antibody reactivity, and histopathology. Our results indicated clearly that at the maximum dosage of 3 mg/kg, the pcDNA-CCOL2A1 vaccine was safe and well-tolerated. No abnormal clinical signs or deaths occurred in the pcDNA-CCOL2A1 group compared with the NS group. Furthermore, no major alterations were observed in hematology, biochemistry, and histopathology, even at the maximum dose. In particularly, no anti-CII IgG antibodies were detected in vaccinated normal rats at 14 d after vaccination; this was relevant because we previously demonstrated that the pcDNA-CCOL2A1 vaccine, when administered at the therapeutic dosage of 300 ?g/kg alone, did not induce anti-CII IgG antibody production and significantly reduced levels of anti-CII IgG antibodies in the plasma of rats with established collagen-induced arthritis (CIA). This is the first study demonstrating the safety and immunogenicity of a DNA vaccine encoding CCII for treating RA in normal rats. These results may support the use of this novel therapeutic DNA vaccine for the treatment of RA in the future.

SUBMITTER: Juan L

PROVIDER: S-EPMC5054790 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Safety and immunogenicity of a novel therapeutic DNA vaccine encoding chicken type II collagen for rheumatoid arthritis in normal rats.

Juan Long L Xiao Zhao Z Song Yun Y Zhijian Zhang Z Jing Jin J Kun Yu Y Yuna Hao H Dongfa Dai D Lili Ding D Liuxin Tan T Fei Liang L Nan Liu L Fang Yuan Y Yuying Sun S Yongzhi Xi X

Human vaccines & immunotherapeutics 20150101 12

Current clinically available treatments for rheumatoid arthritis (RA) fail to cure the disease or unsatisfactorily halt disease progression. To overcome these limitations, the development of therapeutic DNA vaccines and boosters may offer new promising strategies. Because type II collagen (CII) as a critical autoantigen in RA and native chicken type II collagen (nCCII) has been used to effectively treat RA, we previously developed a novel therapeutic DNA vaccine encoding CCII (pcDNA-CCOL2A1) wit ...[more]

PMID: 26697972

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Project description:A major challenge in the development of effective therapies for rheumatoid arthritis (RA) is finding a method for the specific inhibition of the inflammatory disease processes without the induction of generalized immunosuppression. Of note, the development of therapeutic DNA vaccines and boosters that may restore immunological tolerance remains a high priority. pcDNA-CCOL2A1 is a therapeutic DNA vaccine encoding chicken type II collagen(CCII). This vaccine was developed by our laboratory and has been shown to exhibit efficacy comparable to that of the current "gold standard" treatment, methotrexate (MTX). Here, we used enzyme-linked immunosorbent assays with anti-CII IgG antibodies, quantified the expression levels of Th1, Th2, and Th3 cytokines, and performed flow cytometric analyses of different T-cell subsets, including Th1, Th2, Th17, Tc, Ts, Treg, and CD4(+)CD29(+)T cells to systemically evaluate humoral and cellular immune responses to pcDNA-CCOL2A1 vaccine in normal rats. Similar to our observations at maximum dosage of 3 mg/kg, vaccination of normal rats with 300 ?g/kg pcDNA-CCOL2A1 vaccine did not induce the production of anti-CII IgG. Furthermore, no significant changes were observed in the expression levels of pro-inflammatory cytokines interleukin (IL)-1?, IL-5, IL-6, IL-12(IL-23p40), monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1?, regulated on activation in normal T-cell expressed and secreted (RANTES), receptor activator for nuclear factor-?B ligand (RANKL), and granulocyte colony-stimulating factor (G-CSF) or anti-inflammatory cytokines IL-4 and IL-10 in vaccinated normal rats relative to that in controls(P > 0.05). However, transforming growth factor (TGF)-? levels were significantly increased on days 10 and 14, while interferon (IFN)-? and tumor necrosis factor (TNF)-? levels were significantly decreased on days 28 and 35 after vaccination(P < 0.05). Similarly, there were no significant differences in the percentages of Tc, Ts, Th1/Th2, and Th17 cells between the 2 groups(P > 0.05), with the exception of Treg cells, which were significantly reduced on days 14 and 21 after vaccination (P < 0.05), and CD4(+)CD29(+)T cells, which were significantly increased on days 7 and 14 after vaccination(P < 0.05).Taken together, these results suggested that pcDNA-CCOL2A1 vaccine did not markedly affect the balance of immune system components in vaccinated normal rats, indicating that this DNA vaccine may have clinical applications in the treatment of RA.

Project description:PurposeJintiange capsule (JTG), an approved drug developed as a substitute for tiger bone (TB), has been clinically applied for osteoporosis therapy since 2003. The drug is composed of bionic TB powder, in which peptides and proteins are primarily enriched from other bone extracts. However, as a precious material of traditional Chinese medicine (TCM), TB has been mainly understood and used in TCM to relieve osteoporosis, rheumatoid arthritis and bone injury. Inspired by those, the purpose of this study was to investigate whether JTG also had an effect on relieving rheumatoid arthritis in collagen-induced arthritic (CIA) rats and explore potential mechanism from the perspective of serum metabolic profile changes.MethodsJTG was analyzed using Nano LC-MS/MS and orally administered in CIA rats for 6 weeks. After administration, intervention effects of JTG on synovial inflammation, bone micro-architecture and bone metabolism were studied, and the impact of JTG on serum metabolic profiles in CIA rats was investigated by metabolomics.ResultsNine bioactive peptides were identified in JTG. In animal treatments, JTG alleviated paw swelling (P < 0.01), arthritic severity (P < 0.01) and synovial tissue proliferation, as well as inflammatory cell infiltration of ankle joint, decreased bone loss, improved microstructure of bone in CIA rats by regulating bone absorption and formation, specifically increasing bone mineral density (BMD) (P < 0.05), bone volume fraction (BVF) (P < 0.05), trabecular number (Tb.N) (P < 0.05) and decreasing trabecular separation (Tb.Sp) (P < 0.05). Besides, serum IL-6 was down-regulated remarkably in CIA rats (P < 0.05). Furthermore, metabolomics analysis revealed that 32 metabolites were regulated significantly (P < 0.05) by comparison between CIA model and JTG in 360 mg/kg dose. The pathway analysis implied that JTG was involved in regulation of biosynthesis of phenylalanine.ConclusionJTG alleviates rheumatoid arthritis and reverses changes in serum metabolic profile in CIA rats.

Project description:The aim of this study was to investigate the inhibitory effect of salvianolic acid on inflammatory mediators of rats with collagen-induced rheumatoid arthritis (RA). Thirty rats were randomly divided into the normal control group, collagen-induced arthritis model group (CIA model group) and drug group (Salvianolic Acid-CIA group). In the model group, the CIA models were established through intradermal injection of collagen emulsion at the toes. At 3 weeks after the model establishment, grouped drug administration was conducted, of which salvianolic acid was given by gavage to Salvianolic Acid-CIA group. The degrees of joint swelling of each group of rats were recorded. Enzyme-linked immunosorbent assay (ELISA) was applied to detect the levels of relevant inflammatory mediators, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to measure the messenger RNA (mRNA) expression levels of serum necrosis factor-alpha (TNF-?), interleukin-6 (IL-6) and prostaglandin E2 (PGE2), and hematoxylin and eosin staining was utilized to detect the pathological characteristics of the synovial tissues. After the establishment of models, the ankle joint swelling degree of rats in the model group was more obvious compared with that in the normal control group (P<0.01). After 3 weeks of drug administration, the ankle joint swelling degree of rats in the Salvianolic Acid-CIA group was alleviated compared with that in the model group (P<0.05). The contents of TNF-?, IL-6 and PGE2 in Salvianolic Acid-CIA group were obviously lower than those in the model group (P<0.01). The mRNA expression levels of TNF-?, IL-6 and PGE2 in the Salvianolic Acid-CIA group were markedly lower than those in the model group. The hyperemia of rat synovial tissues in Salvianolic Acid-CIA group was obviously relieved compared with that in the CIA model group. In conclusion, the models of CIA rats are successfully established, and the results show salvianolic acid has an inhibitory effect on the RA of CIA model rats and can significantly inhibit the expression levels of relevant inflammatory mediators.

Project description:BackgroundRheumatoid arthritis is characterized by chronic polyarticular synovitis and presents systemic changes that impact quality of life, such as impaired muscle function, seen in up to 66% of the patients. This can progress to severely debilitating state known as rheumatoid cachexia-without loss of fat mass and body weight-for which there is little consensus in terms of diagnosis or treatment. This study aims to evaluate whether the collagen-induced arthritis (CIA) animal model also develops clinical and functional features characteristic of rheumatoid cachexia.MethodsMale DBA1/J mice were randomly divided into 2 groups: healthy animals (CO, n = 11) and CIA animals (n = 13). The clinical score and edema size, animal weight and food intake, free exploratory locomotion, grip strength, and endurance exercise performance were tested 0, 18, 35, 45, 55, and 65 days after disease induction. After euthanasia, several organs, visceral and brown fat, and muscles were dissected and weighed. Muscles were used to assess myofiber diameter. Ankle joint was used to assess arthritis severity by histological score. Statistical analysis were performed using one-way and two-way analyses of variance followed by Tukey's and Bonferroni's test or t-test of Pearson and statistical difference were assumed for a P value under 0.05.ResultsThe CIA had significantly higher arthritis scores and larger hind paw edema volumes than CO. The CIA had decreased endurance exercise performance total time (fatigue; 23, 22, 24, and 21% at 35, 45, 55, and 65 days, respectively), grip strength (27, 55, 63, 60, and 66% at 25, 35, 45, 55, and 65 days, respectively), free locomotion (43, 57, 59, and 66% at 35, 45, 55, and 65 days, respectively), and tibialis anterior and gastrocnemius muscle weight (25 and 24%, respectively) compared with CO. Sarcoplasmic ratios were also reduced in CIA (TA: 23 and GA: 22% less sarcoplasmic ratio), confirming the atrophy of skeletal muscle mass in these animals than in CO. Myofiber diameter was also reduced 45% in TA and 41% in GA in CIA when compared with the CO. Visceral and brown fat were lighter in CIA (54 and 39%, respectively) than CO group.ConclusionsThe CIA model is a valid experimental model for rheumatoid cachexia given that the clinical changes observed were similar to those described in patients with rheumatoid arthritis.

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Safety and immunogenicity of a novel therapeutic DNA vaccine encoding chicken type II collagen for rheumatoid arthritis in normal rats.

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Safety and immunogenicity of a novel therapeutic DNA vaccine encoding chicken type II collagen for rheumatoid arthritis in normal rats.

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