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J Korean Med Sci. 2009;24(5):860-6.

The effect of CpG-oligodeoxynucleotides with different backbone structures and 3' hexameric deoxyriboguanosine run conjugation on the treatment of asthma in mice.

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제1저자 장윤석 · 교신저자 조상헌

PMID 19794984 PMC2752769 DOI 10.3346/jkms.2009.24.5.860 IF 3.2 알레르기내과
소속 (1)
  1. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

Abstract

CpG-Oligodeoxynucleotide (ODN) has two backbones. Phosphorothioate backbone (PS) shows a strong immunostimulating effect while phosphodiester (PE) shows little in vivo. 3' hexameric deoxyriboguanosine-run (3' dG(6)-run) conjugation to PE CpG-ODN has been reported to enhance immunostimulation and to protect against asthma when injected at the time of sensitization in mice. We evaluated the treatment effects of PE and PS CpG-ODN with or without 3' dG(6)-run on asthma in presensitized mice. BALB/c mice sensitized with ovalbumin and alum were challenged with 1% ovalbumin on three days. CpG-ODNs (100 microg) or PBS were injected 4 times; 27 hr before challenge and 3 hr before each challenge (CpG-dG(6): CpG-ODN with 3' dG(6)-run, PE*-CpG-dG(6): PE-CpG-dG(6) with two PS backbones at the 5' terminus). PE-CpG showed no treatment effect. PE-CpG-dG(6) only increased ovalbumin-specific IgG2a. PE*-CpG-dG(6) increased ovalbumin-specific IgG2a but also reduced BAL fluid eosinophils and airway hyperresponsiveness. PS-CpG increased ovalbumin-specific IgG2a, reduced airway inflammation and airway hyperresponsiveness. PS-CpG-dG(6) was less effective than PS-CpG on airway inflammation and airway hyperresponsiveness. In pre-sensitized mice, PE-CpG required not only 3' dG(6)-run but also the modification of two PS linkages at 5' terminus to inhibit features of asthma. PS-CpG was strong enough to inhibit asthma but PS-CpG-dG(6) was less effective.

Keywords

AllergyAsthmaCpG-ODNImmunotherapyModels, AnimalPoly G

Figures

Fig. 1
Fig. 1 Experimental protocols of sensitization and challenge. (A) Sequences and modifications of CpG ODNs used in this study. Immunostimulatory CpG motifs are underlined. Capital letters represent phosphodiester backbones and small letters phosphorothioate backbones. (B) BALB/c mice were sensitized by injecting OVA/alum intraperitoneally (i.p.) and later challenged with OVA on the indicated days (six mice per group). Mice were administered four injections of 100 µg of CpG ODNs or PBS i.p. in a total volume of 100 µL PBS at 24 hr intervals from 27 hr before the first OVA inhalation challenge.
Fig. 2
Fig. 2 Effects of the 3' dG6 run conjugated to CpG ODNs on the development of airway hyperresponsiveness (AHR) (A) (*: P<0.05, ns: no significant difference), and cellular proportions in bronchoalveolar lavage (BAL) fluid (B) (P<0.05, eosinophil proportions, *: vs. PBS, †: vs. PE-CpG-dG6, ‡: vs. PE*-CpG-dG6, #: vs. PS-CpG). AHR is represented by PC200, and cellular proportions are expressed as relative percentages of cell counts. Representative data of two independent experiments are shown. Bars indicate mean values±SEM of six mice.
Fig. 3
Fig. 3 Antibody responses in the sera of OVA-challenged BALB/c mice. Representative data of two independent experiments are shown. Bars indicate the mean values±SEM of six mice. (P<0.05, *: vs. PBS, †: vs. PE-CpG-dG6, ‡: vs. PE*-CpG-dG6, #: vs. PS-CpG).
Fig. 4
Fig. 4 Spleen to body weight ratios were the highest in animals treated with PS-CpG, followed by those treated with PS-CpG-dG6 or PE*-CpG-dG6. Mean spleen to body ratio was higher for PS-CpG-dG6 than for PE*-CpG-dG6, and these ratios were higher than those of PBS, PE-CpG, or PE-CpG-dG6. *: P<0.05.
Fig. 5
Fig. 5 Cytokine production by splenocytes. Repeat experiments produced similar results. Bars represent means value±SEM of experiments performed in triplicate. (P<0.05, *: vs. PBS, †: vs. PE-CpG-dG6, ‡: vs. PE*-CpG-dG6).

그림 출처: PubMed Central 공개 논문 (PMC2752769)

그 밖의 정보
출판 형태
Journal Article, Research Support, Non-U.S. Gov't
저널
Journal of Korean medical science · eISSN 1598-6357
전자 출판
2009-09-23
MeSH
Animals · Anti-Asthmatic Agents / therapeutic use · Asthma / drug therapy / physiopathology · Bronchial Hyperreactivity / drug therapy · Bronchoalveolar Lavage Fluid / immunology · Deoxyguanosine / analogs & derivatives / chemistry · Female · Immunoglobulin G / metabolism · Interleukin-12 / analysis · Interleukin-4 / analysis · Interleukin-5 / analysis · Lung / pathology · Mice · Mice, Inbred BALB C · Oligodeoxyribonucleotides / therapeutic use · Phosphorothioate Oligonucleotides / therapeutic use · Splenomegaly / pathology
Substances
Anti-Asthmatic Agents · CPG-oligonucleotide · Immunoglobulin G · Interleukin-5 · Oligodeoxyribonucleotides · Phosphorothioate Oligonucleotides · Interleukin-12 · Interleukin-4 · Deoxyguanosine
참고문헌
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