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Changes in Immune Responses to Antigen Applied to Tape-Stripped Skin with CpG-Oligodeoxynucleotide in NC/Nga Mice

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Abstract

Purpose

CpG-oligodeoxynucleotide (CpG-ODN) plays a critical role in immunity via the augmentation of Th1 and the suppression of Th2 responses. We examined here the effect of CpG-ODN on the immune response to an antigen applied to a tape-stripped skin of NC/Nga mouse, a human atopic dermatitis (AD) model, by evaluating the production of cytokines and immunoglobulin isotypes.

Methods

Model antigen, ovalbumin (OVA), and CpG-ODN were applied on to the shaved skin. The penetration of OVA and CpG-ODN was evaluated using confocal laser scanning microscopy (CLSM). Secretion of cytokine from splenocytes and changes in immunoglobulin isotype levels were determined by enzyme-linked immunosorbent assay (ELISA).

Results

Through CLSM it was revealed that the model antigen, OVA, and CpG-ODN easily penetrated the tape-stripped skin. Coadministration of CpG-ODN and OVA to the skin elicited an antigen-specific, Th1-predominant immune response and enhanced the production of IFN-γ. On the other hand, the production of a Th2-type cytokine, IL-4, was drastically suppressed. In terms of antigen-specific antibody production, the level of IgG2a regulated by IFN-γ was increased by CpG-ODN, but IgE production regulated by IL-4 was suppressed.

Conclusions

Administration of CpG-ODN with antigen through the skin may shift the immune response from a Th2- to Th1-like response. These results suggested that administration of CpG-ODN via skin is a simple strategy for patients with diseases such as AD, which is characterized by Th2-dominated inflammation.

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References

  1. H. Nakamura M. Aoki K. Tamai M. Oishi T. Ogihara Y. Kaneda R. Morishita (2002) ArticleTitlePrevention and regression of atopic dermatitis by ointment containing NF-κB decoy oligodeoxynucleotides in NC/Nga atopic mouse model Gene Ther. 9 1221–1229 Occurrence Handle10.1038/sj.gt.3301724 Occurrence Handle12215889

    Article  PubMed  Google Scholar 

  2. D. Y. Leung M. Boguniewicz M. D. Howell I. Nomura Q. A. Hamid (2004) ArticleTitleNew insights into atopic dermatitis J. Clin. Invest. 113 651–657 Occurrence Handle10.1172/JCI200421060 Occurrence Handle14991059

    Article  PubMed  Google Scholar 

  3. T. R. Mosmann R. L. Coffman (1989) ArticleTitleTh1 and Th2 cells: different patterns of lymphokine secretion lead to different functional properties Annu. Rev. Immunol. 7 145–173 Occurrence Handle10.1146/annurev.iy.07.040189.001045 Occurrence Handle2523712

    Article  PubMed  Google Scholar 

  4. D. F. Fiorentino M. W. Bond T. R. Mosmann (1989) ArticleTitleTwo types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones J. Exp. Med. 170 2081–2095 Occurrence Handle10.1084/jem.170.6.2081 Occurrence Handle2531194

    Article  PubMed  Google Scholar 

  5. M. Grewe C. A. Bruijnzeel-Koomen E. Schopf T. Thepen A. G. Langeveld-Wildschut T. Ruzicka J. Krutmann (1998) ArticleTitleA role for Th1 and Th2 cells in the immunopathogenesis of atopic dermatitis Immunol. Today 19 359–361 Occurrence Handle10.1016/S0167-5699(98)01285-7 Occurrence Handle9709503

    Article  PubMed  Google Scholar 

  6. J. M. Spergel E. Mizoguchi H. Oettgen A. K. Bhan R. S. Geha (1999) ArticleTitleRoles of Th1 and Th2 cytokines in a murine model of allergic dermatitis J. Clin. Invest. 103 1103–1111 Occurrence Handle10207161

    PubMed  Google Scholar 

  7. C. Vestergaard H. Yoneyama M. Murai K. Nakamura K. Tamaki Y. Terashima T. Imai O. Yoshie T. Irimura H. Mizutani K. Matsushima (1999) ArticleTitleOverproduction of Th2-specific chemokines in NC/Nga mice exhibiting atopic dermatitis-like lesions J. Clin. Invest. 104 1097–1105 Occurrence Handle10525048

    PubMed  Google Scholar 

  8. A. G. Jarnicki P. G. Fallon (2003) ArticleTitleT helper type-2 cytokine responses: potential therapeutic targets Curr. Opin. Pharmacol 3 449–455 Occurrence Handle10.1016/S1471-4892(03)00077-8 Occurrence Handle12901956

    Article  PubMed  Google Scholar 

  9. T. M. Tuttle C. W. McCrady T. H. Inge M. Salour H. D. Bear (1993) ArticleTitleGamma-interferon plays a key role in T-cell-induced tumor regression Cancer Res. 53 833–839 Occurrence Handle8428364

    PubMed  Google Scholar 

  10. A. M. Krieg (2002) ArticleTitleCpG motifs in bacterial DNA and their immune effects Annu. Rev. Immunol 20 709–760 Occurrence Handle10.1146/annurev.immunol.20.100301.064842 Occurrence Handle11861616

    Article  PubMed  Google Scholar 

  11. S. Agrawal E.R. Kandimalla (2003) ArticleTitleModulation of Toll-like receptor 9 responses through synthetic immunostimulatory motifs of DNA Ann. N. Y. Acad. Sci. 1002 30–42 Occurrence Handle10.1196/annals.1281.005 Occurrence Handle14751820

    Article  PubMed  Google Scholar 

  12. H. Hemmi T. Kaisho K. Takeda S. Akira (2003) ArticleTitleThe roles ofToll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets J. Immunol. 170 3059–3064 Occurrence Handle12626561

    PubMed  Google Scholar 

  13. B. Spies H. Hochrein M. Vabulas K. Huster D. H. Busch F. Schmitz A. Heit H. Wagner (2003) ArticleTitleVaccination with plasmid DNA activates dendritic cells via Toll-like receptor 9 (TLR9) but functions in TLR9-deficient mice J. Immunol. 171 5908–5912 Occurrence Handle14634101

    PubMed  Google Scholar 

  14. A. S. Stern J. Magram D. H. Presky (1996) ArticleTitleInterleukin-12 an integral cytokine in the immune response Life Sci. 58 639–654 Occurrence Handle10.1016/S0024-3205(96)80003-8 Occurrence Handle8594314

    Article  PubMed  Google Scholar 

  15. A. K. Yi J. H. Chace J. S. Cowdery A. M. Krieg (1996) ArticleTitleIFN-gamma promotes IL-6 and IgM secretion in response to CpG motifs in bacterial DNA and oligodeoxynucleotides J. Immunol. 156 558–564 Occurrence Handle8543806

    PubMed  Google Scholar 

  16. S. Sivori M. Falco M. Chiesa ParticleDella S. Carlomagno M. Vitale L. Moretta A. Moretta (2004) ArticleTitleCpG and double-stranded RNA trigger human NK cells by Toll-like receptors: induction of cytokine release and cytotoxicity against tumors and dendritic cells Proc. Natl. Acad. Sci. USA 101 10116–10121 Occurrence Handle10.1073/pnas.0403744101 Occurrence Handle15218108

    Article  PubMed  Google Scholar 

  17. D. M. Klinman D. Currie I. Gursel D. Verthelyi (2004) ArticleTitleUse of CpG oligodeoxynucleotides as immune adjuvants Immunol. Rev. 199 201–216 Occurrence Handle10.1111/j.0105-2896.2004.00148.x Occurrence Handle15233736

    Article  PubMed  Google Scholar 

  18. H. Matsuda N. Watanabe G. P. Geba J. Sperl M. Tsudzuki J. Hiroi M. Matsumoto H. Ushio S. Saito P. W. Askenase C. Ra (1997) ArticleTitleDevelopment of atopic dermatitis-like skin lesion with IgE hyperproduction in NC/Nga mice Int. Immunol. 9 461–466 Occurrence Handle10.1093/intimm/9.3.461 Occurrence Handle9088984

    Article  PubMed  Google Scholar 

  19. S. Yotsumoto Y. Aramaki T. Kakiuchi S. Tsuchiya (2004) ArticleTitleInduction of antigen-dependent interleukin-12 production by negatively charged liposomes encapsulating antigens Vaccine 22 3503–3509 Occurrence Handle10.1016/j.vaccine.2004.01.071 Occurrence Handle15308378

    Article  PubMed  Google Scholar 

  20. T. Sakamoto E. Miyazaki Y. Aramaki H. Arima M. Takahashi Y. Kato M. Koga S. Tsuchiya (2004) ArticleTitleImprovement of dermatitis by iontophoretically delivered antisense oligonucleotides for interleukin-10 in NC/Nga mice Gene Ther. 11 317–324 Occurrence Handle10.1038/sj.gt.3302171 Occurrence Handle14737092

    Article  PubMed  Google Scholar 

  21. J. N. Kline T. J. Waldschmidt T. R. Businga J. E. Lemish J. V. Weinstock P. S. Thorne A. M. Krieg (1998) ArticleTitleModulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma J. Immunol. 160 2555–2559 Occurrence Handle9510150

    PubMed  Google Scholar 

  22. J. N. Kline K. Kitagaki T. R. Businga V. V. Jain (2002) ArticleTitleTreatment of established asthma in a murine model using CpG oligodeoxynucleotides Am. J. Physiol. Lung Cell Mol. Physiol. 283 L170–L179 Occurrence Handle12060574

    PubMed  Google Scholar 

  23. I. Hussain J. N. Kline (2003) ArticleTitleCpG oligodeoxynucleotides: a novel therapeutic approach for atopic disorders Curr. Drug Targets Inflamm. Allergy 2 199–205 Occurrence Handle10.2174/1568010033484151 Occurrence Handle14561154

    Article  PubMed  Google Scholar 

  24. S. C. Morris K. B. Madden J. J. Adamovicz W. C. Gause B. R. Hubbard M. K. Gately F. D. Finkelman (1994) ArticleTitleEffects of IL-12 on in vivo cytokine gene expression and Ig isotype selection J. Immunol. 152 1047–1056 Occurrence Handle7905496

    PubMed  Google Scholar 

  25. P. G. van der ParticleValk H. I. Maibach (1990) ArticleTitleA functional study of the skin barrier to evaporative water loss by means of repeated cellophane-tape stripping Clin. Exp. Dermatol. 15 180–182 Occurrence Handle2364571

    PubMed  Google Scholar 

  26. G. B. Lipford T. Sparwasser (2000) ArticleTitleHematopoietic remodeling triggered by CpG DNA Curr. Top Microbiol. Immunol. 247 119–129 Occurrence Handle10689783

    PubMed  Google Scholar 

  27. E. Davila M. G. Velez C. J. Heppelmann E. Celis (2002) ArticleTitleCreating space: an antigen-independent, CpG-induced peripheral expansion of naive and memory T lymphocytes in a full T-cell compartment Blood 100 2537–2545 Occurrence Handle10.1182/blood-2002-02-0401 Occurrence Handle12239167

    Article  PubMed  Google Scholar 

  28. M. Yazdanbakhsh A. van den Particle Biggelaar R. M. Maizels (2001) ArticleTitleTh2 responses without atopy: immunoregulation in chronic helminth infections and reduced allergic disease Trends Immunol. 22 372–377 Occurrence Handle10.1016/S1471-4906(01)01958-5 Occurrence Handle11429321

    Article  PubMed  Google Scholar 

  29. Y. Wu Q. Zhou P. Zheng Y. Liu (1998) ArticleTitleCD28-independent induction of T helper cells and immunoglobulin class switches requires costimulation by the heat-stable antigen J. Exp. Med. 187 1151–1156 Occurrence Handle10.1084/jem.187.7.1151 Occurrence Handle9529332

    Article  PubMed  Google Scholar 

  30. E. Y. So H. H. Park C. E. Lee (2000) ArticleTitleIFN-gamma and IFN-alpha posttranscriptionally down-regulate the IL-4-induced IL-4 receptor gene expression J. Immunol. 165 5472–5479 Occurrence Handle11067899

    PubMed  Google Scholar 

  31. M. Kimura S. Tsuruta T. Yoshida (2000) ArticleTitleIL-4 production by PBMCs on stimulation with mite allergen is correlated with the level of serum IgE antibody against mite in children with bronchial asthma J. Allergy Clin. Immunol. 105 327–332 Occurrence Handle10.1016/S0091-6749(00)90083-6 Occurrence Handle10669854

    Article  PubMed  Google Scholar 

  32. H. J. Cho K. Takabayashi P. M. Cheng M. D. Nguyen M. Corr S. Tuck E. Raz (2000) ArticleTitleImmunostimulatory DNA-based vaccines induce cytotoxic lymphocyte activity by a T-helper cell-independent mechanism Nat. Biotechnol. 18 509–514 Occurrence Handle10.1038/75365 Occurrence Handle10802617

    Article  PubMed  Google Scholar 

  33. H. Shirota K. Sano N. Hirasawa T. Terui K. Ohuchi T. Hattori K. Shirato G. Tamura (2001) ArticleTitleNovel roles of CpG oligodeoxynucleotides as a leader for the sampling and presentation of CpG-tagged antigen by dendritic cells J. Immunol. 167 66–74 Occurrence Handle11418633

    PubMed  Google Scholar 

  34. A. Boonstra C. Asselin-Paturel M. Gilliet C. Crain G. Trinchieri Y. J. Liu A. O'Garra (2003) ArticleTitleFlexibility of mouse classical and plasmacytoid-derived dendritic cells in directing T helper type 1 and 2 cell development: dependency on antigen dose and differential Toll-like receptor ligation J. Exp. Med. 197 101–109 Occurrence Handle10.1084/jem.20021908 Occurrence Handle12515817

    Article  PubMed  Google Scholar 

  35. L. Liu X. Zhou J. Shi X. Xie Z. Yuan (2003) ArticleTitleToll-like receptor-9 induced by physical trauma mediates release of cytokines following exposure to CpG motif in mouse skin Immunology 110 341–347 Occurrence Handle10.1046/j.1365-2567.2003.01739.x Occurrence Handle14632662

    Article  PubMed  Google Scholar 

  36. S. K. Klimuk H. M. Najar S. C. Semple S. Aslanian J. P. Dutz (2004) ArticleTitleEpicutaeous application of CpG oligodeoxynucleotides with peptide or protein antigen promotes the generation of CTL J. Invest. Dermatol. 122 1042–1049 Occurrence Handle10.1111/j.0022-202X.2004.22411.x Occurrence Handle15102096

    Article  PubMed  Google Scholar 

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Acknowledgments

We are grateful to Miss T. Yoshida for technical assistance. This work was supported in part by the Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan to Y. A. (14657594).

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Authors and Affiliations

  1. School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan

    Joe Inoue, Satoshi Yotsumoto, Takatoshi Sakamoto, Seishi Tsuchiya & Yukihiko Aramaki

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  1. Joe Inoue
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  2. Satoshi Yotsumoto
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  3. Takatoshi Sakamoto
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  5. Yukihiko Aramaki
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Correspondence to Yukihiko Aramaki.

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Inoue, J., Yotsumoto, S., Sakamoto, T. et al. Changes in Immune Responses to Antigen Applied to Tape-Stripped Skin with CpG-Oligodeoxynucleotide in NC/Nga Mice. Pharm Res 22, 1627–1633 (2005). https://doi.org/10.1007/s11095-005-6834-7

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