Molecular & Cellular Toxicology

The Korean Society of Toxicogenomics and Toxicoproteomics (대한독성유전 단백체학회)
권호 표지

Immunotoxicological Effects of Mouse CpG Oligodeoxynucleotides in Lupus-prone NZB/NZW F1 Mice

  • Kim, Bo-Hwan (Department of Endocrinology, Wonju College of Medicine, Yonsei University) ;
  • Seo, Dong-Jin (Central Research Laboratory, Wonju College of Medicine, Yonsei University) ;
  • Jung, Soon-Hee (Department of Pathology, Wonju College of Medicine, Yonsei University) ;
  • Kim, Soo-Ki (Department of Microbiology, Wonju College of Medicine, Yonsei University)
  • Published : 2009.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

Despite wide therapeutic use of CpG ODN against infection, allergy and cancer, the safety and toxicity of CpG ODNs were poorly delineated. Thus, we investigated whether optimal dosing of CpG ODN would affect immunotoxicological parameters in NZB/NZW F1 mice. Comparisons were made among control, non-CpG ODN and mouse CpG ODN ($10{\mu}g$)-treated groups for 4 weeks. To gauge the immunotoxicity of CpG ODNs, we measured nonspecific parameters, degree of lupus nephritis, proteinuria, or autoantibody, and cytokine expression in mRNA level of lymphocytes. We found that there were no significant differences among groups in nonspecific immunotoxicological profiles and in evaluation profiles of glomerulonephritis. However, titer of anti-dsDNA and anti-cardiolipin antibodies in mouse CpG ODN group rose three or eight-fold higher than in control group. Collectively, CpG ODN might be clinically less immunotoxic in terms of clinical profiles in lupus-prone NZB/NZW F1 mice, in spite of high autoantibody titer in CpG ODN treated groups.

Keywords

References

  1. Krieg, A. M. CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol 20:709-760 (2002) https://doi.org/10.1146/annurev.immunol.20.100301.064842
  2. Takeda, K. & Akira, S. Toll-like receptors in innate immunity. Int Immunol 17:1-14 (2005) https://doi.org/10.1093/intimm/dxh186
  3. Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nat Immunol 5:987-995 (2004) https://doi.org/10.1038/ni1112
  4. Akira, S., Takeda, K. & Kaisho, T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2:675-680 (2001) https://doi.org/10.1038/90609
  5. Chu, R. S., Targoni, O. S., Krieg, A. M., Lehmann, P. V. & Harding, C. V. CpG oligodeoxynucleotides act as adjuvants that switch on T helper 1 (Th1) immunity. J Exp Med 186:1623-1631 (1997) https://doi.org/10.1084/jem.186.10.1623
  6. van Duin, D., Medzhitov, R. & Shaw, A. C. Triggering TLR signaling in vaccination. Trends Immunol 27:49-55 (2006) https://doi.org/10.1016/j.it.2005.11.005
  7. Klinman, D. M., Yi, A. K., Beaucage, S. L., Conover, J. & Krieg, A. M. CpG motifs present in bacteria DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon gamma. Proc Natl Acad Sci USA 93: 2879-2883 (1996) https://doi.org/10.1073/pnas.93.7.2879
  8. Klinman, D. M. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol 4:249-258 (2004) https://doi.org/10.1038/nri1329
  9. Bhattacharjee, R. N. & Akira, S. Modifying toll-like receptor 9 signaling for therapeutic use. Mini Rev Med Chem 6:287-291 (2006) https://doi.org/10.2174/138955706776073411
  10. Anders, H. J. et al. Activation of toll-like receptor-9 induces progression of renal disease in MRL-Fas(lpr) mice. FASEB J 18:534-536 (2004) https://doi.org/10.1096/fj.03-0646fje
  11. Anders, H. J. A Toll for lupus. Lupus 14:417-422 (2005) https://doi.org/10.1191/0961203305lu2102rr
  12. Anders, H. J. et al. Bacterial CpG-DNA aggravates immune complex glomerulonephritis: role of TLR9-mediated expression of chemokines and chemokine receptors. J Am Soc Nephrol 14:317-326 (2003) https://doi.org/10.1097/01.ASN.0000042169.23931.73
  13. Aringer, M. & Smolen, J. S. Cytokine expression in lupus kidneys. Lupus 14:13-18 (2005) https://doi.org/10.1191/0961203305lu2053oa
  14. Cho, H. C. et al. Cancer immunotherapeutic effects of novel CpG ODN in murine tumor model. Int Immunopharmacol 8:1401-1407 (2008) https://doi.org/10.1016/j.intimp.2008.05.010
  15. Link, B. K. et al. Oligodeoxynucleotide CpG 7909 delivered as intravenous infusion demonstrates immunologic modulation in patients with previously treated non-Hodgkin lymphoma. J Immunother 29:558-568 (2006) https://doi.org/10.1097/01.cji.0000211304.60126.8f
  16. Friedberg, J. W. et al. Combination immunotherapy with a CpG oligonucleotide (1018 ISS) and rituximab in patients with non-Hodgkin lymphoma: increased interferon-alpha/beta-inducible gene expression, without significant toxicity. Blood 105:489-495 (2005) https://doi.org/10.1182/blood-2004-06-2156
  17. Cooper, C. L. et al. CPG 7909, an immunostimulatory TLR9 agonist oligodeoxynucleotide, as adjuvant to Engerix-B HBV vaccine in healthy adults: a double-blind phase I/II study. J Clin Immunol 24:693-701 (2004) https://doi.org/10.1007/s10875-004-6244-3
  18. Gilkeson, G. S. et al. Modulation of renal disease in autoimmune NZB/NZW mice by immunization with bacterial DNA. J Exp Med 183:1389-1397 (1996) https://doi.org/10.1084/jem.183.4.1389
  19. Gilkeson, G. S. et al. Effects of bacterial DNA on cytokine production by (NZB/NZW)F1 mice. J Immunol 161:3890-3895 (1998)
  20. Hofmann, M. A. et al. Phase 1 evaluation of intralesionally injected TLR9-agonist PF-3512676 in patients with basal cell carcinoma or metastatic melanoma. J Immunother 31:520-527 (2008) https://doi.org/10.1097/CJI.0b013e318174a4df
  21. Lipsky, P. E. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat Immunol 2:764-766 (2001) https://doi.org/10.1038/ni0901-764
  22. Hayakawa, K., Hardy, R. R., Parks, D. R. & Herzenberg, L. A. The 'Ly-1 B' cell subpopulation in normal immunodefective, and autoimmune mice. J Exp Med 157:202-218 (1983) https://doi.org/10.1084/jem.157.1.202
  23. Wofsy, D. & Chiang, N. Y. Proliferation of Ly-1 B cells in autoimmune NZB and (NZB×NZW)F1 mice. Eur J Immunol 17:809-814 (1987) https://doi.org/10.1002/eji.1830170612
  24. Sidman, C. L., Shultz, L. D., Hardy, R. R., Hayakawa, K. & Herzenberg, L. A. Production of immunoglobulin isotypes by Ly-1+ B cells in viable motheaten and normal mice. Science 232:1423-1425 (1986) https://doi.org/10.1126/science.3487115
  25. Burastero, S. E., Casali, P., Wilder, R. L. & Notkins, A. L. Monoreactive high affinity and polyreactive low affinity rheumatoid factors are produced by CD5+ B cells from patients with rheumatoid arthritis. J Exp Med 168:1979-1992 (1988) https://doi.org/10.1084/jem.168.6.1979
  26. Viau, M. & Zouali, M. B-lymphocytes, innate immunity, and autoimmunity. Clin Immunol 114:17-26 (2005) https://doi.org/10.1016/j.clim.2004.08.019