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. 1995 Oct;69(10):5929–5934. doi: 10.1128/jvi.69.10.5929-5934.1995

Nucleic acid vaccination primes hepatitis B virus surface antigen-specific cytotoxic T lymphocytes in nonresponder mice.

R Schirmbeck 1, W Böhm 1, K Ando 1, F V Chisari 1, J Reimann 1
PMCID: PMC189487  PMID: 7666497

Abstract

The efficiency of different vaccination techniques to prime in vivo major histocompatibility complex class I-restricted murine cytotoxic T-lymphocyte (CTL) precursors to hepatitis B virus small surface antigen (HBsAg) was investigated. Mice were immunized either by injection of a low dose of recombinant HBsAg protein preparations (native HBsAg particles or denatured HBsAg monomers) without adjuvants, by infection with recombinant vaccinia virus carrying an HBsAg-encoding gene, or by intramuscular transfer of plasmid DNA encoding HBsAg under appropriate promoter control. In H-2d mice, an Ld-restricted, S28-39-specific CTL response was efficiently primed by all alternative vaccination techniques tested, but the most potent priming of class I-restricted CTL to HBsAg in vivo was observed with DNA immunization. Priming of anti-HBsAg CTL in H-2b mice was not detectable after infection with a recombinant vaccinia virus or after injection with exogenous recombinant HBsAg preparations. After DNA immunization, however, both Kb- and Db-restricted CTL reactivity to HBsAg emerged in H-2b mice. Hence, nucleic acid immunization revealed class I-restricted CTL responsiveness to HBsAg in a mouse strain previously considered to be a nonresponder at the CTL level. These results demonstrate that the simple technique of nucleic acid immunization not only is extremely efficient but also reveals an extended spectrum of potentially immunogenic epitopes of protein antigens.

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Selected References

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  1. Ando K., Guidotti L. G., Wirth S., Ishikawa T., Missale G., Moriyama T., Schreiber R. D., Schlicht H. J., Huang S. N., Chisari F. V. Class I-restricted cytotoxic T lymphocytes are directly cytopathic for their target cells in vivo. J Immunol. 1994 Apr 1;152(7):3245–3253. [PubMed] [Google Scholar]
  2. Ando K., Moriyama T., Guidotti L. G., Wirth S., Schreiber R. D., Schlicht H. J., Huang S. N., Chisari F. V. Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis. J Exp Med. 1993 Nov 1;178(5):1541–1554. doi: 10.1084/jem.178.5.1541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Davis H. L., Demeneix B. A., Quantin B., Coulombe J., Whalen R. G. Plasmid DNA is superior to viral vectors for direct gene transfer into adult mouse skeletal muscle. Hum Gene Ther. 1993 Dec;4(6):733–740. doi: 10.1089/hum.1993.4.6-733. [DOI] [PubMed] [Google Scholar]
  4. Davis H. L., Michel M. L., Whalen R. G. DNA-based immunization induces continuous secretion of hepatitis B surface antigen and high levels of circulating antibody. Hum Mol Genet. 1993 Nov;2(11):1847–1851. doi: 10.1093/hmg/2.11.1847. [DOI] [PubMed] [Google Scholar]
  5. Davis H. L., Whalen R. G., Demeneix B. A. Direct gene transfer into skeletal muscle in vivo: factors affecting efficiency of transfer and stability of expression. Hum Gene Ther. 1993 Apr;4(2):151–159. doi: 10.1089/hum.1993.4.2-151. [DOI] [PubMed] [Google Scholar]
  6. Engelhard V. H. Structure of peptides associated with class I and class II MHC molecules. Annu Rev Immunol. 1994;12:181–207. doi: 10.1146/annurev.iy.12.040194.001145. [DOI] [PubMed] [Google Scholar]
  7. Germain R. N., Margulies D. H. The biochemistry and cell biology of antigen processing and presentation. Annu Rev Immunol. 1993;11:403–450. doi: 10.1146/annurev.iy.11.040193.002155. [DOI] [PubMed] [Google Scholar]
  8. Guilhot S., Fowler P., Portillo G., Margolskee R. F., Ferrari C., Bertoletti A., Chisari F. V. Hepatitis B virus (HBV)-specific cytotoxic T-cell response in humans: production of target cells by stable expression of HBV-encoded proteins in immortalized human B-cell lines. J Virol. 1992 May;66(5):2670–2678. doi: 10.1128/jvi.66.5.2670-2678.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Janowicz Z. A., Melber K., Merckelbach A., Jacobs E., Harford N., Comberbach M., Hollenberg C. P. Simultaneous expression of the S and L surface antigens of hepatitis B, and formation of mixed particles in the methylotrophic yeast, Hansenula polymorpha. Yeast. 1991 Jul;7(5):431–443. doi: 10.1002/yea.320070502. [DOI] [PubMed] [Google Scholar]
  10. Jiao S., Williams P., Berg R. K., Hodgeman B. A., Liu L., Repetto G., Wolff J. A. Direct gene transfer into nonhuman primate myofibers in vivo. Hum Gene Ther. 1992 Feb;3(1):21–33. doi: 10.1089/hum.1992.3.1-21. [DOI] [PubMed] [Google Scholar]
  11. Karasuyama H., Melchers F. Establishment of mouse cell lines which constitutively secrete large quantities of interleukin 2, 3, 4 or 5, using modified cDNA expression vectors. Eur J Immunol. 1988 Jan;18(1):97–104. doi: 10.1002/eji.1830180115. [DOI] [PubMed] [Google Scholar]
  12. Montgomery D. L., Shiver J. W., Leander K. R., Perry H. C., Friedman A., Martinez D., Ulmer J. B., Donnelly J. J., Liu M. A. Heterologous and homologous protection against influenza A by DNA vaccination: optimization of DNA vectors. DNA Cell Biol. 1993 Nov;12(9):777–783. doi: 10.1089/dna.1993.12.777. [DOI] [PubMed] [Google Scholar]
  13. Moriyama T., Guilhot S., Klopchin K., Moss B., Pinkert C. A., Palmiter R. D., Brinster R. L., Kanagawa O., Chisari F. V. Immunobiology and pathogenesis of hepatocellular injury in hepatitis B virus transgenic mice. Science. 1990 Apr 20;248(4953):361–364. doi: 10.1126/science.1691527. [DOI] [PubMed] [Google Scholar]
  14. Nabel E. G., Plautz G., Nabel G. J. Gene transfer into vascular cells. J Am Coll Cardiol. 1991 May;17(6 Suppl B):189B–194B. doi: 10.1016/0735-1097(91)90957-b. [DOI] [PubMed] [Google Scholar]
  15. Nabel E. G., Plautz G., Nabel G. J. Transduction of a foreign histocompatibility gene into the arterial wall induces vasculitis. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):5157–5161. doi: 10.1073/pnas.89.11.5157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Nabel E. G., Pompili V. J., Plautz G. E., Nabel G. J. Gene transfer and vascular disease. Cardiovasc Res. 1994 Apr;28(4):445–455. doi: 10.1093/cvr/28.4.445. [DOI] [PubMed] [Google Scholar]
  17. Plautz G. E., Nabel E. G., Fox B., Yang Z. Y., Jaffe M., Gordon D., Chang A., Nabel G. J. Direct gene transfer for the understanding and treatment of human disease. Ann N Y Acad Sci. 1994 May 31;716:144–153. doi: 10.1111/j.1749-6632.1994.tb21709.x. [DOI] [PubMed] [Google Scholar]
  18. Raz E., Carson D. A., Parker S. E., Parr T. B., Abai A. M., Aichinger G., Gromkowski S. H., Singh M., Lew D., Yankauckas M. A. Intradermal gene immunization: the possible role of DNA uptake in the induction of cellular immunity to viruses. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9519–9523. doi: 10.1073/pnas.91.20.9519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Schirmbeck R., Melber K., Kuhröber A., Janowicz Z. A., Reimann J. Immunization with soluble hepatitis B virus surface protein elicits murine H-2 class I-restricted CD8+ cytotoxic T lymphocyte responses in vivo. J Immunol. 1994 Feb 1;152(3):1110–1119. [PubMed] [Google Scholar]
  20. Schirmbeck R., Melber K., Mertens T., Reimann J. Antibody and cytotoxic T-cell responses to soluble hepatitis B virus (HBV) S antigen in mice: implication for the pathogenesis of HBV-induced hepatitis. J Virol. 1994 Mar;68(3):1418–1425. doi: 10.1128/jvi.68.3.1418-1425.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Schirmbeck R., Melber K., Mertens T., Reimann J. Selective stimulation of murine cytotoxic T cell and antibody responses by particulate or monomeric hepatitis B virus surface (S) antigen. Eur J Immunol. 1994 May;24(5):1088–1096. doi: 10.1002/eji.1830240512. [DOI] [PubMed] [Google Scholar]
  22. Schirmbeck R., Melber K., Reimann J. Hepatitis B virus small surface antigen particles are processed in a novel endosomal pathway for major histocompatibility complex class I-restricted epitope presentation. Eur J Immunol. 1995 Apr;25(4):1063–1070. doi: 10.1002/eji.1830250431. [DOI] [PubMed] [Google Scholar]
  23. Sedegah M., Hedstrom R., Hobart P., Hoffman S. L. Protection against malaria by immunization with plasmid DNA encoding circumsporozoite protein. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9866–9870. doi: 10.1073/pnas.91.21.9866. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Tang D. C., DeVit M., Johnston S. A. Genetic immunization is a simple method for eliciting an immune response. Nature. 1992 Mar 12;356(6365):152–154. doi: 10.1038/356152a0. [DOI] [PubMed] [Google Scholar]
  25. Townsend A., Bodmer H. Antigen recognition by class I-restricted T lymphocytes. Annu Rev Immunol. 1989;7:601–624. doi: 10.1146/annurev.iy.07.040189.003125. [DOI] [PubMed] [Google Scholar]
  26. Ulmer J. B., Donnelly J. J., Parker S. E., Rhodes G. H., Felgner P. L., Dwarki V. J., Gromkowski S. H., Deck R. R., DeWitt C. M., Friedman A. Heterologous protection against influenza by injection of DNA encoding a viral protein. Science. 1993 Mar 19;259(5102):1745–1749. doi: 10.1126/science.8456302. [DOI] [PubMed] [Google Scholar]
  27. Wang B., Ugen K. E., Srikantan V., Agadjanyan M. G., Dang K., Refaeli Y., Sato A. I., Boyer J., Williams W. V., Weiner D. B. Gene inoculation generates immune responses against human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4156–4160. doi: 10.1073/pnas.90.9.4156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Wolff J. A., Ludtke J. J., Acsadi G., Williams P., Jani A. Long-term persistence of plasmid DNA and foreign gene expression in mouse muscle. Hum Mol Genet. 1992 Sep;1(6):363–369. doi: 10.1093/hmg/1.6.363. [DOI] [PubMed] [Google Scholar]
  29. Xiang Z. Q., Spitalnik S., Tran M., Wunner W. H., Cheng J., Ertl H. C. Vaccination with a plasmid vector carrying the rabies virus glycoprotein gene induces protective immunity against rabies virus. Virology. 1994 Feb 15;199(1):132–140. doi: 10.1006/viro.1994.1105. [DOI] [PubMed] [Google Scholar]
  30. Yewdell J. W., Bennink J. R. Cell biology of antigen processing and presentation to major histocompatibility complex class I molecule-restricted T lymphocytes. Adv Immunol. 1992;52:1–123. doi: 10.1016/s0065-2776(08)60875-5. [DOI] [PubMed] [Google Scholar]

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