Skip to main content

Advertisement

SpringerLink
Log in

Polyclonal cytomegalovirus-specific antibodies not only prevent virus dissemination from the portal of entry but also inhibit focal virus spread within target tissues

  • Original Investigation
  • Published:
Medical Microbiology and Immunology Aims and scope Submit manuscript

Abstract

Therapy of cytomegalovirus (CMV) infection in recipients of hematopoietic stem cell transplantation (HSCT) by immune serum transfer did not fulfill the high clinical expectations, although immune sera or immunoglobulin-enriched preparations pooled from many CMV-immune donors are likely to contain virus neutralizing antibodies covering a broad range of virus variants. Likewise, the highest risk of CMV disease in HSCT recipients results from the reactivation of the latently infected recipient’s own virus despite pre-transplantation humoral immunity. These findings suggest the conclusion that antiviral antibodies are inefficient in controlling CMV. Rather than B cells and antibodies, T cells, in particular CD8 T cells, are thought to play a major role in resolving established organ infection. In theory, antibodies, though being capable of neutralizing free virions, could fail to prevent cell-bound virus dissemination from the portal of entry to distant target tissues and also could fail in preventing cell-to-cell spread within tissue. Here we have used murine model systems, including B cell deficient C57BL/6 μ− μ− (μMT) mutants, to revisit the role of antiviral antibodies in the control of CMV infection and to reevaluate the prospects of an antibody-based immunotherapy from a basic science point of view.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Mach M (2006) Antibody-mediated neutralization of infectivity. In: Reddehase MJ (ed) Cytomegaloviruses: molecular biology and immunology. Caister Academic Press, Norfolk, pp 265–283

    Google Scholar 

  2. Pepperl-Klindworth S, Plachter B (2006) Current perspectives in vaccine development. In: Reddehase MJ (ed) Cytomegaloviruses: molecular biology and immunology. Caister Academic Press, Norfolk, pp 551–572

    Google Scholar 

  3. Britt WJ (1996) Vaccines against human cytomegalovirus: time to test. Trends Microbiol 4:34–38

    Article  CAS  PubMed  Google Scholar 

  4. Gonczol E, Plotkin S (2001) Development of a cytomegalovirus vaccine: lessons from recent clinical trials. Expert Opin Biol Ther 1:401–412

    Article  CAS  PubMed  Google Scholar 

  5. Arvin AM, Fast P, Myers M, Plotkin S, Rabinovich R; National Vaccine Advisory Committee (2004) Vaccine development to prevent cytomegalovirus disease: report from the national vaccine advisory committee. Clin Infect Dis 39:233–239

    Article  PubMed  Google Scholar 

  6. Emery VC (1998) Relative importance of cytomegalovirus load as a risk factor for cytomegalovirus disease in the immunocompromised host. In: Scholz M, Rabenau HF, Doerr HW, Cinatl J Jr (eds) Monographs in virology, vol 21: CMV-related immunopathology. Karger, Basel, pp 288–301

    Google Scholar 

  7. Araullo-Cruz TP, Ho M, Armstrong JA (1978) Protective effect of early serum from mice after cytomegalovirus infection. Infect Immun 21:840–842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shanley JD, Jordan MC, Stevens JG (1981) Modification by adoptive humoral immunity of murine cytomegalovirus infection. J Infect Dis 143:231–237

    Article  CAS  PubMed  Google Scholar 

  9. Gorman S, Harvey NL, Moro D, Lloyd ML, Voigt V, Smith LM, Lawson MA, Shellam GR (2006) Mixed infection with multiple strains of murine cytomegalovirus occurs following simultaneous or sequential infection of immunocompetent mice. J Gen Virol 87:1123–1132

    Article  CAS  PubMed  Google Scholar 

  10. Dix RD, Cray C, Cousins SW (1987) Antibody alone does not prevent experimental cytomegalovirus retinitis in mice with retrovirus-induced immunodeficiency (MAIDS). Ophthalmic Res 29:381–392

    Article  Google Scholar 

  11. Kitamura D, Roes J, Kühn R, Rajewsky K (1991) A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature 350:423–426

    Article  CAS  PubMed  Google Scholar 

  12. Reddehase MJ, Balthesen M, Rapp M, Jonjić S, Pavić I, Koszinowski UH (1994) The conditions of primary infection define the load of latent viral genome in organs and the risk of recurrent cytomegalovirus disease. J Exp Med 179:185–193

    Article  CAS  PubMed  Google Scholar 

  13. Jonjić S, Pavić I, Polić B, Crnković I, Lucin P, Koszinowski UH (1994) Antibodies are not essential for the resolution of primary cytomegalovirus infection but limit dissemination of recurrent virus. J Exp Med 179:1713–1717

    Article  PubMed  Google Scholar 

  14. Klenovsek K, Weisel F, Schneider A, Appelt U, Jonjić S, Messerle M, Bradel-Tretheway B, Winkler TH, Mach M (2007) Protection from CMV infection in immunodeficient hosts by adoptive transfer of memory B cells. Blood 110:3472–3479

    Article  CAS  PubMed  Google Scholar 

  15. Reddehase MJ (2002) Antigens and immunoevasins: opponents in cytomegalovirus immune surveillance. Nat Rev Immunol 2:831–844

    Article  CAS  PubMed  Google Scholar 

  16. Holtappels R, Munks WM, Podlech J, Reddehase MJ (2006) CD8 T-cell-based immunotherapy of cytomegalovirus disease in the mouse model of the immunocompromised bone marrow transplantation recipient. In: Reddehase MJ (ed) Cytomegaloviruses: molecular biology and immunology. Caister Academic Press, Norfolk, pp 383–418

    Google Scholar 

  17. Streblow DN, Varnum SM, Smith RD, Nelson JA (2006) A proteomics analysis of human cytomegalovirus particles. In: Reddehase MJ (ed) Cytomegaloviruses: molecular biology and immunology. Caister Academic Press, Norfolk, pp 91–110

    Google Scholar 

  18. Holtappels R, Thomas D, Podlech J, Reddehase MJ (2002) Two antigenic peptides from genes m123 and m164 of murine cytomegalovirus quantitatively dominate CD8 T-cell memory in the H-2d haplotype. J Virol 76:151–164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Erlach KC, Böhm V, Seckert CK, Reddehase MJ, Podlech J (2006) Lymphoma cell apoptosis in the liver induced by distant murine cytomegalovirus infection. J Virol 80:4801–4819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Podlech J, Holtappels R, Grzimek NKA, Reddehase MJ (2002) Animal models: murine cytomegalovirus. In: Kaufmann SHE, Kabelitz D (eds) Methods in microbiology 32. Immunology of infection. Academic Press, San Diego, pp 493–525

    Chapter  Google Scholar 

  21. Simon CO, Holtappels R, Tervo HM, Böhm V, Däubner T, Oehrlein-Karpi SA, Kühnapfel B, Renzaho A, Strand D, Podlech J, Reddehase MJ, Grzimek NK (2006) CD8 T cells control cytomegalovirus latency by epitope-specific sensing of transcriptional reactivation. J Virol 80:10436–10456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Podlech J, Holtappels R, Wirtz N, Steffens HP, Reddehase MJ (1998) Reconstitution of CD8 T cells is essential for the prevention of multiple-organ cytomegalovirus histopathology after bone marrow transplantation. J Gen Virol 79:2099–2104

    Article  CAS  PubMed  Google Scholar 

  23. Sacher T, Podlech J, Mohr AC, Jordan S, Ruzsics Z, Reddehase MJ, Koszinowski UH (2008) The major virus producing cell type during murine cytomegalovirus infection, the hepatocyte, is not the source of virus dissemination in the host. Cell Host Microbe (in press)

  24. Noda S, Aguirre SA, Bitmansour A, Brown JM, Sparer TE, Huang J, Mocarski ES (2006) Cytomegalovirus MCK-2 controls mobilization and recruitment of myeloid progenitor cells to facilitate dissemination. Blood 107:30–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mocarski ES, Hahn G, White KL, Xu J, Slobedman B, Hertel L, Aguirre SA, Noda S (2006) Myeloid cell recruitment and function in pathogenesis and latency. In: Reddehase MJ (ed) Cytomegaloviruses: molecular biology and immunology. Caister Academic Press, Norfolk, pp 465–481

    Google Scholar 

  26. Ménard C, Wagner M, Ruzsics Z, Holak K, Brune W, Campbell AE, Koszinowski UH (2003) Role of murine cytomegalovirus US22 gene family members in replication in macrophages. J Virol 77:5557–5570

    Article  PubMed  PubMed Central  Google Scholar 

  27. Čičin-Šain L, Podlech J, Messerle M, Reddehase MJ, Koszinowski UH (2005) Frequent coinfection of cells explains functional in vivo complementation between cytomegalovirus variants in the multiply infected host. J Virol 79:9492–9502

    Article  PubMed  PubMed Central  Google Scholar 

  28. Čičin-Šain L, Ruzsics Z, Podlech J, Bubić I, Ménard C, Jonjić S, Reddehase MJ, Koszinowski UH (2008) Dominant-negative FADD rescues the in vivo fitness of a cytomegalovirus lacking an anti-apoptotic viral gene. J Virol 82:2056–2064

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We greatly appreciate the help by Stipan Jonjić (Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Croatia) who generously supplied us with immune sera and monoclonal antibodies. This work is part of the MD thesis of the first author N.W. Support was provided by the Deutsche Forschungsgemeinschaft, SFB 490, individual projects E2 (C.O.S. and M.J.R.), E4 (M.J.R.) and E3 (R.H. and S.I.S.), SFB 432, individual project A10 (J.P.) and Clinical Research Group KFO 183, individual project TP8 “Establishment of a challenge model to optimize the immunotherapy of cytomegalovirus diseases” (M.J.R. and N.A.W.L). Special thanks go to the “Dr. Gerhard und Martha Röttger-Stiftung” for a generous donation.

Author information

Authors and Affiliations

  1. Institute for Virology, Johannes Gutenberg-University, Obere Zahlbacher Strasse 67, Hochhaus am Augustusplatz, 55131, Mainz, Germany

    Nikolaus Wirtz, Sina I. Schader, Rafaela Holtappels, Christian O. Simon, Niels A. W. Lemmermann, Matthias J. Reddehase & Jürgen Podlech

Authors
  1. Nikolaus Wirtz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sina I. Schader
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rafaela Holtappels
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christian O. Simon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Niels A. W. Lemmermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Matthias J. Reddehase
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jürgen Podlech
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jürgen Podlech.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wirtz, N., Schader, S.I., Holtappels, R. et al. Polyclonal cytomegalovirus-specific antibodies not only prevent virus dissemination from the portal of entry but also inhibit focal virus spread within target tissues. Med Microbiol Immunol 197, 151–158 (2008). https://doi.org/10.1007/s00430-008-0095-0

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00430-008-0095-0

Keywords

Search

Navigation