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Targeted antigen delivery to antigen–presenting cells including dendritic cells by engineered Fas-mediated apoptosis

Nature Biotechnology volume 18, pages 974–979 (2000)Cite this article

Abstract

Immunity to tumors as well as to viral and bacterial pathogens is often mediated by cytotoxic T lymphocytes (CTLs). Thus, the ability to induce a strong cell-mediated immune response is an important requirement of novel immunotherapies. Antigen-presenting cells (APCs), including dendritic cells (DCs), are specialized in initiating T-cell immunity. Harnessing this innate ability of these cells to acquire and present antigens, we sought to improve antigen presentation by targeting antigens directly to DCs in vivo through apoptosis. We engineered Fas-mediated apoptotic death of antigen-bearing cells in vivo by co-expressing the immunogen and Fas in the same cell. We then observed that the death of antigen-bearing cells results in increased antigen acquisition by APCs including DCs. This in vivo strategy led to enhanced antigen-specific CTLs, and the elaboration of T helper-1 (Th1) type cytokines and chemokines. This adjuvant approach has important implications for viral and nonviral delivery strategies for vaccines or gene therapies.

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Figure 1: Engagement of Fas on cells transfected with pCFas triggers apoptosis.
Figure 2: Expression of Fas induces tissue infiltration in vivo.
Figure 3: Immunization with Fas in vivo induces infiltration of T cells and dendritic cells.
Figure 4: Fas co-immunization improves delivery of antigen to lymph node dendritic cells.
Figure 5: Effect of Fas coexpression on in vivo CD8+ T-cell priming using the DNA inoculation model.
Figure 6: Production of cytokines and chemokines by stimulated CTL effector cells.
Figure 7: Production of cytokines by FasL-stimulated CTL effector cells.

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References

  1. Janeway, C. The immune system evolved to discriminate infectious nonself from noninfectious self. Immunology Today 13, 11–16 (1992).

    Article  CAS  Google Scholar 

  2. Matzinger, P. Tolerance, danger, and the extended family. Ann. Rev. Immunol. 12, 991–1045 (1994).

    Article  CAS  Google Scholar 

  3. Gallucci, S., Lolkema, M. & Matzinger, P. Natural adjuvants: endogenous activators of dendritic cells. Nat. Med. 5, 1249–1255 (1999).

    Article  CAS  Google Scholar 

  4. Sigal, L.J., Crotty, R., Andino, R. & Rock, K. Cytotoxic T-cell immunity to virus-infected non-haematopoietic cells requires presentation of exogenous antigen. Nature 398, 77–80 (1999).

    Article  CAS  Google Scholar 

  5. Albert, M., Sauter, B. & Bhardwaj, N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392, 86–89 (1998).

    Article  CAS  Google Scholar 

  6. Mitchell, D., Nair, S. & Gilboa, E. Dendritic cell/macrophage prescursors capture exogenous antigen for MHC class I presentation by dendritic cells. Eur. J. Immunol. 28, 1923–1933 (1998).

    Article  CAS  Google Scholar 

  7. Kim, J., Tsai, A., Nottingham, L., Morrison, L. & Cunning, D. Intracellular Adhesion Molecule-1 (ICAM-1) modulates β-chemokines and provides costimulatory signals required for T-cell activation and expansion in vivo. J. Clin. Invest. 103, 869–877 (1999).

    Article  CAS  Google Scholar 

  8. Kim, J. et al. CD8 positive T cells influence antigen-specific immune responses through the expression of chemokines. J. Clin. Invest. 102, 1112–1124 (1998).

    Article  CAS  Google Scholar 

  9. Kim, J. et al. Engineering of in vivo immune responses to DNA immunization via codelivery of costimulatory molecule genes. Nat. Biotechnol. 15, 641–646 (1997).

    Article  CAS  Google Scholar 

  10. Chattergoon, M., Robinson, T., Boyer, J. & Weiner, D. Specific immune induction following DNA-based immunization through in vivo transfection and activation of macrophages. J. Immunol. 160, 5707–5718 (1998).

    CAS  PubMed  Google Scholar 

  11. Agadjanyan, M. et al. CD86 (B7-2) can function to drive MHC-restricted antigen-specific CTL responses in vivo. J. Immunol. 162, 3417–3427 (1999).

    CAS  PubMed  Google Scholar 

  12. Porgador, A. et al. Predominant role for directly transfected dendritic cells in antigen presentation to CD8+ T-cells after gene gun immunization. J. Exp. Med. 188, 1075–1082 (1998).

    Article  CAS  Google Scholar 

  13. Coney, L. et al. Facilitated DNA inoculation induces anti-HIV immunity in vivo. Vaccines 12, 1545–1550 (1994).

    Article  CAS  Google Scholar 

  14. Takahashi, H. et al. Induction of broadly cross-reactive cytotoxic T–cells recognizing an HIV-1 envelope determinant. Science 255, 333–336 (1992).

    Article  CAS  Google Scholar 

  15. Shirai, M., Pendleton, C. & Berzofsky, J. Broad recognition of cytotoxic T-cell epitopes from the HIV-1 envelope protein with multiple class I histocompatibility molecules. J. Immunol. 148, 1657–1667 (1992).

    CAS  PubMed  Google Scholar 

  16. Mogensen, S. & Virelizier, J. The interferon–macrophage alliance [Review]. Inteferon 8, 55–84 (1987).

    CAS  Google Scholar 

  17. Seder, R. & Paul, W. Acquisition of lymphokine-producing phenotype by CD4+ T-cells. Ann. Rev. Immunol. 12, 635–673 (1994).

    Article  CAS  Google Scholar 

  18. Banchereau, J. & Steinman, R. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).

    Article  CAS  Google Scholar 

  19. Porgador, A., Snyder, D. & Gilboa, E. Induction of antitumor immunity using bone marrow–generated dendritic cells. J. Immunol. 156, 2918–2926 (1996).

    CAS  PubMed  Google Scholar 

  20. Celluzzi, C.M., Mayordomo, J.I., Storkus, W.J., Lotze, M.T. & Falo, L.D.J. Peptide-pulsed dendritic cells induce antigen-specific, CTL-mediated protective tumor immunity. J. Exp. Med. 183, 283–287 (1996).

    Article  CAS  Google Scholar 

  21. Mayordomo, J.I. et al. Bone marrow–derived dendritic cells serve as potent adjuvants for peptide-based antitumor vaccines. Stem Cells 15, 94–103. (1997).

    Article  CAS  Google Scholar 

  22. Hsu, F.J. et al. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat. Med. 52–58 (1996).

  23. Murphy, G., Tjoa, B., Ragde, H., Kenny, G. & Boynton, A. Phase I clinical trial: T-cell therapy for prostate cancer using autologous dendritic cells pulsed with HLA-A0201–specific peptides from prostate-specific membrane antigen. Prostate 29, 371–380 (1996).

    Article  CAS  Google Scholar 

  24. Nestle, F.O. et al. Vaccination of melanoma patients with peptide- or tumor lysate–pulsed dendritic cells. Nat. Med. 4, 328–332 (1998).

    Article  CAS  Google Scholar 

  25. Nagata, S. & Goldstein, P. The Fas death factor. Science 267, 1449–1456 (1995).

    Article  CAS  Google Scholar 

  26. Trauth, B. et al. Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science 245, 301–305 (1989).

    Article  CAS  Google Scholar 

  27. Vignaux, F. et al. TCR/CD3 coupling to Fas-based cytotoxicity. J. Exp. Med. 181, 781–786 (1995).

    Article  CAS  Google Scholar 

  28. Matzinger, P. An innate sense of danger. Semin. Immunol. 10, 399–415 (1998).

    Article  CAS  Google Scholar 

  29. Kim, J.J. et al. Modulation of amplitude and direction of in vivo immune responses by co-administration of cytokine gene expression cassettes with DNA immunogens. Eur. J. Immunol. 28, 1089–1103 (1998).

    Article  CAS  Google Scholar 

  30. Kim, J. et al. Molecular and immunological analysis of genetic prostate-specific antigen. Oncogene 17, 3125–3135 (1999).

    Article  Google Scholar 

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Acknowledgements

This work was supported in part by grants from the NIH to D.B. Weiner. We wish to thank R. Ciccarelli from Wyeth Lederle Vaccines for thoughtful discussion and providing material for this study. We also wish to thank J. Faust at the Wistar Institute Flow Cytometry Core for expert technical assistance. M. Chattergoon would like to thank A. Moise for thoughtful discussion and support of this work.

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Author notes

  1. J. Joseph Kim

    Present address: Merck Research Laboratories, West Point, PA, 19486

  2. Michael A. Chattergoon and J. Joseph Kim: Both authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 422 Curie Blvd, Philadelphia, 19104, PA

    Michael A. Chattergoon, J. Joseph Kim, Joo-Sung Yang, Tara M. Robinson, Daniel J. Lee, Tzvete Dentchev, Darren M. Wilson, Velpandi Ayyavoo & David B. Weiner

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  1. Michael A. Chattergoon
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Correspondence to David B. Weiner.

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Chattergoon, M., Kim, J., Yang, JS. et al. Targeted antigen delivery to antigen–presenting cells including dendritic cells by engineered Fas-mediated apoptosis. Nat Biotechnol 18, 974–979 (2000). https://doi.org/10.1038/79470

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