Dendritic Cell Vaccination and Viral Infection — Animal Models

  • B. Ludewig
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 276)


Dendritic cells (DCs) play a pivotal role in the initiation and maintenance of immune responses against viruses and other microbial pathogens. Adoptively transferred, in vitro manipulated DCs presenting antigen derived from different viruses have been shown to elicit cytotox­ic T cell (CTL) and T helper (Th) cell responses and to induce protective antiviral immunity. Furthermore, DC-based adoptive immunotherapies have the potential to specifically (re)activate antiviral immunity in chronic viral diseases such as HIV or hepatitis virus infections. Cellular dendritic cell vaccines, however, are not suitable for large-scale prophy­lactic immunization. Strategies for vaccine development should there­fore aim at the specific delivery of microbial antigens to DCs in situ. Fur­thermore, appropriate mobilization and activation of DCs by the vaccine is important for the generation of optimal antimicrobial immune responses. Here, we discuss recent data on induction of antiviral immunity with various DC-vaccination approaches and outline future directions for the development of specific antigen targeting to DCs.


Dendritic Cell Secondary Lymphoid Organ Antiviral Immunity Dendritic Cell Vaccination Antigen Delivery 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adams M, Borysiewicz L, Fiander A, Man S, Jasani B, Navabi H, Lipetz C, Evans AS, and Mason M (2001) Clinical studies of human papilloma vaccines in pre-invasive and invasive cancer. Vaccine 19: 2549–2556PubMedCrossRefGoogle Scholar
  2. Akbari O, Panjwani N, Garcia S, Tascon R, Lowrie D, and Stockinger B (1999) DNA vaccination: transfection and activation of dendritic cells as key events for immunity. J.Exp.Med. 189: 169–178PubMedCrossRefGoogle Scholar
  3. Bender A, Albert M, Reddy A, Feldman M, Sauter B, Kaplan G, Hellman W, and Bhardwaj N (1998) The distinctive features of influenza virus infection of dendritic cells. Immunobiology 198: 552–567PubMedCrossRefGoogle Scholar
  4. Bocher WO, Dekel B, Schwerin W, Geissler M, Hoffmann S, Rohwer A, Arditti F, Cooper A, Bernhard H, Berrebi A, Rose-John S, Shaul Y, Galle PR, Lohr HF, and Reisner Y (2001) Induction of strong hepatitis B virus ( HBV) specific T helper cell and cytotoxic T lymphocyte responses by therapeutic vaccination in the trimera mouse model of chronic HBV infection. Eur.J.Immunol. 31: 2071–2079Google Scholar
  5. Bonkobara M, Zukas PK, Shikano S, Nakamura S, Cruz PDJ, and Ariizumi K (2001) Epidermal langerhans cell-targeted gene expression by a Dectin-2 promoter. J.Immunol. 167: 6893–6900PubMedGoogle Scholar
  6. Brocker T, Riedinger M, and Karjalainen K (1997) Targeted expression of major histocompatibility complex ( MHC) class II molecules demonstrates that dendritic cells can induce negative but not positive selection of thymocytes in vivo. J.Exp.Med. 185: 541–550Google Scholar
  7. Caux C, Dezutter-Dambuyant C, Schmitt D, and Banchereau J (1992) GM-CSF and TNF-alpha cooperate in the generation of dendritic Langerhans cells. Nature 360: 258–261PubMedCrossRefGoogle Scholar
  8. Cella M, Engering A, Pinet V, Pieters J, and Lanzavecchia A (1997) Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells. Nature 388: 782–787PubMedCrossRefGoogle Scholar
  9. Cella M, Jarrossay D, Facchetti F, Alebardi O, Nakajima H, Lanzavecchia A, and Colonna M (1999) Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat.Med. 5: 919–923PubMedCrossRefGoogle Scholar
  10. Chakravarti DN, Fiske MJ, Fletcher LD, and Zagursky RJ (2000) Application of genomics and proteomics for identification of bacterial gene products as potential vaccine candidates. Vaccine 19: 601–612PubMedCrossRefGoogle Scholar
  11. Chikh GG, Kong S, Bally MB, Meunier JC, and Schutze-Redelmeier MP (2001) Efficient delivery of antennapedia homeodomain fused to CTL epitope with liposomes into dendritic cells results in the activation of CD8+ T cells. J.Immunol. 167: 6462–6470PubMedGoogle Scholar
  12. Condon C, Watkins SC, Celluzi CM, Thompson K, and Falo LD (1996) DNA-based immunization by in vivo transfection of dendritic cells. Nat.Med. 2: 1122–1128PubMedCrossRefGoogle Scholar
  13. De Bruijn ML, Schuurhuis DH, Vierboom MP, Vermeulen H, de Cock KA, Ooms ME, Ressing ME, Toebes M, Franken KL, Drijfhout JW, Ottenhoff TH, Offringa R, and Melief CJ (1998) Immunization with human papillomavirus type 16 (HPV16) oncoprotein-loaded dendritic cells as well as protein in adjuvant induces MHC class I-restricted protection to HPV 16-induced tumor cells. Cancer Res. 58: 724–731PubMedGoogle Scholar
  14. de St Groth BF (1998) The evolution of self-tolerance: a new cell arises to meet the challenge of self-reactivity. Immunol.Today 19: 448–454CrossRefGoogle Scholar
  15. Demangel C, Bean AG, Martin E, Feng CG, Kamath AT, and Britton WJ (1999) Protection against aerosol Mycobacterium tuberculosis infection using Mycobacterium bovis Bacillus Calmette Guerin-infected dendritic cells. Eur.J.Immunol. 29: 1972–1979PubMedCrossRefGoogle Scholar
  16. DeSmedt T, Pajak B, Muraille E, Lespagnard L, Heinen E, DeBaetselier P, Urbain J, Leo O, and Moser M (1996) Regulation of dendritic cell numbers and maturation by lipopolysaccharide in vivo. J.Exp.Med. 184: 1413–1424CrossRefGoogle Scholar
  17. Dhodapkar MV, Steinman RM, Sapp M, Desai H, Fossella C, Krasovsky J, Donahoe SM, Dunbar PR, Cerundolo V, Nixon DF, and Bhardwaj N (1999) Rapid generation of broad T-cell immunity in humans after a single injection of mature dendritic cells. J.Clin.Invest. 104: 173–180PubMedCrossRefGoogle Scholar
  18. Dieu MC, Vanbervliet B, Vicari A, Bridon JM, Oldham E, Ait-Yahia S, Briere F, Zlotnik A, Lebecque S, and Caux C (1998) Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J.Exp.Med. 188: 373–386PubMedCrossRefGoogle Scholar
  19. Forster R, Schubel A, Breitfeld D, Kremmer E, Renner-Muller I, Wolf E, and Lipp M (1999) CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99: 23–33PubMedCrossRefGoogle Scholar
  20. Ghanekar S, Zheng L, Logar A, Navratil J, Borowski L, Gupta P, and Rinaldo C (1996) Cytokine expression by human peripheral blood dendritic cells stimulated in vitro with HIV-1 and herpes simplex virus. J.Immunol. 157: 4028–4036PubMedGoogle Scholar
  21. Gilboa E, Nair SK, and Lyerly HK (1998) Immunotherapy of cancer with dendriticcell-based vaccines. Cancer Immunol.Immunother. 46: 82–87PubMedCrossRefGoogle Scholar
  22. Grosjean I, Caux C, Bella C, Berger I, Wild F, Banchereau J, and Kaiserlian D (1997) Measles virus infects human dendritic cells and blocks their allostimulatory properties for CD4+ T cells. J.Exp.Med. 186: 801–812PubMedCrossRefGoogle Scholar
  23. Hawiger D, Inaba K, Dorsett Y, Guo M, Mahnke K, Rivera M, Ravetch JV, Steinman RM, and Nussenzweig MC (200 1) Dendritic cells induce peripheral Tcell unresponsiveness under steady state conditions in vivo. J.Exp.Med. 194: 769–779Google Scholar
  24. Hengel H, Lindner M, Wagner H, and Heeg K (1987) Frequency of herpes simplex virus-specific murine cytotoxic T lymphocyte precursors in mitogen-and antigen-driven primary in vitro T cell responses. J.Immunol. 139: 4196–4202PubMedGoogle Scholar
  25. Inaba K, Inaba M, Deguchi M, Hagi K, Yasumizu R, Ikehara S, Muramatsu S, and Steinman RM (1993a) Granulocytes, macrophages, and dendritic cells arise from a common major histocompatibility complex class II-negative progenitor in mouse bone marrow. Proc.Natl.Acad.Sci.U.S.A. 90: 3038–3042PubMedCrossRefGoogle Scholar
  26. Inaba K, Inaba M, Naito M, and Steinman RM (1993b) Dendritic cell progenitors phagocytose particulates, including bacillus Calmette-Guerin organisms, and sensitize mice to mycobacterial antigens in vivo. J.Exp.Med. 178: 479–488PubMedCrossRefGoogle Scholar
  27. Inaba K, Pack M, Inaba M, Sakuta H, Isdell F, and Steinman RM (1997) High levels of a major histocompatibility complex II-self peptide complex on dendritic cells from the T cell areas of lymph nodes. J.Exp.Med. 186: 665–672PubMedCrossRefGoogle Scholar
  28. Kast WM, Boog CJ, Roep BO, Voordouw AC, and Melief CJ (1988) Failure or success in the restoration of virus-specific cytotoxic T lymphocyte response defects by dendritic cells. J.Immunol. 140: 3186–3193PubMedGoogle Scholar
  29. Klagge IM and Schneider-Schaulies S (1999) Virus interactions with dendritic cells. J.Gen.Virol. 80: 823–833PubMedGoogle Scholar
  30. Knight SC, Elsley W, and Wang H (1997) Mechanisms of loss of functional dendritic cells in HIV-1 infection. J.Leukoc.Biol. 62: 78–81PubMedGoogle Scholar
  31. Kripke ML, Munn CG, Jeevan A, Tang JM, and Bucana C (1990) Evidence that cutaneous antigen-presenting cells migrate to regional lymph nodes during contact sensitization. J.Immunol. 145: 2833–2838PubMedGoogle Scholar
  32. Kundig TM, Bachmann MF, Oehen S, Hoffmann UW, Simard JJL, Kalberer CP, Pircher H, Ohashi PS, Hengartner H, and Zinkernagel RM (1996) On the role of antigen in maintaining cytotoxic T-cell memory. Proc.Natl.Acad.Sci.U.S.A. 93: 9716–9723PubMedCrossRefGoogle Scholar
  33. Laus R, Graddis TJ, Hakim I, and Vidovic D (2000) Enhanced major histocompatibility complex class I-dependent presentation of antigens modified with cationic and fusogenic peptides. Nat.Biotechnol. 18: 1269–1272PubMedCrossRefGoogle Scholar
  34. Lauvau G, Vijh S, Kong P, Horng T, Kerksiek K, Serbina N, Tuma RA, and Pamer EG (2001) Priming of memory but not effector CD8 T cells by a killed bacterial vaccine. Science 294: 1735–1739PubMedCrossRefGoogle Scholar
  35. Lenz P, Day PM, Pang YY, Frye SA, Jensen PN, Lowy DR, and Schiller JT (2001) Papillomavirus-like particles induce acute activation of dendritic cells. J.Immunol. 166: 5346–5355PubMedGoogle Scholar
  36. Levine MM, Galen J, Barry E, Noriega F, Chatfield S, Sztein M, Dougan G, and Tacket C (1996) Attenuated Salmonella as live oral vaccines against typhoid fever and as live vectors. J.Biotechnol. 44: 193–196PubMedCrossRefGoogle Scholar
  37. Ludewig B, Barchiesi F, Pericin M, Zinkernagel RM, Hengartner H, and Schwendener RA (2000a) In vivo antigen loading and activation of dendritic cells via a liposomal peptide vaccine mediates protective antiviral and anti-tumour immunity. Vaccine 2000 19: 23–32CrossRefGoogle Scholar
  38. Ludewig B, Ehl S, Karrer U, Odermatt B, Hengartner H, and Zinkernagel RM (1998) Dendritic cells efficiently induce protective antiviral immunity. J.Virol. 72:3812– 3818Google Scholar
  39. Ludewig B, Maloy KJ, Lopez-Macias C, Odermatt B, Hengartner H, and Zinkernagel RM (2000b) Induction of optimal anti-viral neutralizing B cell responses by dendritic cells requires transport and release of virus particles in secondary lymphoid organs. Eur.J.Immunol. 2000 30: 185–196CrossRefGoogle Scholar
  40. Ludewig B, Oehen S, Barchiesi F, Schwendener RA, Hengartner H, and Zinkernagel RM (1999) Protective antiviral cytotoxic T cell memory is most efficiently maintained by restimulation via dendritic cells. J.Immunol. 163: 1839–1844PubMedGoogle Scholar
  41. Macatonia SE, Knight SC, Edwards AJ, Griffiths S, and Fryer P (1987) Localization of antigen on lymph node dendritic cells after exposure to the contact sensitizer fluorescein isothiocyanate. Functional and morphological studies. J.Exp.Med. 166: 1654–1667Google Scholar
  42. Macatonia SE, Taylor PM, Knight SC, and Askonas BA (1989) Primary stimulation by dendritic cells induces antiviral proliferative and cytotoxic T cell responses in vitro. J.Exp.Med. 169: 1255–1264PubMedCrossRefGoogle Scholar
  43. Maldonado-Lopez R, De Smedt T, Pajak B, Heirman C, Thielemans K, Leo O, Urbain J, Maliszewski CR, and Moser M (1999) Role of CD8alpha+ and CD8alpha– dendritic cells in the induction of primary immune responses in vivo. J.Leukoc.Biol. 66: 242–246PubMedGoogle Scholar
  44. Mbow ML, Zeidner N, Panella N, Titus RG, Piesman J, and Titus (1997) Borrelia burgdorferi-pulsed dendritic cells induce a protective immune response against tick-transmitted spirochetes. Infect.Immun. 65: 3386–3390PubMedGoogle Scholar
  45. Merad M, Fong L, Bogenberger J, and Engleman EG (2000) Differentiation of myeloid dendritic cells into CD8alpha-positive dendritic cells in vivo. Blood 96: 1865–1872PubMedGoogle Scholar
  46. Moll H (1993) Epidermal Langerhans cells are critical for immunoregulation of cutaneous leishmaniasis. Immunol.Today 14: 383–387PubMedCrossRefGoogle Scholar
  47. Nair S, Babu JS, Dunham RG, Kanda P, Burke RL, and Rouse BT (1993) Induction of primary, antiviral cytotoxic, and proliferative responses with antigens administered via dendritic cells. J.Virol. 67: 4062–4069PubMedGoogle Scholar
  48. Nair SK, Boczkowski D, Morse M, Cumming RI, Lyerly HK, and Gilboa E (1998) Induction of primary carcinoembryonic antigen ( CEA)-specific cytotoxic T lymphocytes in vitro using human dendritic cells transfected with RNA. Nat.Biotechnol. 16: 364–369Google Scholar
  49. Nonacs R, Humborg C, Tam JP, and Steinman RM (1992) Mechanisms of mouse spleen dendritic cell function in the generation of influenza-specific, cytolytic T lymphocytes. J.Exp.Med. 176: 519–529PubMedCrossRefGoogle Scholar
  50. Ossevoort MA, Feltkamp MC, van Veen KJ, Melief CJ, and Kast WM (1995) Dendritic cells as carriers for a cytotoxic T-lymphocyte epitope-based peptide vaccine in protection against a human papillomavirus type 16-induced tumor. J.Immunother.Emphasis.Tumor Immunol. 18: 86–94PubMedCrossRefGoogle Scholar
  51. Palker TJ, Monteiro JM, Martin MM, Kakareka C, Smith JF, Cook JC, Joyce JG, and Jansen KU (2001) Antibody, cytokine and cytotoxic T lymphocyte responses in chimpanzees immunized with human papillomavirus virus-like particles. Vaccine 19: 3733–3743PubMedCrossRefGoogle Scholar
  52. Pierre P, Turley SJ, Gatti E, Hull M, Meltzer J, Mirza A, Inaba K, Steinman RM, and Mellman I (1997) Developmental regulation of MHC class II transport in mouse dendritic cells [see comments]. Nature 388: 787–792PubMedCrossRefGoogle Scholar
  53. Pulendran B, Banchereau J, Maraskovsky E, and Maliszewski C (2001) Modulating the immune response with dendritic cells and their growth factors. Trends.Immunol. 22: 41–47PubMedCrossRefGoogle Scholar
  54. Raychaudhuri S and Rock KL (1998) Fully mobilizing host defense: building better vaccines. Nat.Biotechnol. 16: 1025–1031PubMedCrossRefGoogle Scholar
  55. Rea D, Havenga MJ, van Den Assem M, Sutmuller RP, Lemckert A, Hoeben RC, Bout A, Melief CJ, and Offringa R (2001a) Highly efficient transduction of human monocyte-derived dendritic cells with subgroup B fiber-modified adenovirus vectors enhances transgene-encoded antigen presentation to cytotoxic T cells. J.Immunol. 166: 5236–5244PubMedGoogle Scholar
  56. Rea D, Johnson ME, Havenga MJ, Melief CJ, and Offringa R (2001b) Strategies for improved antigen delivery into dendritic cells. Trends.Mol.Med. 7: 91–94PubMedCrossRefGoogle Scholar
  57. Reis, Sher A, and Kaye P (1999) The role of dendritic cells in the induction and regulation of immunity to microbial infection. Curr.Opin.Immunol. 11: 392–399CrossRefGoogle Scholar
  58. Reis S-C, Stahl PD, and Austyn JM (1993) Phagocytosis of antigens by Langerhans cells in vitro. J.Exp.Med. 178: 509–519CrossRefGoogle Scholar
  59. Ridge JP, Di Rosa F, and Matzinger P (1998) A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393: 474–478PubMedCrossRefGoogle Scholar
  60. Romani N, Gruner S, Brang D, Kampgen E, Lenz A, Trockenbacher B, Konwalinka G, Fritsch P, Steinman RM, and Schuler G (1994) Proliferating dendritic cell progenitors in human blood. J.Exp.Med. 180: 83–93PubMedCrossRefGoogle Scholar
  61. Romani N, Lenz A, Glassel H, Stoessel H, Stanzl U, Majdic O, Fritsch P, and Schuler G (1989) Cultured human Langerhans cells resemble lymphoid dendritic cells in phenotype and function. J Invest Dermatol 93: 600–609PubMedCrossRefGoogle Scholar
  62. Ruedl C and Bachmann MF (1999) CTL priming by CD8(+) and CD8(–) dendritic cells in vivo. Eur.J.Immunol. 29: 3762–3767PubMedCrossRefGoogle Scholar
  63. Sallusto F, Cella M, Danieli C, and Lanzavecchia A (1995) Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products. J.Exp.Med. 182: 389–400PubMedCrossRefGoogle Scholar
  64. Sallusto F and Lanzavecchia A (1994) Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J.Exp.Med. 179: 1109–1118PubMedCrossRefGoogle Scholar
  65. Sallusto F, Lanzavecchia A, and Mackay CR (1998) Chemokines and chemokine receptors in T-cell priming and Th1/Th2-mediated responses. Immunol.Today 19: 568–574PubMedCrossRefGoogle Scholar
  66. Santin AD, Hermonat PL, Ravaggi A, Chiriva-Internati M, Zhan D, Pecorelli S, Parham GP, and Cannon MJ (1999) Induction of human papillomavirus-specificGoogle Scholar
  67. CD4(+) and CD8(+) lymphocytes by E7-pulsed autologous dendritic cells in patients with human papillomavirus type 16- and 18-positive cervical cancer. J.Virol. 73:5402–5410Google Scholar
  68. Sato Y, Roman M, Tighe H, Lee D, Corr M, Nguyen MD, Silverman GJ, Lotz M, Carson DA, and Raz E (1996) Immunostimulatory DNA sequences necessary for effective intradermal gene immunization. Science 273: 352–354PubMedCrossRefGoogle Scholar
  69. Schon E, Harandi AM, Nordstrom I, Holmgren J, and Eriksson K (2001) Dendritic cell vaccination protects mice against lethality caused by genital herpes simplex virus type 2 infection. J.Reprod.Immunol. 50: 87–104PubMedCrossRefGoogle Scholar
  70. Shimizu Y, Guidotti LG, Fowler P, and Chisari FV (1998) Dendritic cell immunization breaks cytotoxic T lymphocyte tolerance in hepatitis B virus transgenic mice. J.Immunol. 161: 4520–4529PubMedGoogle Scholar
  71. Spira AI, Marx PA, Patterson BK, Mahoney J, Koup RA, Wolinsky SM, and Ho DD (1996) Cellular targets of infection and route of viral dissemination after an intra-vaginal inoculation of simian immunodeficiency virus into rhesus macaques. J.Exp.Med. 183: 215–225PubMedCrossRefGoogle Scholar
  72. Steinbach F, Borchers K, Ricciardi-Castagnoli P, Ludwig H, Stingl G, and Elbe-Burger A (1998) Dendritic cells presenting equine herpesvirus-1 antigens induce protective anti-viral immunity. J.Gen.Virol. 79: 3005–3014PubMedGoogle Scholar
  73. Su H, Messer R, Whitmire W, Fischer E, Portis JC, and Caldwell HD (1998) Vaccination against chlamydial genital tract infection after immunization with dendritic cells pulsed ex vivo with nonviable Chlamydiae. J.Exp.Med. 188: 809–818PubMedCrossRefGoogle Scholar
  74. Suss G and Shortman K (1996) A subclass of dendritic cells kills CD4 T cells via Fas Fas-ligand-induced apoptosis. J.Exp.Med. 183: 1789–1796PubMedCrossRefGoogle Scholar
  75. Thomas R, Davis LS, and Lipsky PE (1993) Comparative accessory cell function of human peripheral blood dendritic cells and monocytes. J.Immunol. 151:6840– 6852Google Scholar
  76. Tillman BW, Hayes TL, DeGruijl TD, Douglas JT, and Curiel DT (2000) Adenoviral vectors targeted to CD40 enhance the efficacy of dendritic cell-based vaccination against human papillomavirus 16-induced tumor cells in a murine model. Cancer Res. 60: 5456–5463PubMedGoogle Scholar
  77. Vremec D and Shortman K (1997) Dendritic cell subtypes in mouse lymphoid organs: cross-correlation of surface markers, changes with incubation, and differences among thymus, spleen, and lymph nodes. J.Immunol. 159: 565–573PubMedGoogle Scholar
  78. Wang H, Griffiths MN, Burton DR, and Ghazal P (2000) Rapid antibody responses by low-dose, single-step, dendritic cell-targeted immunization. Proc.Natl.Acad. Sci.U.S.A. 97: 847–852Google Scholar
  79. Zinkernagel RM, Ehl S, Aichele P, Oehen S, Kundig T, and Hengartner H (1997) Antigen localisation regulates immune responses in a dose-and time-dependent fashion: a geographical view of immune reactivity. Immunol. Rev. 156:199–209:199– 209Google Scholar
  80. Zinkernagel RM, Lamarre A, Ciurea A, Hunziker L, Ochsenbein AF, McCoy KD, Fehr T, Bachmann MF, Kalinke U, and Hengartner H (2001) Neutralizing antiviral antibody responses. Adv.Immunol. 79:1–53.: 1–53Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2003

Authors and Affiliations

  • B. Ludewig
    • 1
  1. 1.Institute of Experimental Immunology, Department of PathologyUniversity of ZürichZürichSwitzerland

Personalised recommendations