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British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Jun;84(11):1564–1570. doi: 10.1054/bjoc.2001.1801

Administration route-dependent vaccine efficiency of murine dendritic cells pulsed with antigens

N Okada 1, M Tsujino 1, Y Hagiwara 1, A Tada 1, Y Tamura 1, K Mori 1, T Saito 1, S Nakagawa 2, T Mayumi 2, T Fujita 1, A Yamamoto 1
PMCID: PMC2363668  PMID: 11384109

Abstract

 Dendritic cells (DCs) loaded with tumour antigens have been successfully used to induce protective tumour immunity in murine models and human trials. However, it is still unclear which DC administration route elicits a superior therapeutic effect. Herein, we investigated the vaccine efficiency of DC2.4 cells, a murine dendritic cell line, pulsed with ovalbumin (OVA) in the murine E.G7-OVA tumour model after immunization via various routes. After a single vaccination using 1 × 106OVA-pulsed DC2.4 cells, tumour was completely rejected in the intradermally (i.d.; three of four mice), subcutaneously (s.c.; three of four mice), and intraperitoneally (i.p.; one of four mice) immunized groups. Double vaccinations enhanced the anti-tumour effect in all groups except the intravenous (i.v.) group, which failed to achieve complete rejection. The anti-tumour efficacy of each immunization route was correlated with the OVA-specific cytotoxic T lymphocyte (CTL) activity evaluated on day 7 post-vaccination. Furthermore, the accumulation of DC2.4 cells in the regional lymph nodes was detected only in the i.d.-and s.c.-injected groups. These results demonstrate that the administration route of antigen-loaded DCs affects the migration of DCs to lymphoid tissues and the magnitude of antigen-specific CTL response. Furthermore, the immunization route affects vaccine efficiency. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: dendritic cell, administration route, vaccine efficiency, cytotoxic T lymphocyte, migration

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Selected References

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  1. Alters S. E., Gadea J. R., Sorich M., O'Donoghue G., Talib S., Philip R. Dendritic cells pulsed with CEA peptide induce CEA-specific CTL with restricted TCR repertoire. J Immunother. 1998 Jan;21(1):17–26. doi: 10.1097/00002371-199801000-00002. [DOI] [PubMed] [Google Scholar]
  2. Arthur J. F., Butterfield L. H., Roth M. D., Bui L. A., Kiertscher S. M., Lau R., Dubinett S., Glaspy J., McBride W. H., Economou J. S. A comparison of gene transfer methods in human dendritic cells. Cancer Gene Ther. 1997 Jan-Feb;4(1):17–25. [PubMed] [Google Scholar]
  3. Ashley D. M., Faiola B., Nair S., Hale L. P., Bigner D. D., Gilboa E. Bone marrow-generated dendritic cells pulsed with tumor extracts or tumor RNA induce antitumor immunity against central nervous system tumors. J Exp Med. 1997 Oct 6;186(7):1177–1182. doi: 10.1084/jem.186.7.1177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Austyn J. M., Kupiec-Weglinski J. W., Hankins D. F., Morris P. J. Migration patterns of dendritic cells in the mouse. Homing to T cell-dependent areas of spleen, and binding within marginal zone. J Exp Med. 1988 Feb 1;167(2):646–651. doi: 10.1084/jem.167.2.646. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Banchereau J., Steinman R. M. Dendritic cells and the control of immunity. Nature. 1998 Mar 19;392(6673):245–252. doi: 10.1038/32588. [DOI] [PubMed] [Google Scholar]
  6. Bernhard H., Disis M. L., Heimfeld S., Hand S., Gralow J. R., Cheever M. A. Generation of immunostimulatory dendritic cells from human CD34+ hematopoietic progenitor cells of the bone marrow and peripheral blood. Cancer Res. 1995 Mar 1;55(5):1099–1104. [PubMed] [Google Scholar]
  7. Brossart P., Grünebach F., Stuhler G., Reichardt V. L., Möhle R., Kanz L., Brugger W. Generation of functional human dendritic cells from adherent peripheral blood monocytes by CD40 ligation in the absence of granulocyte-macrophage colony-stimulating factor. Blood. 1998 Dec 1;92(11):4238–4247. [PubMed] [Google Scholar]
  8. Celluzzi C. M., Mayordomo J. I., Storkus W. J., Lotze M. T., Falo L. D., Jr Peptide-pulsed dendritic cells induce antigen-specific CTL-mediated protective tumor immunity. J Exp Med. 1996 Jan 1;183(1):283–287. doi: 10.1084/jem.183.1.283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cikes M., Friberg S., Jr, Klein G. Progressive loss of H-2 antigens with concomitant increase of cell-surface antigen(s) determined by Moloney leukemia virus in cultured murine lymphomas. J Natl Cancer Inst. 1973 Feb;50(2):347–362. doi: 10.1093/jnci/50.2.347. [DOI] [PubMed] [Google Scholar]
  10. Eggert A. A., Schreurs M. W., Boerman O. C., Oyen W. J., de Boer A. J., Punt C. J., Figdor C. G., Adema G. J. Biodistribution and vaccine efficiency of murine dendritic cells are dependent on the route of administration. Cancer Res. 1999 Jul 15;59(14):3340–3345. [PubMed] [Google Scholar]
  11. Fallarino F., Uyttenhove C., Boon T., Gajewski T. F. Improved efficacy of dendritic cell vaccines and successful immunization with tumor antigen peptide-pulsed peripheral blood mononuclear cells by coadministration of recombinant murine interleukin-12. Int J Cancer. 1999 Jan 18;80(2):324–333. doi: 10.1002/(sici)1097-0215(19990118)80:2<324::aid-ijc25>3.0.co;2-d. [DOI] [PubMed] [Google Scholar]
  12. Fearnley D. B., McLellan A. D., Mannering S. I., Hock B. D., Hart D. N. Isolation of human blood dendritic cells using the CMRF-44 monoclonal antibody: implications for studies on antigen-presenting cell function and immunotherapy. Blood. 1997 May 15;89(10):3708–3716. [PubMed] [Google Scholar]
  13. Gong J., Chen D., Kashiwaba M., Kufe D. Induction of antitumor activity by immunization with fusions of dendritic and carcinoma cells. Nat Med. 1997 May;3(5):558–561. doi: 10.1038/nm0597-558. [DOI] [PubMed] [Google Scholar]
  14. Harding C. V. Techniques for studying phagocytic processing of bacteria for class I or II MHC-restricted antigen recognition by T lymphocytes. Methods Cell Biol. 1994;45:313–326. doi: 10.1016/s0091-679x(08)61859-2. [DOI] [PubMed] [Google Scholar]
  15. Hayashi A., Nakanishi T., Kunisawa J., Kondoh M., Imazu S., Tsutsumi Y., Tanaka K., Fujiwara H., Hamaoka T., Mayumi T. A novel vaccine delivery system using immunopotentiating fusogenic liposomes. Biochem Biophys Res Commun. 1999 Aug 11;261(3):824–828. doi: 10.1006/bbrc.1999.1044. [DOI] [PubMed] [Google Scholar]
  16. Henkart P. A. Lymphocyte-mediated cytotoxicity: two pathways and multiple effector molecules. Immunity. 1994 Aug;1(5):343–346. doi: 10.1016/1074-7613(94)90063-9. [DOI] [PubMed] [Google Scholar]
  17. Hsu F. J., Benike C., Fagnoni F., Liles T. M., Czerwinski D., Taidi B., Engleman E. G., Levy R. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med. 1996 Jan;2(1):52–58. doi: 10.1038/nm0196-52. [DOI] [PubMed] [Google Scholar]
  18. Janik P., Briand P., Hartmann N. R. The effect of estrone-progesterone treatment on cell proliferation kinetics of hormone-dependent GR mouse mammary tumors. Cancer Res. 1975 Dec;35(12):3698–3704. [PubMed] [Google Scholar]
  19. Kronenberg M., Siu G., Hood L. E., Shastri N. The molecular genetics of the T-cell antigen receptor and T-cell antigen recognition. Annu Rev Immunol. 1986;4:529–591. doi: 10.1146/annurev.iy.04.040186.002525. [DOI] [PubMed] [Google Scholar]
  20. Lappin M. B., Weiss J. M., Delattre V., Mai B., Dittmar H., Maier C., Manke K., Grabbe S., Martin S., Simon J. C. Analysis of mouse dendritic cell migration in vivo upon subcutaneous and intravenous injection. Immunology. 1999 Oct;98(2):181–188. doi: 10.1046/j.1365-2567.1999.00850.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lodge P. A., Jones L. A., Bader R. A., Murphy G. P., Salgaller M. L. Dendritic cell-based immunotherapy of prostate cancer: immune monitoring of a phase II clinical trial. Cancer Res. 2000 Feb 15;60(4):829–833. [PubMed] [Google Scholar]
  22. Ludewig B., Ochsenbein A. F., Odermatt B., Paulin D., Hengartner H., Zinkernagel R. M. Immunotherapy with dendritic cells directed against tumor antigens shared with normal host cells results in severe autoimmune disease. J Exp Med. 2000 Mar 6;191(5):795–804. doi: 10.1084/jem.191.5.795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lutz M. B., Kukutsch N., Ogilvie A. L., Rössner S., Koch F., Romani N., Schuler G. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods. 1999 Feb 1;223(1):77–92. doi: 10.1016/s0022-1759(98)00204-x. [DOI] [PubMed] [Google Scholar]
  24. Machy P., Serre K., Leserman L. Class I-restricted presentation of exogenous antigen acquired by Fcgamma receptor-mediated endocytosis is regulated in dendritic cells. Eur J Immunol. 2000 Mar;30(3):848–857. doi: 10.1002/1521-4141(200003)30:3<848::AID-IMMU848>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
  25. Mayordomo J. I., Zorina T., Storkus W. J., Zitvogel L., Celluzzi C., Falo L. D., Melief C. J., Ildstad S. T., Kast W. M., Deleo A. B. Bone marrow-derived dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic antitumour immunity. Nat Med. 1995 Dec;1(12):1297–1302. doi: 10.1038/nm1295-1297. [DOI] [PubMed] [Google Scholar]
  26. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983 Dec 16;65(1-2):55–63. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  27. Müller G., Müller A., Jonuleit H., Steinbrink K., Szalma C., Paragnik L., Lingnau K., Schmidt E., Knop J., Enk A. H. Fetal calf serum-free generation of functionally active murine dendritic cells suitable for in vivo therapeutic approaches. J Invest Dermatol. 2000 Jan;114(1):142–149. doi: 10.1046/j.1523-1747.2000.00832.x. [DOI] [PubMed] [Google Scholar]
  28. Nair S. K., Snyder D., Rouse B. T., Gilboa E. Regression of tumors in mice vaccinated with professional antigen-presenting cells pulsed with tumor extracts. Int J Cancer. 1997 Mar 17;70(6):706–715. doi: 10.1002/(sici)1097-0215(19970317)70:6<706::aid-ijc13>3.0.co;2-7. [DOI] [PubMed] [Google Scholar]
  29. Nair S., Zhou F., Reddy R., Huang L., Rouse B. T. Soluble proteins delivered to dendritic cells via pH-sensitive liposomes induce primary cytotoxic T lymphocyte responses in vitro. J Exp Med. 1992 Feb 1;175(2):609–612. doi: 10.1084/jem.175.2.609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Nakanishi T., Hayashi A., Kunisawa J., Tsutsumi Y., Tanaka K., Yashiro-Ohtani Y., Nakanishi M., Fujiwara H., Hamaoka T., Mayumi T. Fusogenic liposomes efficiently deliver exogenous antigen through the cytoplasm into the MHC class I processing pathway. Eur J Immunol. 2000 Jun;30(6):1740–1747. doi: 10.1002/1521-4141(200006)30:6<1740::AID-IMMU1740>3.0.CO;2-U. [DOI] [PubMed] [Google Scholar]
  31. Nestle F. O., Alijagic S., Gilliet M., Sun Y., Grabbe S., Dummer R., Burg G., Schadendorf D. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med. 1998 Mar;4(3):328–332. doi: 10.1038/nm0398-328. [DOI] [PubMed] [Google Scholar]
  32. Norbury C. C., Chambers B. J., Prescott A. R., Ljunggren H. G., Watts C. Constitutive macropinocytosis allows TAP-dependent major histocompatibility complex class I presentation of exogenous soluble antigen by bone marrow-derived dendritic cells. Eur J Immunol. 1997 Jan;27(1):280–288. doi: 10.1002/eji.1830270141. [DOI] [PubMed] [Google Scholar]
  33. Paglia P., Chiodoni C., Rodolfo M., Colombo M. P. Murine dendritic cells loaded in vitro with soluble protein prime cytotoxic T lymphocytes against tumor antigen in vivo. J Exp Med. 1996 Jan 1;183(1):317–322. doi: 10.1084/jem.183.1.317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Philip R., Alters S. E., Brunette E., Ashton J., Gadea J., Yau J., Lebkowski J., Philip M. Dendritic cells loaded with MART-1 peptide or infected with adenoviral construct are functionally equivalent in the induction of tumor-specific cytotoxic T lymphocyte responses in patients with melanoma. J Immunother. 2000 Jan;23(1):168–176. doi: 10.1097/00002371-200001000-00020. [DOI] [PubMed] [Google Scholar]
  35. Rock K. L. A new foreign policy: MHC class I molecules monitor the outside world. Immunol Today. 1996 Mar;17(3):131–137. doi: 10.1016/0167-5699(96)80605-0. [DOI] [PubMed] [Google Scholar]
  36. Rock K. L., Rothstein L., Gamble S. Generation of class I MHC-restricted T-T hybridomas. J Immunol. 1990 Aug 1;145(3):804–811. [PubMed] [Google Scholar]
  37. Rodriguez A., Regnault A., Kleijmeer M., Ricciardi-Castagnoli P., Amigorena S. Selective transport of internalized antigens to the cytosol for MHC class I presentation in dendritic cells. Nat Cell Biol. 1999 Oct;1(6):362–368. doi: 10.1038/14058. [DOI] [PubMed] [Google Scholar]
  38. Romani N., Gruner S., Brang D., Kämpgen E., Lenz A., Trockenbacher B., Konwalinka G., Fritsch P. O., Steinman R. M., Schuler G. Proliferating dendritic cell progenitors in human blood. J Exp Med. 1994 Jul 1;180(1):83–93. doi: 10.1084/jem.180.1.83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Roskrow M. A., Dilloo D., Suzuki N., Zhong W., Rooney C. M., Brenner M. K. Autoimmune disease induced by dendritic cell immunization against leukemia. Leuk Res. 1999 Jun;23(6):549–557. doi: 10.1016/s0145-2126(99)00045-4. [DOI] [PubMed] [Google Scholar]
  40. Shen Z., Reznikoff G., Dranoff G., Rock K. L. Cloned dendritic cells can present exogenous antigens on both MHC class I and class II molecules. J Immunol. 1997 Mar 15;158(6):2723–2730. [PubMed] [Google Scholar]
  41. Steinman R. M. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991;9:271–296. doi: 10.1146/annurev.iy.09.040191.001415. [DOI] [PubMed] [Google Scholar]
  42. Tillman B. W., de Gruijl T. D., Luykx-de Bakker S. A., Scheper R. J., Pinedo H. M., Curiel T. J., Gerritsen W. R., Curiel D. T. Maturation of dendritic cells accompanies high-efficiency gene transfer by a CD40-targeted adenoviral vector. J Immunol. 1999 Jun 1;162(11):6378–6383. [PubMed] [Google Scholar]
  43. Volgmann T., Klein-Struckmeier A., Mohr H. A fluorescence-based assay for quantitation of lymphokine-activated killer cell activity. J Immunol Methods. 1989 Apr 21;119(1):45–51. doi: 10.1016/0022-1759(89)90379-7. [DOI] [PubMed] [Google Scholar]
  44. Wong C., Morse M., Nair S. K. Induction of primary, human antigen-specific cytotoxic T lymphocytes in vitro using dendritic cells pulsed with peptides. J Immunother. 1998 Jan;21(1):32–40. doi: 10.1097/00002371-199801000-00004. [DOI] [PubMed] [Google Scholar]
  45. Zitvogel L., Regnault A., Lozier A., Wolfers J., Flament C., Tenza D., Ricciardi-Castagnoli P., Raposo G., Amigorena S. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med. 1998 May;4(5):594–600. doi: 10.1038/nm0598-594. [DOI] [PubMed] [Google Scholar]

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