Biodistribution of radiolabelled human dendritic cells injected by various routes

  • Véronique QuillienEmail author
  • Annick Moisan
  • Andre Carsin
  • Thierry Lesimple
  • Claudia Lefeuvre
  • Henri Adamski
  • Nicolas Bertho
  • Anne Devillers
  • Claudine Leberre
  • Louis Toujas
Molecular Imaging



The purpose of this study was to investigate the biodistribution of mature dendritic cells (DCs) injected by various routes, during a cell therapy protocol.


In the context of a vaccine therapy protocol for melanoma, DCs matured with Ribomunyl and interferon-gamma were labelled with 111In-oxine and injected into eight patients along various routes: afferent lymphatic vessel (IL) (4 times), lymph node (IN) (5 times) and intradermally (ID) (6 times).


Scintigraphic investigations showed that the IL route allowed localisation of 80% of injected radioactivity in eight to ten nodes. In three cases of IN injection, the entire radioactivity stagnated in the injected nodes, while in two cases, migration to adjacent nodes was observed. This migration was detected rapidly after injection, as with IL injections, suggesting that passive transport occurred along the physiological lymphatic pathways. In two of the six ID injections, 1–2% of injected radioactivity reached a proximal lymph node. Migration was detectable in the first hour, but increased considerably after 24 h, suggesting an active migration mechanism. In both of the aforementioned cases, DCs were strongly CCR7-positive, but this feature was not a sufficient condition for effective migration. In comparison with DCs matured with TNF-α, IL-1β, IL-6 and PGE2, our DCs showed a weaker in vitro migratory response to CCL21, despite comparable CCR7 expression, and higher allostimulatory and TH1 polarisation capacities.


The IL route allowed reproducible administration of specified numbers of DCs. The IN route sometimes yielded fairly similar results, but not reproducibly. Lastly, we showed that DCs matured without PGE2 that have in vitro TH1 polarisation capacities can migrate to lymph nodes after ID injection.


Dendritic cells 111In-oxine Clinical trial Migration CC chemokine receptor 7 



We thank A. Gaudin, G. Duval, S. Abgrall and A. Trichet for their invaluable technical contribution. We are grateful to IDM company for its constant help and for provision of the VacCell Processor systems. The clinical protocol was carried out in conformity with the regulations in force in France, and, in particular, was accepted by the CCPPRB.

This trial was financed by a Hospital Clinical Research Programme (PHRC).


  1. 1.
    Ribas A, Butterfield LH, Glaspy JA, Economou JS. Current developments in cancer vaccines and cellular immunotherapy. J Clin Oncol 2003;21:2415–32Google Scholar
  2. 2.
    Figdor CG, De Vries IJ, Lesterhuis WJ, Melief CJ. Dendritic cell immunotherapy: mapping the way. Nat Med 2004;10:475–80CrossRefPubMedGoogle Scholar
  3. 3.
    Dhodapkar MV, Steinman RM, Krasovsky J, Munz C, Bhardwaj N. Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med 2001;193:233–8CrossRefPubMedGoogle Scholar
  4. 4.
    Jonuleit H, Schmitt E, Schuler G, Knop J, Enk AH. Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J Exp Med 2000;192:1213–22CrossRefPubMedGoogle Scholar
  5. 5.
    Vieira PL, de Jong EC, Wierenga EA, Kapsenberg ML, Kalinski P. Development of Th1-inducing capacity in myeloid dendritic cells requires environmental instruction. J Immunol 2000;164:4507–12PubMedGoogle Scholar
  6. 6.
    Sallusto F, Palermo B, Lenig D, Miettinen M, Matikainen S, Julkunen I, et al. Distinct patterns and kinetics of chemokine production regulate dendritic cell function. Eur J Immunol 1999;29:1617–25CrossRefPubMedGoogle Scholar
  7. 7.
    Jonuleit H, Giesecke-Tuettenberg A, Tuting T, Thurner-Schuler B, Stuge TB, Paragnik L, et al. A comparison of two types of dendritic cell as adjuvants for the induction of melanoma-specific T-cell responses in humans following intranodal injection. Int J Cancer 2001;93:243–51CrossRefPubMedGoogle Scholar
  8. 8.
    Gilliet M, Kleinhans M, Lantelme E, Schadendorf D, Burg G, Nestle FO. Intranodal injection of semimature monocyte-derived dendritic cells induces T helper type 1 responses to protein neoantigen. Blood 2003;102:36–42.CrossRefGoogle Scholar
  9. 9.
    Bedrosian I, Mick R, Xu S, Nisenbaum H, Faries M, Zhang P, et al. Intranodal administration of peptide-pulsed mature dendritic cell vaccines results in superior CD8+ T-cell function in melanoma patients. J Clin Oncol 2003;21:3826–35Google Scholar
  10. 10.
    Lesimple T, Moisan A, Carsin A, Ollivier I, Mousseau M, Meunier B, et al. Injection by various routes of melanoma antigen-associated macrophages: biodistribution and clinical effects. Cancer Immunol Immunother 2003;52:438–44CrossRefPubMedGoogle Scholar
  11. 11.
    Schuler-Thurner B, Schultz ES, Berger TG, Weinlich G, Ebner S, Woerl P, et al. Rapid induction of tumor-specific type 1 T helper cells in metastatic melanoma patients by vaccination with mature, cryopreserved, peptide-loaded monocyte-derived dendritic cells. J Exp Med 2002;195:1279–88PubMedGoogle Scholar
  12. 12.
    Kalinski P, Hilkens CM, Snijders A, Snijdewint FG, Kapsenberg ML. IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. J Immunol 1997;159:28–35PubMedGoogle Scholar
  13. 13.
    Goxe B, Latour N, Chokri M, Abastado JP, Salcedo M. Simplified method to generate large quantities of dendritic cells suitable for clinical applications. Immunol Invest 2000;29:319–36PubMedGoogle Scholar
  14. 14.
    Boccaccio C, Jacod S, Kaiser A, Boyer A, Abastado JP, Nardin A. Identification of a clinical-grade maturation factor for dendritic cells. J Immunother 2002;25:88–96CrossRefPubMedGoogle Scholar
  15. 15.
    Blocklet D, Toungouz M, Kiss R, Lambermont M, Velu T, Duriau D, et al. 111In-oxine and 99mTc-HMPAO labelling of antigen-loaded dendritic cells: in vivo imaging and influence on motility and actin content. Eur J Nucl Med Mol Imaging 2003;30:440–7PubMedGoogle Scholar
  16. 16.
    Thomas R, Chambers M, Boytar R, Barker K, Cavanagh LL, MacFadyen S, et al. Immature human monocyte-derived dendritic cells migrate rapidly to draining lymph nodes after intradermal injection for melanoma immunotherapy. Melanoma Res 1999;9:474–81PubMedGoogle Scholar
  17. 17.
    Fong L, Brockstedt D, Benike C, Wu L, Engleman EG. Dendritic cells injected via different routes induce immunity in cancer patients. J Immunol 2001;166:4254–9PubMedGoogle Scholar
  18. 18.
    De Vries IJ, Krooshoop DJ, Scharenborg NM, Lesterhuis WJ, Diepstra JH, Van Muijen GN, et al. Effective migration of antigen-pulsed dendritic cells to lymph nodes in melanoma patients is determined by their maturation state. Cancer Res 2003;63:12–7PubMedGoogle Scholar
  19. 19.
    Nestle FO, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R, et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 1998;4:328–32PubMedGoogle Scholar
  20. 20.
    Eggert AA, Schreurs MW, Boerman OC, Oyen WJ, de Boer AJ, Punt CJ, et al. Biodistribution and vaccine efficiency of murine dendritic cells are dependent on the route of administration. Cancer Res 1999;59:3340–5PubMedGoogle Scholar
  21. 21.
    Barratt-Boyes SM, Zimmer MI, Harshyne LA, Meyer EM, Watkins SC, Capuano S III, et al. Maturation and trafficking of monocyte-derived dendritic cells in monkeys: implications for dendritic cell-based vaccines. J Immunol 2000;164:2487–95PubMedGoogle Scholar
  22. 22.
    Morse MA, Coleman RE, Akabani G, Niehaus N, Coleman D, Lyerly HK. Migration of human dendritic cells after injection in patients with metastatic malignancies. Cancer Res 1999;59:56–8PubMedGoogle Scholar
  23. 23.
    Nair S, McLaughlin C, Weizer A, Su Z, Boczkowski D, Dannull J, et al. Injection of immature dendritic cells into adjuvant-treated skin obviates the need for ex vivo maturation. J Immunol 2003;171:6275–82PubMedGoogle Scholar
  24. 24.
    Scandella E, Men Y, Gillessen S, Forster R, Groettrup M. Prostaglandin E2 is a key factor for CCR7 surface expression and migration of monocyte-derived dendritic cells. Blood 2002;100:1354–61CrossRefPubMedGoogle Scholar
  25. 25.
    Luft T, Jefford M, Luetjens P, Toy T, Hochrein H, Masterman KA, et al. Functionally distinct dendritic cell (DC) populations induced by physiologic stimuli: prostaglandin E(2) regulates the migratory capacity of specific DC subsets. Blood 2002;100:1362–72CrossRefPubMedGoogle Scholar
  26. 26.
    Kalinski P, Schuitemaker JH, Hilkens CM, Kapsenberg ML. Prostaglandin E2 induces the final maturation of IL-12-deficient CD1a+CD83+ dendritic cells: the levels of IL-12 are determined during the final dendritic cell maturation and are resistant to further modulation. J Immunol 1998;161:2804–9PubMedGoogle Scholar
  27. 27.
    Scandella E, Men Y, Legler DF, Gillessen S, Prikler L, Ludewig B, et al. CCL19/CCL21-triggered signal transduction and migration of dendritic cells requires prostaglandin E2. Blood 2004;103:1595–601CrossRefPubMedGoogle Scholar
  28. 28.
    MartIn-Fontecha A, Sebastiani S, Hopken UE, Uguccioni M, Lipp M, Lanzavecchia A, et al. Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming. J Exp Med 2003;198:615–21CrossRefPubMedGoogle Scholar
  29. 29.
    Mullins DW, Sheasley SL, Ream RM, Bullock TN, Fu YX, Engelhard VH. Route of immunization with peptide-pulsed dendritic cells controls the distribution of memory and effector T cells in lymphoid tissues and determines the pattern of regional tumor control. J Exp Med 2003;198:1023–34PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Véronique Quillien
    • 1
    • 4
    Email author
  • Annick Moisan
    • 1
  • Andre Carsin
    • 1
  • Thierry Lesimple
    • 1
  • Claudia Lefeuvre
    • 1
  • Henri Adamski
    • 2
  • Nicolas Bertho
    • 1
  • Anne Devillers
    • 1
  • Claudine Leberre
    • 3
  • Louis Toujas
    • 1
  1. 1.Centre Régional de Lutte Contre le CancerRennesFrance
  2. 2.Service de dermatologieCHURennesFrance
  3. 3.Etablissement Français du Sang (EFS)RennesFrance
  4. 4.Unité de thérapie cellulaireCentre Eugène MarquisRennesFrance

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