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Biodistribution of radiolabelled human dendritic cells injected by various routes

  • Molecular Imaging
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

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

Methods

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).

Results

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.

Conclusion

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.

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References

  1. Ribas A, Butterfield LH, Glaspy JA, Economou JS. Current developments in cancer vaccines and cellular immunotherapy. J Clin Oncol 2003;21:2415–32

    Google Scholar 

  2. Figdor CG, De Vries IJ, Lesterhuis WJ, Melief CJ. Dendritic cell immunotherapy: mapping the way. Nat Med 2004;10:475–80

    Article  CAS  PubMed  Google Scholar 

  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;193:233–8

    Article  CAS  PubMed  Google Scholar 

  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;192:1213–22

    Article  CAS  PubMed  Google Scholar 

  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;164:4507–12

    CAS  PubMed  Google Scholar 

  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;29:1617–25

    Article  CAS  PubMed  Google Scholar 

  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;93:243–51

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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;21:3826–35

    Google Scholar 

  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;52:438–44

    Article  CAS  PubMed  Google Scholar 

  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;195:1279–88

    CAS  PubMed  Google Scholar 

  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;159:28–35

    CAS  PubMed  Google Scholar 

  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;29:319–36

    CAS  PubMed  Google Scholar 

  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;25:88–96

    Article  PubMed  Google Scholar 

  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;30:440–7

    CAS  PubMed  Google Scholar 

  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;9:474–81

    CAS  PubMed  Google Scholar 

  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;166:4254–9

    CAS  PubMed  Google Scholar 

  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;63:12–7

    PubMed  Google Scholar 

  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;4:328–32

    CAS  PubMed  Google Scholar 

  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;59:3340–5

    CAS  PubMed  Google Scholar 

  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;164:2487–95

    CAS  PubMed  Google Scholar 

  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;59:56–8

    CAS  PubMed  Google Scholar 

  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;171:6275–82

    CAS  PubMed  Google Scholar 

  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;100:1354–61

    Article  CAS  PubMed  Google Scholar 

  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;100:1362–72

    Article  CAS  PubMed  Google Scholar 

  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;161:2804–9

    CAS  PubMed  Google Scholar 

  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;103:1595–601

    Article  CAS  PubMed  Google Scholar 

  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;198:615–21

    Article  CAS  PubMed  Google Scholar 

  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;198:1023–34

    CAS  PubMed  Google Scholar 

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Acknowledgements

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).

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Authors and Affiliations

  1. Centre Régional de Lutte Contre le Cancer, Rennes, France

    Véronique Quillien, Annick Moisan, Andre Carsin, Thierry Lesimple, Claudia Lefeuvre, Nicolas Bertho, Anne Devillers & Louis Toujas

  2. Service de dermatologie, CHU, Rennes, France

    Henri Adamski

  3. Etablissement Français du Sang (EFS), Rennes, France

    Claudine Leberre

  4. Unité de thérapie cellulaire, Centre Eugène Marquis, Rue de la bataille Flandres-Dunkerque, CS 44229, 35042, Rennes, France

    Véronique Quillien

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  1. Véronique Quillien
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  2. Annick Moisan
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Correspondence to Véronique Quillien.

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Quillien, V., Moisan, A., Carsin, A. et al. Biodistribution of radiolabelled human dendritic cells injected by various routes. Eur J Nucl Med Mol Imaging 32, 731–741 (2005). https://doi.org/10.1007/s00259-005-1825-9

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  • DOI: https://doi.org/10.1007/s00259-005-1825-9

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