Skip to main content

Advertisement

SpringerLink
Log in

Depletion of inflammatory dendritic cells with anti-CD209 conjugated to saporin toxin

  • IMMUNOLOGY AT STANFORD UNIVERSITY
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Monocytes rapidly infiltrate inflamed tissues and differentiate into CD209+ inflammatory dendritic cells (DCs) that promote robust immunity or, if unregulated, inflammatory disease. Previous studies in experimental animal models indicate that inflammatory DC depletion through systemic elimination of their monocyte precursors with clodronate-loaded liposomes ameliorates the development of psoriasis and other diseases. However, translation of systemic monocyte depletion strategies is difficult due to the importance of monocytes during homeostasis and infection clearance. Here, we describe a strategy that avoids the monocyte intermediates to deplete inflammatory DCs through antibody-loaded toxin. Mice with an abundance of inflammatory DCs as a consequence of lipopolysaccharide exposure were treated with anti-CD209 antibody conjugated to saporin, a potent ribosome inactivator. The results demonstrate depletion of CD209+ DCs. This strategy could prove useful for the targeted reduction of inflammatory DCs in disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Auffray C, Sieweke MH, Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol. 2009;27:669–92. doi:10.1146/annurev.immunol.021908.132557.

    Article  CAS  PubMed  Google Scholar 

  2. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8(12):958–69. doi:10.1038/nri2448.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5(12):953–64. doi:10.1038/nri1733.

    Article  CAS  PubMed  Google Scholar 

  4. Weber C, Belge KU, von Hundelshausen P, Draude G, Steppich B, Mack M, et al. Differential chemokine receptor expression and function in human monocyte subpopulations. J Leukoc Biol. 2000;67(5):699–704.

    CAS  PubMed  Google Scholar 

  5. Serbina NV, Pamer EG. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol. 2006;7(3):311–7. doi:10.1038/ni1309.

    Article  CAS  PubMed  Google Scholar 

  6. Serbina NV, Jia T, Hohl TM, Pamer EG. Monocyte-mediated defense against microbial pathogens. Annu Rev Immunol. 2008;26:421–52. doi:10.1146/annurev.immunol.26.021607.090326.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Juarez E, Nunez C, Sada E, Ellner JJ, Schwander SK, Torres M. Differential expression of Toll-like receptors on human alveolar macrophages and autologous peripheral monocytes. Respir Res. 2010;11:2. doi:10.1186/1465-9921-11-2.

    Article  PubMed Central  PubMed  Google Scholar 

  8. Muzio M, Mantovani A. Toll-like receptors (TLRs) signalling and expression pattern. J Endotoxin Res. 2001;7(4):297–300.

    Article  CAS  PubMed  Google Scholar 

  9. Leon B, Lopez-Bravo M, Ardavin C. Monocyte-derived dendritic cells formed at the infection site control the induction of protective T helper 1 responses against Leishmania. Immunity. 2007;26(4):519–31. doi:10.1016/j.immuni.2007.01.017.

    Article  CAS  PubMed  Google Scholar 

  10. Wakim LM, Waithman J, van Rooijen N, Heath WR, Carbone FR. Dendritic cell-induced memory T cell activation in nonlymphoid tissues. Science. 2008;319(5860):198–202. doi:10.1126/science.1151869.

    Article  CAS  PubMed  Google Scholar 

  11. Cheong C, Matos I, Choi JH, Dandamudi DB, Shrestha E, Longhi MP, et al. Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209(+) dendritic cells for immune T cell areas. Cell. 2010;143(3):416–29. doi:10.1016/j.cell.2010.09.039.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Varol C, Vallon-Eberhard A, Elinav E, Aychek T, Shapira Y, Luche H, et al. Intestinal lamina propria dendritic cell subsets have different origin and functions. Immunity. 2009;31(3):502–12. doi:10.1016/j.immuni.2009.06.025.

    Article  CAS  PubMed  Google Scholar 

  13. Traynor TR, Kuziel WA, Toews GB, Huffnagle GB. CCR2 expression determines T1 versus T2 polarization during pulmonary Cryptococcus neoformans infection. J Immunol. 2000;164(4):2021–7.

    Article  CAS  PubMed  Google Scholar 

  14. Jia T, Serbina NV, Brandl K, Zhong MX, Leiner IM, Charo IF, et al. Additive roles for MCP-1 and MCP-3 in CCR2-mediated recruitment of inflammatory monocytes during Listeria monocytogenes infection. J Immunol. 2008;180(10):6846–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Dunay IR, Fuchs A, Sibley LD. Inflammatory monocytes but not neutrophils are necessary to control infection with Toxoplasma gondii in mice. Infect Immun. 2010;78(4):1564–70. doi:10.1128/IAI.00472-09.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Osterholzer JJ, Curtis JL, Polak T, Ames T, Chen GH, McDonald R, et al. CCR2 mediates conventional dendritic cell recruitment and the formation of bronchovascular mononuclear cell infiltrates in the lungs of mice infected with Cryptococcus neoformans. J Immunol. 2008;181(1):610–20.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. te Velde AA, van Kooyk Y, Braat H, Hommes DW, Dellemijn TA, Slors JF, et al. Increased expression of DC-SIGN + IL-12 + IL-18 + and CD83 + IL-12-IL-18- dendritic cell populations in the colonic mucosa of patients with Crohn’s disease. Eur J Immunol. 2003;33(1):143–51. doi:10.1002/immu.200390017.

    Article  Google Scholar 

  18. Baumgart DC, Metzke D, Schmitz J, Scheffold A, Sturm A, Wiedenmann B, et al. Patients with active inflammatory bowel disease lack immature peripheral blood plasmacytoid and myeloid dendritic cells. Gut. 2005;54(2):228–36. doi:10.1136/gut.2004.040360.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Ward NL, Loyd CM, Wolfram JA, Diaconu D, Michaels CM, McCormick TS. Depletion of antigen-presenting cells by clodronate liposomes reverses the psoriatic skin phenotype in KC-Tie2 mice. Br J Dermatol. 2011;164(4):750–8. doi:10.1111/j.1365-2133.2010.10129.x.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Alonso MN, Wong MT, Zhang AL, Winer D, Suhoski MM, Tolentino LL, et al. T(H)1, T(H)2, and T(H)17 cells instruct monocytes to differentiate into specialized dendritic cell subsets. Blood. 2011;118(12):3311–20. doi:10.1182/blood-2011-03-341065.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Davidson MG, Alonso MN, Yuan R, Axtell RC, Kenkel JA, Suhoski MM, et al. Th17 cells induce Th1-polarizing monocyte-derived dendritic cells. J Immunol. 2013;191(3):1175–87. doi:10.4049/jimmunol.1203201.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Rafei M, Berchiche YA, Birman E, Boivin MN, Young YK, Wu JH, et al. An engineered GM-CSF-CCL2 fusokine is a potent inhibitor of CCR2-driven inflammation as demonstrated in a murine model of inflammatory arthritis. J Immunol. 2009;183(3):1759–66. doi:10.4049/jimmunol.0900523.

    Article  CAS  PubMed  Google Scholar 

  23. Gong JH, Ratkay LG, Waterfield JD, Clark-Lewis I. An antagonist of monocyte chemoattractant protein 1 (MCP-1) inhibits arthritis in the MRL-lpr mouse model. J Exp Med. 1997;186(1):131–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Andres PG, Beck PL, Mizoguchi E, Mizoguchi A, Bhan AK, Dawson T, et al. Mice with a selective deletion of the CC chemokine receptors 5 or 2 are protected from dextran sodium sulfate-mediated colitis: lack of CC chemokine receptor 5 expression results in a NK1.1 + lymphocyte-associated Th2-type immune response in the intestine. J Immunol. 2000;164(12):6303–12.

    Article  CAS  PubMed  Google Scholar 

  25. Oelzner P, Kunze A, Henzgen S, Thoss K, Hein G, Stein G, et al. High-dose clodronate therapy prevents joint destruction in chronic antigen-induced arthritis of the rat but inhibits bone formation at the axial skeleton. Inflamm Res. 2000;49(8):424–33.

    Article  CAS  PubMed  Google Scholar 

  26. Tacke F, Ginhoux F, Jakubzick C, van Rooijen N, Merad M, Randolph GJ. Immature monocytes acquire antigens from other cells in the bone marrow and present them to T cells after maturing in the periphery. J Exp Med. 2006;203(3):583–97. doi:10.1084/jem.20052119.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Haringman JJ, Gerlag DM, Smeets TJ, Baeten D, van den Bosch F, Bresnihan B, et al. A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54(8):2387–92. doi:10.1002/art.21975.

    Article  CAS  PubMed  Google Scholar 

  28. Vergunst CE, Gerlag DM, Lopatinskaya L, Klareskog L, Smith MD, van den Bosch F, et al. Modulation of CCR2 in rheumatoid arthritis: a double-blind, randomized, placebo-controlled clinical trial. Arthritis Rheum. 2008;58(7):1931–9. doi:10.1002/art.23591.

    Article  CAS  PubMed  Google Scholar 

  29. Davidson MG, Alonso MN, Kenkel JA, Suhoski MM, Gonzalez JC, Yuan R, et al. In vivo T cell activation induces the formation of CD209(+) PDL-2(+) dendritic cells. PLoS ONE. 2013;8(10):e76258. doi:10.1371/journal.pone.0076258.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Weng A, Bachran C, Fuchs H, Krause E, Stephanowitz H, Melzig MF. Enhancement of saporin cytotoxicity by Gypsophila saponins–more than stimulation of endocytosis. Chem Biol Interact. 2009;181(3):424–9. doi:10.1016/j.cbi.2009.07.007.

    Article  CAS  PubMed  Google Scholar 

  31. Bachran C, Sutherland M, Heisler I, Hebestreit P, Melzig MF, Fuchs H. The saponin-mediated enhanced uptake of targeted saporin-based drugs is strongly dependent on the saponin structure. Exp Biol Med. 2006;231(4):412–20.

    CAS  Google Scholar 

  32. Zhang P, Schwartz O, Pantelic M, Li G, Knazze Q, Nobile C, et al. DC-SIGN (CD209) recognition of Neisseria gonorrhoeae is circumvented by lipooligosaccharide variation. J Leukoc Biol. 2006;79(4):731–8. doi:10.1189/jlb.0405184.

    Article  CAS  PubMed  Google Scholar 

  33. O’Keeffe M, Hochrein H, Vremec D, Caminschi I, Miller JL, Anders EM, et al. Mouse plasmacytoid cells: long-lived cells, heterogeneous in surface phenotype and function, that differentiate into CD8(+) dendritic cells only after microbial stimulus. J Exp Med. 2002;196(10):1307–19.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA

    Michael N. Alonso, Josh G. Gregorio, Matthew G. Davidson, Joseph C. Gonzalez & Edgar G. Engleman

Authors
  1. Michael N. Alonso
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Josh G. Gregorio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthew G. Davidson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joseph C. Gonzalez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Edgar G. Engleman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edgar G. Engleman.

Additional information

Michael N. Alonso and Josh G. Gregorio have contributed equally to this paper.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alonso, M.N., Gregorio, J.G., Davidson, M.G. et al. Depletion of inflammatory dendritic cells with anti-CD209 conjugated to saporin toxin. Immunol Res 58, 374–377 (2014). https://doi.org/10.1007/s12026-014-8511-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-014-8511-6

Keywords

Search

Navigation