GK1 Improves the Immune Response Induced by Dendritic Cells of BALB/c Mice Infected with Leishmania mexicana Promastigotes

Abstract

Purpose

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs), and their capacity to activate the immune response has been widely used in immunotherapies against different diseases, predominantly cancer. However, they have not been so widely used in immunotherapies against infectious diseases. Leishmania mexicana is the causative agent of cutaneous leishmaniasis in Mexico, which can result in localized cutaneous leishmaniasis (LCL) and diffuse cutaneous leishmaniasis (DCL). DCL is characterized by the incapability of the immune response to control the parasite, which thus disseminates to all teguments. Treatments against DCL have shown low efficacy, which is a reason why alternative therapies such as immunotherapies are promising. One adjuvant that has proven its effectiveness in immunotherapies against some cancers and infections is GK1, a component of the SPVac vaccine against porcine cysticercosis. GK1 has the capacity to elicit proinflammatory cytokines and chemokines from DCs and macrophages.

Methods

We pulsed bone marrow-derived dendritic cells (BMDCs) with GK1 and a lysate obtained from L. mexicana promastigotes and tested the efficacy of this combination against the infection of susceptible mice with L. mexicana.

Results

We found that BMDCs stimulated with GK1 and a lysate of L. mexicana promastigotes secreted IFN-γ and IL-12, and when they were adoptively transferred to BALB/c mice which were then infected with L. mexicana promastigotes, there was a reduction in the size of the lesion and in the parasite load.

Conclusions

The adjuvant properties of GK1 along with parasite antigens may have a protective effect against the infection of BALB/c mice with L. mexicana.

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References

  1. 1.

    Alvar J, Velez ID, Bern C, Herrero M, Desjeux P, Cano J, Jannin J, den Boer M, Team WHOLC (2012) Leishmaniasis worldwide and global estimates of its incidence. PloS One 7:e35671. https://doi.org/10.1371/journal.pone.0035671

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    McGwire BS, Satoskar AR (2014) Leishmaniasis: clinical syndromes and treatment. QJM Int J Med 107:7–14. https://doi.org/10.1093/qjmed/hct116

    CAS  Article  Google Scholar 

  3. 3.

    Steinman RM (1991) The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 9:271–296. https://doi.org/10.1146/annurev.iy.09.040191.001415

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K (2000) Immunobiology of dendritic cells. Annu Rev Immunol 18:767–811. https://doi.org/10.1146/annurev.immunol.18.1.767

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Lanzavecchia A, Sallusto F (2001) Regulation of T cell immunity by dendritic cells. Cell 106:263–266. https://doi.org/10.1016/S0092-8674(01)00455-X

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Palucka K, Banchereau J (2013) Human dendritic cell subsets in vaccination. Curr Opin Immunol 25:396–402. https://doi.org/10.1016/j.coi.2013.05.001

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Kumar R, Engwerda C (2014) Vaccines to prevent leishmaniasis. Clin Transl Immunol 3:e13. https://doi.org/10.1038/cti.2014.4

    CAS  Article  Google Scholar 

  8. 8.

    von Stebut E, Belkaid Y, Nguyen BV, Cushing M, Sacks DL, Udey MC (2000) Leishmania major-infected murine langerhans cell-like dendritic cells from susceptible mice release IL-12 after infection and vaccinate against experimental cutaneous leishmaniasis. Eur J Immunol 30:3498–3506. https://doi.org/10.1002/1521-4141(2000012)30:12%3c3498:AID-IMMU3498%3e3.0.CO;2-6

    Article  Google Scholar 

  9. 9.

    Berberich C, Ramirez-Pineda JR, Hambrecht C, Alber G, Skeiky YA, Moll H (2003) Dendritic cell (DC)-based protection against an intracellular pathogen is dependent upon DC-derived IL-12 and can be induced by molecularly defined antigens. J Immunol 170:3171–3179. https://doi.org/10.4049/jimmunol.170.6.3171

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Ramirez-Pineda JR, Frohlich A, Berberich C, Moll H (2004) Dendritic cells (DC) activated by CpG DNA ex vivo are potent inducers of host resistance to an intracellular pathogen that is independent of IL-12 derived from the immunizing DC. J Immunol 172:6281–6289. https://doi.org/10.4049/jimmunol.172.10.6281

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Remer KA, Apetrei C, Schwarz T, Linden C, Moll H (2007) Vaccination with plasmacytoid dendritic cells induces protection against infection with Leishmania major in mice. Eur J Immunol 37:2463–2473. https://doi.org/10.1002/eji.200636780

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Agallou M, Margaroni M, Karagouni E (2011) Cellular vaccination with bone marrow-derived dendritic cells pulsed with a peptide of Leishmania infantum KMP-11 and CpG oligonucleotides induces protection in a murine model of visceral leishmaniasis. Vaccine 29:5053–5064. https://doi.org/10.1016/j.vaccine.2011.04.089

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Schwarz T, Remer KA, Nahrendorf W, Masic A, Siewe L, Muller W, Roers A, Moll H (2013) T cell-derived IL-10 determines leishmaniasis disease outcome and is suppressed by a dendritic cell based vaccine. PLoS Pathog 9:e1003476. https://doi.org/10.1371/journal.ppat.1003476

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Majumder S, Bhattacharjee A, Paul Chowdhury B, Bhattacharyya Majumdar S, Majumdar S (2014) Antigen-pulsed CpG-ODN-activated dendritic cells induce host-protective immune response by regulating the T regulatory cell functioning in Leishmania donovani-infected mice: critical role of CXCL10. Front Immunol 5:261. https://doi.org/10.3389/fimmu.2014.00261

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Diaz MA, Villalobos N, de Aluja A, Rosas G, Gomez-Conde E, Hernandez P, Larralde C, Sciutto E, Fragoso G (2003) Th1 and Th2 indices of the immune response in pigs vaccinated against Taenia solium cysticercosis suggest various host immune strategies against the parasite. Vet Immunol Immunopathol 93:81–90. https://doi.org/10.1016/S0165-2427(03)00071-0

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Segura-Velazquez R, Fragoso G, Sciutto E, Sarukhan A (2009) Towards identification of the mechanisms of action of parasite-derived peptide GK1 on the immunogenicity of an influenza vaccine. Clin Vaccine Immunol 16:1338–1343. https://doi.org/10.1128/CVI.00106-09

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Segura-Velazquez R, Perez-Torres A, Rosas G, Toledo A, Restelli M, Acosta E, Corral R, Rosetti F, Fragoso G, Grinstein S et al (2006) A novel synthetic adjuvant effectively enhances the immunogenicity of the influenza vaccine. Vaccine 24:1073–1080. https://doi.org/10.1016/j.vaccine.2005.09.014

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Perez-Torres A, Vera-Aguilera J, Hernaiz-Leonardo JC, Moreno-Aguilera E, Monteverde-Suarez D, Vera-Aguilera C, Estrada-Barcenas D (2013) The synthetic parasite-derived peptide GK1 increases survival in a preclinical mouse melanoma model. Cancer Biother Radiopharm 28:682–690. https://doi.org/10.1089/cbr.2012.1438

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Pinon-Zarate G, Herrera-Enriquez MA, Hernandez-Tellez B, Jarquin-Yanez K, Castell-Rodriguez AE (2014) GK-1 improves the immune response induced by bone marrow dendritic cells loaded with MAGE-AX in mice with melanoma. J Immunol Res. https://doi.org/10.1155/2014/158980

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Torres-Garcia D, Perez-Torres A, Manoutcharian K, Orbe U, Servin-Blanco R, Fragoso G, Sciutto E (2017) GK-1 peptide reduces tumor growth, decreases metastatic burden, and increases survival in a murine breast cancer model. Vaccine 35:5653–5661. https://doi.org/10.1016/j.vaccine.2017.08.060

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Lutz MB, Kukutsch N, Ogilvie AL, Rossner S, Koch F, Romani N, Schuler G (1999) An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods 223:77–92. https://doi.org/10.1016/S0022-1759(98)00204-X

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Zal T, Volkmann A, Stockinger B (1994) Mechanisms of tolerance induction in major histocompatibility complex class II-restricted T cells specific for a blood-borne self-antigen. J Exp Med 180:2089–2099. https://doi.org/10.1084/jem.180.6.2089

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Bates PA, Tetley L (1993) Leishmania mexicana: induction of metacyclogenesis by cultivation of promastigotes at acidic pH. Exp Parasitol 76:412–423. https://doi.org/10.1006/expr.1993.1050

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Padigel UM, Alexander J, Farrell JP (2003) The role of interleukin-10 in susceptibility of BALB/c mice to infection with Leishmania mexicana and Leishmania amazonensis. J Immunol 171:3705–3710. https://doi.org/10.4049/jimmunol.171.7.3705

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Rosas LE, Keiser T, Barbi J, Satoskar AA, Septer A, Kaczmarek J, Lezama-Davila CM, Satoskar AR (2005) Genetic background influences immune responses and disease outcome of cutaneous L. mexicana infection in mice. Int Immunol 17:1347–1357. https://doi.org/10.1093/intimm/dxh313

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Scott P, Novais FO (2016) Cutaneous leishmaniasis: immune responses in protection and pathogenesis. Nat Rev Immunol 16:581–592. https://doi.org/10.1038/nri.2016.72

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Moll H, Berberich C (2001) Dendritic cells as vectors for vaccination against infectious diseases. Int J Med Microbiol 291:323–329

    CAS  Article  Google Scholar 

  28. 28.

    Masic A, Hurdayal R, Nieuwenhuizen NE, Brombacher F, Moll H (2012) Dendritic cell-mediated vaccination relies on interleukin-4 receptor signaling to avoid tissue damage after Leishmania major infection of BALB/c mice. PLoS Negl Trop Dis 6:e1721. https://doi.org/10.1371/journal.pntd.0001721

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Agallou M, Smirlis D, Soteriadou KP, Karagouni E (2012) Vaccination with Leishmania histone H1-pulsed dendritic cells confers protection in murine visceral leishmaniasis. Vaccine 30:5086–5093. https://doi.org/10.1016/j.vaccine.2012.05.075

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Kling JC, Darby J, Korner H (2014) CCR30 facilitates the pro-inflammatory function of dendritic cells in experimental leishmaniasis. Parasite Immunol 36:177–185. https://doi.org/10.1111/pim.12097

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Cravens PD, Lipsky PE (2002) Dendritic cells, chemokine receptors and autoimmune inflammatory diseases. Immunol Cell Biol 80:497–505. https://doi.org/10.1046/j.1440-1711.2002.01118.x

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

We thank Adriana Ruiz Remigio for her technical assistance in the ELISA assays. This research was funded by Papiit, DGAPA, UNAM, Grant number IN-225116.

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Correspondence to Laila Gutiérrez-Kobeh.

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Gutiérrez-Kobeh, L., Wilkins-Rodríguez, A.A. GK1 Improves the Immune Response Induced by Dendritic Cells of BALB/c Mice Infected with Leishmania mexicana Promastigotes. Acta Parasit. 65, 27–35 (2020). https://doi.org/10.2478/s11686-019-00125-w

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Keywords

  • Dendritic cells
  • GK1
  • Leishmania mexicana