Top

Inflammopharmacology

Published in:

01-02-2020 | Cytokines | Original Article

Dendritic cells generated in the presence of interferon-α and modulated with dexamethasone as a novel tolerogenic vaccine platform

Authors: Olga Leplina, Yulia Kurochkina, Marina Tikhonova, Ekaterina Shevela, Alexandr Ostanin, Elena Chernykh

Published in: Inflammopharmacology | Issue 1/2020

Abstract

Background

Tolerogenic dendritic cells (tDCs) are considered a novel therapeutic tool in treating autoimmune diseases, allergies, and transplantation reactions. Among numerous pharmacological immune modulators, dexamethasone (Dex) is known to induce potent tolerogenicity in DCs generated from human monocytes with granulocyte–macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4), and these cells (IL-4-DCs/Dex) are being appraised as a tDC-based platform in clinical settings. Interferon-α (IFNα) represents another powerful inducer of monocyte-derived DCs, which possess higher migratory activity and stability. However, the functions of IFN-DCs/Dex have not been sufficiently analyzed and there are no comparative studies of the tolerogenicity of IFN-DCs/Dex and IL-4-DCs/Dex. This study aimed to investigate the properties of IFN-DCs/Dex in comparison with IL-4-DCs/Dex.

Results

DCs were obtained by cultivation of an adherent fraction of peripheral blood mononuclear cells (MNCs) in the presence of GM-CSF and IFNα or IL-4 with subsequent lipopolysaccharide-driven maturation. Dex (10⁻⁶ M) was added to the cultures at day 3. We showed that generation of IFN-DCs with Dex resulted in decrease in percentage of CD83⁺ and CD86⁺ DCs and increase in numbers of CD14⁺, B7-H1⁺, and Toll-like receptor 2 (TLR2⁺) DCs. Treatment with Dex downregulated pro-inflammatory cytokine production, reduced DC allostimulatory activity, and inhibited DC capacity to stimulate Th1/pro-inflammatory cytokine production, altogether evidencing the induction of a tolerogenic phenotype. As compared to IL-4-DCs/Dex, IFN-DCs/Dex were characterized by larger proportion of TLR2⁺ and CD14⁺ cells, higher production of IL-10 and lower TNFα/IL-10 ratio, more potent capacity to induce T cell anergy, and more efficiently skewed T cell cytokine balance towards Th2/anti‐inflammatory profile.

Conclusions

The data obtained indicate that potent tDCs could be generated by treating IFN-DCs with dexamethasone. The tolerogenic properties of IFN-DCs/Dex are better than or at least equal to those of the IL-4-DCs/Dex, as assessed by in vitro phenotypic and functional assays, suggesting these cells as a new tolerogenic vaccine platform.

Canning M, Grotenhuis K, de Wit H, Drexhage H (2000) Opposing effects of dehydroepiandrosterone and dexamethasone on the generation of monocyte-derived dendritic cells. Eur J Endocrinol 143:687–695CrossRef

Chamorro S (2009) TLR triggering on tolerogenic dendritic cells results in TLR2 up-regulation and a reduced proinflammatory immune program. J Immunol 183:2984–2994CrossRef

Della Bella S, Nicola S, Riva A, Biasin M, Clerici M, Villa M (2004) Functional repertoire of dendritic cells generated in granulocyte macrophage-colony stimulating factor and interferon-alpha. J Leukoc Biol 75:106–116CrossRef

Domogalla MP, Rostan PV, Raker VK, Steinbrink K (2017) Tolerance through education: how tolerogenic dendritic cells shape immunity. Front Immunol 8:1764. https://doi.org/10.3389/fimmu.2017.01764.eCollection CrossRefPubMedPubMedCentral

Franzke A, Piao W, Lauber J, Gatzlaff P, Kцnecke C, Hansen W, Schmitt-Thomsen A, Hertenstein B, Buer J, Ganser A (2003) G-CSF as immune regulator in T cells expressing the G-CSF receptor: implications for transplantation and autoimmune diseases. Blood 102(2):734–739CrossRef

Garcia-Gonzalez P, Morales R, Hoyos L, Maggi J, Campos J, Pesce B, Gárate D, Larrondo M, González R, Soto L, Ramos V, Tobar P, Molina MC, Pino-Lagos K, Catalán D, Aguillyn JC (2013) A short protocol using dexamethasone and monophosphoryl lipid A generates tolerogenic dendritic cells that display a potent migratory capacity to lymphoid chemokines. J Transl Med 11:128. https://doi.org/10.1186/1479-5876-11-128 CrossRefPubMedPubMedCentral

Gessani S, Conti L, Del Cornt M, Belardelli F (2014) Type I interferons as regulators of human antigen presenting cell functions. Toxins (Basel) 6:1696–1723CrossRef

Gordon J, Ma Y, Churchman L, Gordon S, Dawicki W (2014) Regulatory dendritic cells for immunotherapy in immunologic diseases. Front Immunol 5:7. https://doi.org/10.3389/fimmu.2014.00007 CrossRefPubMedPubMedCentral

Gottenberg J, Chiocchia G (2007) Dendritic cells and interferon-mediated autoimmunity. Biochimie 89:856–871CrossRef

Harry R, Anderson A, Isaacs J, Hilkens C (2010) Generation and characterization of therapeutic tolerogenic dendritic cells for rheumatoid arthritis. Ann Rheum Dis 69:2042–2050CrossRef

Hartung T, Docke W, Gantner F, Krieger G, Sauer A, Stevens P, Volk H, Wendel A (1995) Effect of granulocyte colony-stimulating factor treatment on ex vivo blood cytokine response in human volunteers. Blood 85:2482–2489CrossRef

Hilkens C, Isaacs J (2010) Tolerogenic dendritic cells in clinical practice. Open Arthritis J 3:8–12CrossRef

Hilkens C, Isaacs J, Thomson A (2010) Development of dendritic cell-based immunotherapy for autoimmunity. Int Rev Immunol 29:156–183CrossRef

Hubo M, Trinschek B, Kryczanowsky F, Tuettenberg A, Steinbrink K, Jonuleit H (2013) Costimulatory molecules on immunogenic versus tolerogenic human dendritic cells. Front Immunol 4:82. https://doi.org/10.3389/fimmu.2013.00082 CrossRefPubMedPubMedCentral

Kurochkina Y, Leplina O, Tikhonova M, Tyrinova T, Batorov E, Sizikov A, Ostanin A, Chernykh E (2016) Effect of dexamethasone on interferon-α-induced differentiation of monocytes to dendritic cells. Med Immunol 18(4):347–356. https://doi.org/10.15789/1563-0625-2016-4-347-356 (in Russian)CrossRef

Manoharan I, Hong Y, Suryawanshi A, Angus-Hill M, Sun Z, Mellor AL, Munn D, Manicassamy S (2014) TLR2-dependent activation of β-catenin pathway in dendritic cells induces regulatory responses and attenuates autoimmune inflammation. J Immunol 193(8):4203–4213. https://doi.org/10.4049/jimmunol.1400614 CrossRefPubMedPubMedCentral

Matasić R, Dietz A, Vuk-Pavlovic S (1999) Dexamethasone inhibits dendritic cell maturation by redirecting differentiation of a subset of cells. J Leukoc Biol. 66:909–914CrossRef

Morris E, MacDonald K, Rowe V, Johnson D, Banovic T, Clouston A, Hill G (2004) Donor treatment with pegylated G-CSF augments the generation of IL-10-producing regulatory T cells and promotes transplantation tolerance. Blood 103:3573–3581CrossRef

Naranjo-Gymez M, Raпch-Reguй D, Onate C, Grau-Lypez L, Ramo-Tello C, Pujol-Borrell R, Martнnez-Cáceres E, Borras FE (2011) Comparative study of clinical grade human tolerogenic dendritic cells. J Transl Med 9:89CrossRef

Osorio F, Fuentes C, Lypez MN, Salazar-Onfray F, Gonzalez FE (2015) Role of dendritic cells in the induction of lymphocyte tolerance. Front Immunol 6:535. https://doi.org/10.3389/fimmu.2015.00535.eCollection CrossRefPubMedPubMedCentral

Paquette R, Hsu N, Kiertscher S, Park A, Tran L, Roth M, Glaspy J (1998) Interferon-alpha and granulocyte-macrophage colony-stimulating factor differentiate peripheral blood monocytes into potent antigen-presenting cells. J Leukoc Biol 64:358–367CrossRef

Piemonti L, Monti P, Allavena P, Sironi M, Soldini L, Leone B, Socci C, Di Carlo V (1999) Glucocorticoids affect human dendritic cell differentiation and maturation. J Immunol 162:6473–6481PubMed

Rea D, van Kooten C, van Meijgaarden K, Melief Offringa R (2000) Glucocorticoids transform CD40-triggering of dendritic cells into an alternative activation pathway resulting in antigen presenting cells that secrete IL-10. Blood 95:3162–3167CrossRef

Rozkova D, Horvath R, Bartunkova J, Spisek R (2006) Glucocorticoids severely impair differentiation and antigen presenting function of dendritic cells despite up-regulation of Toll-like receptors. Clin Immunol 120:260–271CrossRef

Sagiv-Barfi I, Czerwinski D, Levy S, Alam I, Mayer A, Gambhir S, Levy R (2018) Eradication of spontaneous malignancy by local immunotherapy. Sci Transl Med 10:eaan4488CrossRef

Santini S, Lapenta C, Logozzi M, Parlato S, Spada M, di Pucchio T, Belardelli F (2000) Type I interferon as a powerful adjuvant for monocyte-derived dendritic cell development and activity in vitro and in Hu-PBL-SCID mice. J Exp Med 191:1777–1788CrossRef

Thomson A, Robbins P (2008) Tolerogenic dendritic cells for autoimmune disease and transplantation. Ann Rheum Dis 67(Suppl 3):90–96CrossRef

Thurner B, Rцder C, Dieckmann D, Heuer M, Kruse M, Glaser A, Keikavoussi P, Kдmpgen E, Bender A, Schuler G (1999) Generation of large numbers of fully mature and stable dendritic cells from leukapheresis products for clinical application. J Immunol Methods 223:1–15CrossRef

Ukyo N, Hori T, Yanagita S, Ishikawa T, Uchiyama T (2003) Costimulation through OX40 is crucial for induction of an alloreactive human T-cell response. Immunology 109(2):226–231CrossRef

Unger W, Laban S, Kleijwegt F, van der Slik A, Roep B (2009) Induction of T-reg by monocyte-derived DC modulated by vitamin D3 or dexamethasone: differential role for PD-L1. Eur J Immunol 39:3147–3159CrossRef

Valente J, Alexander J, Li B, Noel J, Custer D, Ogle J, Ogle C (2002) Effect of in vivo infusion of granulocyte colony-stimulating factor on immune function. Shock 17:23–29CrossRef

Van Kooten C, Stax A, Woltman A, Gelderman K (2009) Handbook of experimental pharmacology “dendritic cells”: the use of dexamethasone in the induction of tolerogenic DCs. Handb Exp Pharmacol 188:233–249. https://doi.org/10.1007/978-3-540-71029-5-11 CrossRef

Woltman A, Vander Kooij S, De Fijter J, van Kooten C (2006) Maturation-resistant dendritic cells induce hyporesponsiveness in alloreactive CD45RA⁺ and CD45RO⁺T-cell populations. Am J Transplant 6:2580–2591CrossRef

Xia CQ, Peng R, Beato F, Clare-Salzler M (2005) Dexamethasone induces IL-10-producing monocyte-derived dendritic cells with durable immaturity. Scand J Immunol 62:45–54CrossRef

Title: Dendritic cells generated in the presence of interferon-α and modulated with dexamethasone as a novel tolerogenic vaccine platform
Authors: Olga Leplina
Yulia Kurochkina
Marina Tikhonova
Ekaterina Shevela
Alexandr Ostanin
Elena Chernykh
Publication date: 01-02-2020
Publisher: Springer International Publishing
Keywords: Cytokines
Interferon
Dexamethasone
Published in: Inflammopharmacology / Issue 1/2020
Print ISSN: 0925-4692
Electronic ISSN: 1568-5608
DOI: https://doi.org/10.1007/s10787-019-00641-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Dendritic cells generated in the presence of interferon-α and modulated with dexamethasone as a novel tolerogenic vaccine platform

Abstract

Background

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2020

In vivo antiulcer activity, phytochemical exploration, and molecular modelling of the polyphenolic-rich fraction of Crepis sancta extract

Anti-inflammatory drugs in the prevention of post-operative atrial fibrillation: a literature review

Therapeutic potential of IKK-β inhibitors from natural phenolics for inflammation in cardiovascular diseases

Flavonoids from Rhynchosia minima root exerts anti-inflammatory activity in lipopolysaccharide-stimulated RAW 264.7 cells via MAPK/NF-κB signaling pathway

Thiamine, riboflavin, and nicotinamide inhibit paclitaxel-induced allodynia by reducing TNF-α and CXCL-1 in dorsal root ganglia and thalamus and activating ATP-sensitive potassium channels

Efficacy of preemptive analgesia versus postoperative analgesia of celecoxib on postoperative pain, patients’ global assessment and hip function recovery in femoroacetabular impingement patients underwent hip arthroscopy surgery