Efficacy and Safety of G2013 as a Novel Immunosuppressive Agent on Differentiation, Maturation and Function of Human Dendritic Cells
AbstractBackground: The expanse of dendritic cells (DC) differentiation plays an important role in determining immune response. DC-based immunosuppressive drugs have notable side effects in increasing the risk of infectious diseases and cancers. G2013, as a novel anti-inflammatory and immunosuppressive agent, has been tested in experimental model of multiple sclerosis. The aim of this study was to conduct the safety property of G2013 on dendritic cells biology.Methods: The effect of G2013 on differentiation, maturation, and function of dendritic cells was examined at Tehran University in 2014. To investigate how G2013 affects human dendritic cells (DC) in a defined inflammatory environment, human peripheral blood mononuclear cells (PBMC) were isolated from healthy blood. Monocytes were then purified using anti-CD14 microbeads. Monocytes were treated with G2013 in two different doses (6 and 12 μg/well) along with adding granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 for inducing monocytes to immature DC and adding lipopolysaccharide for running DC maturation. Differentiation, maturation, and function of dendritic cells were examined with flow cytometry and ELISA.Results: G2013 therapy had no significant effect on CD83, CD86 and DR expression, as well as IL-10 and IL-12 cytokine levels and it, has no remarkable side on differentiation, maturation and function of dendritic cells in immature DC and mature DC process in vitro.Conclusion: G2013 is a safe agent with no adverse effect on differentiation, maturation, and function of dendritic cells. It may be recommended as a novel immunosuppressive agent with no or little side effect in increasing the risk of infectious diseases and cancers.
Banchereau J, Steinman RM (1998). Dendritic cells and the control of immunity. Nature, 392:245-252.
Lee CW, Wang XD, Chien KL, Ge Z, Rickman BH, Rogers AB, Varro A, Whary MT, Wang TC, Fox JG (2008). Vitamin C supplementation does not protect L‐gulono‐γ‐lactone oxidase‐deficient mice from Helicobacter pylori‐induced gastritis and gastric premalignancy. Int J Cancer, 122:1068-1076.
Aldinucci A, Biagioli T, Manuelli C, Repice AM, Massacesi L, Ballerini C (2010). Modulating dendritic cells (DC) from immunogenic to tolerogenic responses: a novel mechanism of AZA/6-MP. J Neuroimmunol, 218:28-35.
Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu Y-J, Pulendran B, Palucka K (2000). Immunobiology of dendritic cells. Annu Rev Immunol, 18:767-811.
Tindle RW (2002). Immune evasion in human papillomavirus-associated cervical cancer. Nat Rev Cancer, 2:59-64.
De Smedt T, Van Mechelen M, De Becker G, Urbain J, Leo O, Moser M (1997). Effect of interleukin‐10 on dendritic cell maturation and function. Eur J Immunol, 27:1229-1235.
Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K (2010). Development of monocytes, macrophages, and dendritic cells. Science, 327:656-661.
Rovere P, Grazia Sabbadini M, Vallinoto C, Fascio U, Rescigno M, Crosti M, Ricciardi -Castagnoli P, Balestrieri G, Tincani A, Manfredi AA (1999). Dendritic cell presentation of antigens from apoptotic cells in a proinflammatory context: Role of opsonizing anti–β2-glycoprotein I antibodies. Arthritis Rheum, 42:1412-20.
Sidiropoulos P, Hatemi G, Song I-H, Avouac J, Collantes E, Hamuryudan V, Herold M, Kvien T, Mielants H, Mendoza J (2008). Evidence-based recommendations for the management of ankylosing spondylitis: systematic literature search of the 3E Initiative in Rheumatology involving a broad panel of experts and practising rheumatologists. Rheumatology (Oxford), 47:355-361.
Afraei S, Azizi G, Zargar SJ, Sedaghat R, Mirshafiey A (2015). New therapeutic approach by G2013 in experimental model of multiple sclerosis. Acta Neurol Belg, 115(3):259-66.
Sreevalsan T (2009). Isolation of dendritic cells from human blood for in vitro interaction studies with fungal antigens. Methods Mol Biol, 499:1-8.
Sher A, Pearce E, Kaye P (2003). Shaping the immune response to parasites: role of dendritic cells. Curr Opin Immunol, 15:421-429.
Kapsenberg ML (2003). Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol, 3:984-993.
Albert ML, Sauter B, Bhardwaj N (1998). Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature, 392:86-89.
Zhou L-J, Tedder TF (1996). CD14+ blood monocytes can differentiate into functionally mature CD83+ dendritic cells. Proc Natl Acad Sci U S A, 93:2588-2592.
Yu Y, Bae S, Kim H, Kim Y, Chu NB, Chu NK, Kang JS, Lee WJ (2011). The anti-tumor activity of vitamin C via the increase of Fas (CD95) and MHC I expression on human stomach cancer cell line, SNU1. Immune Network, 11:210-215.
Iijima N, Yanagawa Y, Iwabuchi K, Onoé K (2003). Selective regulation of CD40 expression in murine dendritic cells by thiol antioxidants. Immunology, 110:197-205.
Yao V, Platell C, Hall JC (2002). Dendritic cells. ANZ J Surg, 72:501-506.
Rissoan M-C, Soumelis V, Kadowaki N, Grouard G, Briere F, de Waal Malefyt R, Liu Y-J (1999). Reciprocal control of T helper cell and dendritic cell differentiation. Science, 283:1183-1186.
Steinman RM, Hawiger D, Nussenzweig MC (2003). Tolerogenic dendritic cells. Annu Rev Immunol, 21:685-711.