Skip to main content

Advertisement

Log in

The Molecular Influence of Graphene and Graphene Oxide on the Immune System Under In Vitro and In Vivo Conditions

  • Review
  • Published:
Archivum Immunologiae et Therapiae Experimentalis Aims and scope

Abstract

Graphene and graphene oxide (GO), due to their physicochemical properties and biocompatibility, can be used as an innovative biomedical material in biodetection, drug distribution in the body, treating neoplasms, regenerative medicine, and in implant surgery. Research on the biomedical use of graphene and GO that has been carried out until now is very promising and shows that carbon nanomaterials present high biocompatibility. However, the intolerance of the immune system to graphene nanomaterials, however low, may in consequence make it impossible to use them in medicine. This paper shows the specific mechanism of the molecular influence of graphene and GO on macrophages and lymphocytes under in vitro and in vivo conditions and their practical application in medicine. Under in vitro conditions graphene and GO cause an increased production of pro-inflammatory cytokines, mainly IL-1, IL-6, IL-10 and TNF-α, as a result of the activation of Toll-like receptors in macrophages. Graphene activates apoptosis in macrophages through the TGFbr/Smad/Bcl-2 pathway and also through JNK kinases that are stimulated by an increase of ROS in the cell or through a signal received by Smad proteins. Under in vivo conditions, graphene nanomaterials induce the development of the local inflammatory reaction and the development of granulomas in parenchymal organs. However, there is a huge discrepancy between the results obtained by different research groups, which requires a detailed analysis. In this work we decided to collect and analyze existing research and tried to explain the discrepancies. Understanding the precise mechanism of how this nanomaterial influences immune system cells allows estimating the potential influence of grapheme and GO on the human body.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Andersen PS, Menné C, Mariuzza RA et al (2001) A response calculus for immobilized T cell receptor ligands. J Biol Chem 276:49125–49132

    Article  CAS  PubMed  Google Scholar 

  • Bai JW, Zhong X, Jiang S et al (2010) Graphene nanomesh. Nat Nanotechnol 5:190–194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Balandin AA, Ghosh S, Bao W et al (2008) Superior thermal conductivity of single-layer graphene. Nano Lett 8:902–907

    Article  CAS  PubMed  Google Scholar 

  • Bao HQ, Pan YZ, Ping Y et al (2011) Chitosan-functionalized graphene oxide as a nanocarrier for drug and gene delivery. Small 7:1569–1578

    Article  CAS  PubMed  Google Scholar 

  • Beek JJ, Wimmers F, Hato SV et al (2014) Dendritic cell cross talk with innate and innate-like effector cells in antitumor immunity: implications for DC vaccination. Crit Rev Immunol 34:517–536for drug and gene delivery. Small 7:1569–1578

    Google Scholar 

  • Bianco A, Kostarelos K, Prato M (2011) Making carbon nanotubes biocompatible and biodegradable. Chem Commun 47:10182–10188

    Article  CAS  Google Scholar 

  • Billiau P, Matthys P (2009) Interferon-gamma: a historical perspective. Cytokine Growth Factor Rev 20:97–113

    Article  CAS  PubMed  Google Scholar 

  • Bitounis D, Ali-Boucetta H, Hee B et al (2013) Prospects and challenges of graphene in biomedical applications. Adv Mater 25:2258–2268

    Article  CAS  PubMed  Google Scholar 

  • Bolotin KI, Sikes KJ, Jiang Z (2008) Ultrahigh electron mobility in suspended graphene. State Commun 146:351–355

    Article  CAS  Google Scholar 

  • Bussy C, Ali-Boucetta H, Kostarelos K (2012) Safety considerations for graphene: lessons learnt from carbon nanotubes. Acc Chem Res 46:692–701

    Article  PubMed  CAS  Google Scholar 

  • Cai W, Zhu Z, Li X (2009) Large area few-layer graphene/graphite films as transparent thin conducting electrodes. Phys Lett 95:123115

    Google Scholar 

  • Cargnello M, Roux PP (2011) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 75:50–83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang CK, Wu JS, Mao D et al (2002) Mechanical and histological evaluations of hydroxyapatite coated dnd noncoated TiA14V implants in tibia bone. J Biomed Mater Res 56:17–23

    Article  Google Scholar 

  • Chang Y, Yang ST, Liu JH (2011) In vitro toxicity evaluation of graphene oxide on A549 cells. Toxicol Lett 200:201–210

    Article  CAS  PubMed  Google Scholar 

  • Chatterjee N, Eom HJ, Choi J (2014) A systems toxicology approach to the surface functionality control of graphene cell interaction. Biomaterials 35:1109–1127

    Article  CAS  PubMed  Google Scholar 

  • Chen B, Liu M, Zhang LM et al (2011) Polyethylenimine-functionalized graphene oxide as an efficient gene delivery vector. J Mater Chem 21:7736–7741

    Article  CAS  Google Scholar 

  • Chen GY, Yang H, Lu Ch et al (2012) Simultaneous induction of autophagy and toll-like receptor signaling pathways by graphene oxide. Biomaterials 33:6559–6569

    Article  CAS  PubMed  Google Scholar 

  • Chen B, Liu L, Xu H et al (2015) Effectiveness of immune therapy combined with chemotherapy on the immune function and recurrence rate of cervical cancer. Exp Ther Med 9:1063–1067

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chipuk J, Bouchier-Hayes L, Green D (2006) Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario. Cell Death Differ 13:1396–1402

    Article  CAS  PubMed  Google Scholar 

  • Chithrani BD, Chan WC (2007) Elucidating the mechanism of cellular uptake and removal of protein-coated gold nanoparticles of different sizes and shapes. Nano Lett 7:1542–1550

    Article  CAS  PubMed  Google Scholar 

  • Choe J, Obmolova G, Malia TJ et al (2005) Crystal structure of human Toll-like receptor 3 (TLR3) ectodomain. Science 309:581–585

    Article  CAS  PubMed  Google Scholar 

  • Chong Y, Ma Y, Shen H et al (2014) The in vitro and in vivo toxicity of graphene quantum dots. Biomaterials 19:5041–5048

    Article  CAS  Google Scholar 

  • Chung Ch, Kim YK, Shin D (2013) Biomedical applications of graphene and graphene oxide. Acc Chem Res 46:2211–2224

    Article  CAS  PubMed  Google Scholar 

  • Coccini T, Roda E, Barni S et al (2013) Morphological and cytohistochemical evaluation of renal effects of cadmium-doped silica nanoparticles given intratracheally to rat. J Phys Conf Ser 429:1–8

    Article  CAS  Google Scholar 

  • Cortés I, Pérez-Camarero S, Del LJ et al (2013) Systematic review of economic evaluation analyses of available vaccines in Spain from 1990 to 2012. Vaccine 31:3473–3484

    Article  PubMed  Google Scholar 

  • Cui D, Tian F, Ozkan CS (2005) Effect of single wall carbon nanotubes on human HEK293 cells. Toxicol Lett 155:73–85

    Article  CAS  PubMed  Google Scholar 

  • Das S, Singh S, Singh V et al (2013) Oxygenated functional group density on graphene oxide: its effect on cell toxicity. Part Part Syst Charact 30:148–157

    Article  CAS  Google Scholar 

  • Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103:239–252

    Article  CAS  PubMed  Google Scholar 

  • Devasagayam TP, Tilak JC, Boloor KK et al (2004) Free radicals and antioxidants in human health: current status and future prospect. J Assoc Physicians India 52:794–804

    CAS  PubMed  Google Scholar 

  • Dikin DA, Stankovich S, Zimney EJ (2007) Preparation and characterization of graphene oxide paper. Nature 448:457–460

    Article  CAS  PubMed  Google Scholar 

  • Ding Z, Zhang Z, Ma H et al (2014) In vitro hemocompatibility and toxic mechanism of graphene oxide on human peripheral blood t lymphocytes and serum albumin. ACS Appl Mater Interfaces 6:19797–19807

    Article  CAS  PubMed  Google Scholar 

  • Dobrovolskaia MA, Germolec DR, Weaver JL (2009) Evaluation of nanoparticle immunotoxicity. Nat Nanotechnol 4:411–414

    Article  CAS  PubMed  Google Scholar 

  • Donaldson K, Stone V, Tran L et al (2004) Nanotoxicology. Occup Environ Med 61:727–728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Doyle S (2002) IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 17:251–263

    Article  CAS  PubMed  Google Scholar 

  • Dror-Ehre A, Mamane H, Belenkova T et al (2011) Graphene oxide: a nonspecific enhancer of cellular grow. ASCNANO 10:8100–8107

    Google Scholar 

  • Duch MC, Budinger GR, Liang YT et al (2011) Minimizing oxidation and stable nanoscale dispersion improves the biocompatibility of graphene in the lung. Nano Lett 11:5201–5207

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dudley ME, Rosenberg SA (2003) Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat Rev Cancer 3:666–675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dutta D, Sundaram SK, Teeguarden JG et al (2007) Adsorbed proteins influence the biological activity and molecular targeting of nanomaterials. Toxicol Sci 100:303–315

    Article  CAS  PubMed  Google Scholar 

  • Erickson K, Erni R, Lee Z (2010) Determination of the local chemical structures of graphen oxide and reduce graphene oxide. Adv Mater 22:4467–4472

    Article  CAS  PubMed  Google Scholar 

  • Fadel TR, Fahmy TM (2014) Immunotherapy applications of carbon nanotubes: from design to safe applications. Trends Biotechnol 32:198–209

    Article  CAS  PubMed  Google Scholar 

  • Fadel TR, Sharp FA, Vudattu N et al (2014) A carbon nanotube–polymer composite for T-cell therapy. Nat Nanotechnol 9:639–647

    Article  CAS  PubMed  Google Scholar 

  • Feng LZ, Liu Z (2011) Graphene in biomedicine: opportunities and challenges. Nanomedicine 6:317–324

    Article  CAS  PubMed  Google Scholar 

  • Foged C, Brodin B, Frokjaer S et al (2005) Particle size and surface charge affect particle uptake by human dendritic cells in an in vitro model. Int J Pharm 298:315–322

    Article  CAS  PubMed  Google Scholar 

  • Gao N, Zhang Q, Mu Q et al (2011) Steering carbon nanotubes to scavenger receptor recognition by nanotube surface chemistry modification partially alleviates NFkappaB activation and reduces its immunotoxicity. ACS Nano 5:4581–4591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Geim AK, Novoselov KS (2007) The rise of graphene. Nat Mater 6:183–191

    Article  CAS  PubMed  Google Scholar 

  • Geyer M, Pelka K, Latz E (2015) Synergistic activation of Toll-like receptor 8 by two RNA degradation products. Nat Struct Mol Biol 22:99–101

    Article  CAS  PubMed  Google Scholar 

  • Ghavami S, Hashemi M, Ande SR et al (2009) Apoptosis and cancer: mutations within caspase genes. J Med Genet 46:497–510

    Article  CAS  PubMed  Google Scholar 

  • González PA, Carreño LJ, Coombs D et al (2005) T cell receptor binding kinetics required for T cell activation depend on the density of cognate ligand on the antigen-presenting cell. Proc Natl Acad Sci USA 102:4824–4829

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hasan K, Sandberg MO, Nur O et al (2011) Polycation stabilization of graphene suspensions. Nanoscale Res Lett 6:493

    Article  CAS  Google Scholar 

  • Hejiang Z, Bo Z, Jiajia Z et al (2014) The inhibition of migration and invasion of cancer cells by graphene via the impairment of mitochondrial respiration. Biomaterials 35:1597–1607

    Article  CAS  Google Scholar 

  • Hengartner MO (2000) The biochemistry of apoptosis. Nature 407:770–776

    Article  CAS  PubMed  Google Scholar 

  • Jain KK (2009) Role of nanobiotechnology in the development of personalized medicine. Nanomedicine 4:249–252

    Article  CAS  PubMed  Google Scholar 

  • James MA (2001) Biological responses to materials. Annu Rev Mater Res 31:81–110

    Article  Google Scholar 

  • Jastrzębska A, Kurtycz P, Olszyna AR (2012) Recent advances in graphene family materials toxicity investigations. J Nanopart Res 14:1320

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jędrasiak U, Kępińska M (2011) Role of macrophages in immunological reactions of perinatal period. Nowa Pediatria 4:26–29

    Google Scholar 

  • Jung T, Kamm W, Breitenbach A et al (2001) Tetanus toxoid loaded nanoparticles from sulfobutylated poly(vinyl alcohol)-graft-poly(lactide-co-glycolide): evaluation of antibody response after oral and nasal application in mice. Pharm Res 18:352–360

    Article  CAS  PubMed  Google Scholar 

  • Jurk M, Heil F, Vollmer J et al (2002) Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol 3:499

    Article  CAS  PubMed  Google Scholar 

  • Kanakia S, Toussaint JD, Chowdhury SM (2014) Dose ranging, expanded acute toxicity and safety pharmacology studies for intravenously administered functionalized graphene nanoparticle formulations. Biomaterials 25:7022–7031

    Article  CAS  Google Scholar 

  • Kapai NA, Anisimova NY, Kiselevskii MV et al (2011) Selective cytokine-inducing effects of low dose Echinacea. Bull Exp Biol Med 150:711–713

    Article  CAS  PubMed  Google Scholar 

  • Kawai T, Akira S (2007) Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med 13:460–469

    Article  CAS  PubMed  Google Scholar 

  • Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11:373–384

    Article  CAS  PubMed  Google Scholar 

  • Kim TH, Namgung R, Singha K et al (2011) Graphene oxide-polyethylenimine nanoconstruct as a gene delivery vector and bioimaging tool. Bioconjug Chem 22:2558–2567

    Article  CAS  PubMed  Google Scholar 

  • Kochat V, Nath A, Sneha SE et al (2011) High contrast imaging and thickness determination of graphene with in-column secondary electron microscopy. J Appl Phys 110:1–5

    Article  CAS  Google Scholar 

  • Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87:99–163

    Article  CAS  PubMed  Google Scholar 

  • Kulia T, Bosea S, Mishrab AK et al (2012) Chemical functionalization of graphene and its applications. Prog Mater Sci 57:1061–1105

    Article  CAS  Google Scholar 

  • Lacerda L, Biancob A, Pratoc M et al (2006) Carbon nanotubes as nanomedicines: from toxicology to pharmacology. Adv Drug Deliv Rev 58:1460–1470

    Article  CAS  PubMed  Google Scholar 

  • Lacotte S, García A, Décossas M et al (2008) Interfacing functionalized carbon nanohorns with primary phagocytic cells. Adv Mater 20:2421–2426

    Article  CAS  Google Scholar 

  • Lallemand F, Mazars A, Prunier C et al (2001) Smad7 inhibits the survival nuclear factor kappa B and potentiates apoptosis in epithelial cells. Oncogene 20:879–884

    Article  CAS  PubMed  Google Scholar 

  • Lam CW, James JT, McCluskey R et al (2004) Pulmonary toxicity of single-wall carbon nanotubes in mice 7 and 90 days after intratracheal instillation. Toxicol Sci 77:126–134

    Article  CAS  PubMed  Google Scholar 

  • Lan RY, Selmi C, Gershwin ME (2008) The regulatory, inflammatory, and T cell programming roles of interleukin-2 (IL-2). J Autoimmun 31:7–12

    Article  CAS  PubMed  Google Scholar 

  • Lauw FN, Caffrey DR, Golenbock DT et al (2005) Of mice and man: TLR11 (finally) finds profiling. Trends Immunol 26:509–511

    Article  CAS  PubMed  Google Scholar 

  • Li D, Mueller MB, Gilje S (2008) Processable aqueous dispersions of graphene nanosheet. Nat Nanotechnol 3:101–105

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Liu Y, Fu Y et al (2012) The triggering of apoptosis in macrophages by pristine graphene through the MAPK and TGF-beta signaling pathways. Biomaterials 33:402–411

    Article  PubMed  CAS  Google Scholar 

  • Li N, Zhang Q, Gao S et al (2013a) Three-dimensional graphene foam as abiocompatible and conductive scaffold for neural stemcells. Sci Rep 3:1604

    PubMed  PubMed Central  Google Scholar 

  • Li Y, Yuan H, von dem Bussche A et al (2013b) Graphene microsheets enter cells through spontaneous membrane penetration at edge asperities and corner sites. Proc Natl Acad Sci USA 110:12295–12300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Z, Robinson JT, Sun X et al (2008) PEGylated nano-graphene oxide for delivery of water insoluble cancer drugs. J Am Chem Soc 130:10876–10877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu K, Zhang JJ, Cheng FF (2011a) Green and facile synthesis of highly biocompatible graphene nanosheets and its application for cellular imaging and drug delivery. J Mater Chem 21:12034–12040

    Article  CAS  Google Scholar 

  • Liu S, Zeng TH, Hofmann M et al (2011b) Antibacterial activity of graphite, graphite oxide, graphene oxide, and reduced graphene oxide: membrane and oxidative stress. ACS Nano 5:6971–6980

    Article  CAS  PubMed  Google Scholar 

  • Liu Z, Robinson JT, Tabakman SM et al (2011c) Carbon materials for drug delivery and cancer therapy. Mat Today 14:316–323

    Article  CAS  Google Scholar 

  • Liu B, Zhang J, Liao J et al (2014) Aptamer-functionalized nanoparticles for drug delivery. J Biomed Nanotechnol 10:3189–3203

    Article  CAS  PubMed  Google Scholar 

  • Lockshin RA, Zakeri Z (2001) Programmed cell death and apoptosis: origins of the theory. Nat Rev Mol Cell Biol 2:545–550

    Article  CAS  PubMed  Google Scholar 

  • Lu CH, Yang HH, Zhu CL (2009) A graphene platform for sensing biomolecules. Angew Chem Int Ed Engl 48:4785–4787

    Article  CAS  PubMed  Google Scholar 

  • Luo N, Ni D, Yue H (2015) Surface-engineered graphene navigate divergent biological outcomes toward macrophages. ACS Appl Mater Interfaces 7:5239–5247

    Article  CAS  PubMed  Google Scholar 

  • Lutsiak ME, Kwon GS, Samuel J (2006) Biodegradable nanoparticle delivery of a Th2-biased peptide for induction of Th1 immune responses. J Pharm Pharmacol 58:739–747

    Article  CAS  PubMed  Google Scholar 

  • Majewska M, Szczepanik M (2006) [The role of Toll-like receptors (TLR) in innate and adaptive immune responses and their function in immune response regulation] (in Polish). Postepy Hig Med Dosw 60:52–63

    Google Scholar 

  • Malek TR (2014) The biology of interleukin-2. Annu Rev Immunol 26:453–479

    Article  CAS  Google Scholar 

  • Malhotra S, Kovats S, Zhang W, Coggeshall KM (2009) B cell antigen receptor endocytosis and antigen presentation to T cells require Vav and dynamin. J Biol Chem 284:24088–24097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mao HY, Laurent S, Chen W et al (2013) Graphene: promises, facts, opportunities, and challenges in nanomedicine. Chem Rev 113:3407–3424

    Article  CAS  PubMed  Google Scholar 

  • Markovic ZM, Harhaji-Trajkovic LM, Todorovic-Markovic BM et al (2011) In vitro comparison of the photothermal anticancer activity of graphene nanoparticles and carbon nanotubes. Biomaterials 32:1121–1129

    Article  CAS  PubMed  Google Scholar 

  • Matsuo K, Koizumi H, Akashi M et al (2011) Intranasal immunization with poly(gamma-glutamic acid) nanoparticles entrapping antigenic proteins can induce potent tumor immunity. J Control Release 152:310–316

    Article  CAS  PubMed  Google Scholar 

  • Misterka S, Paluch D, Zywicka B et al (1998) [Changes in the level of interleukin-1 beta and interleukin-6 after implantation of selected medical materials. Introductory report] (in Polish). Polim Med 28:15–24

    CAS  PubMed  Google Scholar 

  • Mondal J, Avijit R, Nikhil R et al (2014) Graphene-nanoparticle composites and their applications in energy, environmental and biomedical science. Rev Nanosci Nanotechnol 16:177–192

    Article  CAS  Google Scholar 

  • Morozov SV, Novoselov KS, Katsnelson MI et al (2008) Giant intrinsic carrier mobilities in graphene and its bilayer. Phys Rev Lett 100:016602

    Article  CAS  PubMed  Google Scholar 

  • Nagasae M, Udagawa E, Schumacher HR et al (1990) Prolonged Inflammatory reactions induced by ceramic powders the rat pouch model. Nihon Seikeigeka Gakkai Zasshi 64:602–611

    Google Scholar 

  • Nalwa HS (2014a) A special issue on reviews in biomedical applications of nanomaterials, tissue engineering, stem cells, bioimaging, and toxicity. J Biomed Nanotechnol 10:2421–2423

    Article  CAS  PubMed  Google Scholar 

  • Nalwa HS (2014b) A special issue on reviews in nanomedicine, drug delivery and vaccine development. J Biomed Nanotechnol 10:1635–1640

    Article  CAS  PubMed  Google Scholar 

  • Nanda SS, An SS, Yi DK (2015) Oxidative stress and antibacterial properties of a graphene oxide-cystamine nanohybrid. Int J Nanomedicine 10:549–556

    PubMed  PubMed Central  Google Scholar 

  • Nemazee D, Gavin A, Hoebe K et al (2006) Immunology: toll-like receptors and antibody responses. Nature 441:E4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ni G, Wang Y, Wu X et al (2012) Graphene oxide absorbed anti-IL10R antibodies enhance LPS induced immune responses in vitro and in vivo. Immunol Let 148:126–132

    Article  CAS  Google Scholar 

  • Nishiya T, DeFranco AL (2004) Ligand-regulated chimeric receptor approach reveals distinctive subcellular localization and signaling proper ties of the Toll-like receptors. J Biol Chem 279:19008–19017

    Article  CAS  PubMed  Google Scholar 

  • Noguchi T, Ishii K, Fukutomi H et al (2008) Requirement of reactive oxygen species-dependent activation of ASK1-p38 MAPK pathway for extracellular ATP-induced apoptosis in macrophage. J Biol Chem 283:7657–7665

    Article  CAS  PubMed  Google Scholar 

  • Orecchioni M, Bedognetti D, Sgarrella F et al (2014) Impact of carbon nanotubes and graphene on immune cells. J Transl Med 12:138

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ozinsky A (2000) The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc Natl Acad Sci USA 97:13766–13771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pardoll DM (2002) Spinning molecular immunology into successful immunotherapy. Nat Rev Immunol 2:227–238

    Article  CAS  PubMed  Google Scholar 

  • Park S, An J, Jung I et al (2009) Colloidal suspensions of highly r educed graphene oxide in a wide variety of organic solvents. Nano Lett 9:1593–1597

    Article  CAS  PubMed  Google Scholar 

  • Pescatori M, Bedognetti D, Venturelli E et al (2013) Functionalized carbon nanotubes as immunomodulator systems. Biomaterials 34:4395–4403

    Article  CAS  PubMed  Google Scholar 

  • Pinto A, Inês C (2013) Graphene-based materials biocompatibility: a review. Colloids Surf B Biointerfaces 111:188–202

    Article  CAS  PubMed  Google Scholar 

  • Porter AE, Gass M, Muller K et al (2007) Direct imaging of single-walled carbon nanotubes in cells. Nat Nanotechnol 2:713–717

    Article  CAS  PubMed  Google Scholar 

  • Qu G, Liu S, Zhang S et al (2013) Graphene oxide induces Toll-like receptor 4 (TLR4)-dependent necrosis in macrophages. ACS Nano 7:5732–5745

    Article  CAS  PubMed  Google Scholar 

  • Ramesh S, Wildey GM, Howe PH (2009) Transforming growth factor beta (TGF-beta)-apoptosis the rise and fall of bim. Cell Cycle 8:11–17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rana VK, Choi MC, Kong JY et al (2011) Synthesis and drug-delivery behavior of chitosan-functionalized graphene oxide hybrid nanosheets. Macromol Mater Eng 296:131–140

    Article  CAS  Google Scholar 

  • Rashid H, Khandaker G, Booy R (2012) Vaccination and herd immunity: what more do we know? Curr Opin Infect Dis 25:243–249

    Article  CAS  PubMed  Google Scholar 

  • Resende RR, Fonseca EA, Tonelli MP et al (2014) Scale/topography of substrates surface resembling extracellular matrix for tissue engineering. J Biomed Nanotechnol 10:1157–1193

    Article  CAS  PubMed  Google Scholar 

  • Ribeiro AM, Souza O, Amaral AC et al (2013) Nanobiotechnological approaches to delivery of dna vaccine against fungal infection. J Biomed Nanotechnol 9:221–230

    Article  CAS  PubMed  Google Scholar 

  • Rochefort A, Wuest JD (2009) Interaction of substituted aromatic compounds with graphene. Langmuir 25:210–215

    Article  CAS  PubMed  Google Scholar 

  • Russier J, Ei Treoss, Scarsi A (2013) Evidencing the mask effect of graphene oxide: a comparative study on primary human and murine phagocytic cells. Nanoscale 5:11234–11247

    Article  CAS  PubMed  Google Scholar 

  • Ryoo SR, Kim YK, Min DH (2010) Behaviors of NIH-3T3 fibroblasts on graphene/carbon nanotubes: proliferation, focal adhesion, and gene transfection studies. ACS Nano 4:6587–6598

    Article  CAS  PubMed  Google Scholar 

  • Sanchez VC, Jachak A, Hurt RH et al (2011) Biological interactions of graphene-family nanomaterials; an interdisciplinary review. Chem Res Toxicol 25:15–34

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sasidharan A, Panchakarla LS, Sadanandan AR et al (2012) Hemocompatibility and macrophage response of pristine and functionalized graphene. Small 8:1251–1263

    Article  CAS  PubMed  Google Scholar 

  • Sato T, Terai M, Tamura Y (2011) Interleukin 10 in the tumor microenvironment: a target for anticancer immunotherapy. Immunol Res 51:170–182

    Article  CAS  PubMed  Google Scholar 

  • Sawosz W, Jaworski S, Kutwin M et al (2014) Toxicity of pristine graphene in experiments in a chicken embryo model. Int J Nanomedicine 9:3913–3922

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schinwald A, Murphy F, Jones A et al (2012) Graphene-based nanoplatelets: a new risk to the respiratory system as a consequence of their unusual aerodynamic properties. ACS Nano 6:736–746

    Article  CAS  PubMed  Google Scholar 

  • Schuster N, Krieglstein K (2002) Mechanisms of TGF-beta-mediated apoptosis. Cell Tissue Res 307:1–14

    Article  CAS  PubMed  Google Scholar 

  • Seabra AB, Paula AJ, de Lima R et al (2014) Nanotoxicity of graphene and graphene oxide. Chem Res Toxicol 27:159–168

    Article  CAS  PubMed  Google Scholar 

  • Sharma M, Schoop R, Suter A et al (2011) The potential use of Echinacea in acne: control of Propionibacterium acnes growth and inflammation. Phytother Res 25:517–521

    Article  CAS  PubMed  Google Scholar 

  • Shas SA, Sanders S, White CM (2007) Evaluation of echinacea for the prevention and treatment of the common cold: a meta analysis. Lancet Infect Dis 7:473–480

    Article  Google Scholar 

  • Shay T, Jojic V, Zuk O et al (2013) Conservation and divergence in the transcriptional programs of the human and mouse immune systems. Proc Natl Acad Sci 110:2946–2951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen H, Zhang L, Liu M et al (2012) Biomedical applications of graphene. Theranostics 2:283–294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Singh S (2010) Nanomedicine-nanoscale drugs and delivery systems. J Nanosci Nanotechnol 10:7906–7918

    Article  CAS  PubMed  Google Scholar 

  • Singh R, Nalwa HS (2011) Medical applications of nanoparticles in biological imaging, cell labeling, antimicrobial agents, and anticancer nanodrugs. J Biomed Nanotechnol 7:489–503

    Article  CAS  PubMed  Google Scholar 

  • Skoda M, Dudek I, Jarosz A et al (2014) Graphene: one material, many possibilities application difficulties in biological systems. J Nanomat. doi:10.1155/2014/890246

    Google Scholar 

  • Soldano C, Mahmood A, Dujardin E (2010) Production, properties and potential of graphene. Carbon 48:2127–2150

    Article  CAS  Google Scholar 

  • Song Q, Jiang Z, Li N (2014) Anti-inflammatory effects of three-dimensional graphene foams cultured with microglial cells. Biomaterials 35:6930–6940

    Article  CAS  PubMed  Google Scholar 

  • Stalińska L, Ferenc T (2005) [The role of TGF-beta in cell cycle regulation] (in Polish). Postepy Hig Med Dosw 59:441–449

    Google Scholar 

  • Steenblock ER, Wrzesinski SH, Flavell AR et al (2009) Antigen presentation on artificial acellular substrates: modular systems for flexible, adaptable immunotherapy. Expert Opin Biol Ther 9:451–464

    Article  CAS  PubMed  Google Scholar 

  • Sun XM, Liu Z, Welsher K et al (2008) Nano-graphene oxide for cellular imaging and drug delivery. Nano Res 1:203–212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tao Y, Ju E, Ren J et al (2014) Immunostimulatory oligonucleotides-loaded cationic graphene oxide with photothermally enhanced immunogenicity for photothermal/immune cancer therapy. Biomaterials 35:9963–9971

    Article  CAS  PubMed  Google Scholar 

  • Tirado Y, Puig A, Alvarez N et al (2015) Protective capacity of proteoliposomes from Mycobacterium bovis BCG in a mouse model of tuberculosis. Hum Vaccin Immunother 11:657–661

    Article  PubMed  PubMed Central  Google Scholar 

  • Tkach AV, Yanamala N, Stanley S et al (2013) graphene oxide, but not fullerenes, targets immunoproteasomes and suppresses antigen presentation by dendritic cells. Small 9:1686–1690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tu Q, Pang L, Chen Y et al (2014) Effects of surface charges of graphene oxide on neuronal outgrowth and branching. Analyst 139:105–115

    Article  CAS  PubMed  Google Scholar 

  • Uto T, Akagi T, Yoshinaga K et al (2010) The induction of innate and adaptive immunity by biodegradable poly(gamma-glutamic acid)nanoparticles via a TLR4 and MyD88 signaling pathway. Biomaterials 32:5206–5212

    Article  CAS  Google Scholar 

  • Vinkler M, Bainová H, Bryjová A et al (2015) Characterisation of Toll-like receptors 4, 5 and 7 and their genetic variation in the grey partridge. Genetica 143:101–112

    Article  CAS  PubMed  Google Scholar 

  • Wajant H (2007) Connection Map for Fas signaling pathway. STKE. doi:10.1126/stke.3802007tr1

    Google Scholar 

  • Wang K, Ruan J, Song H et al (2010) Biocompatibility of graphene oxide. Nanoscale Res Lett 6:1–8

    Google Scholar 

  • Wang Y, Li ZH, Wang J (2011) Graphene and graphene oxide: biofunctionalization and applications in biotechnology. Trends Biotechnol 29:205–212

    Article  PubMed  CAS  Google Scholar 

  • Wang W, Lim Z, Duan J (2014) In vitro enhancement of dendritic cell-mediated anti-glioma immune response by graphene oxide. Nanoscale Res Lett 9:311

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wei Y, Wang B, Wu J et al (2012) Bending rigidity and Gaussian bending stiffness of single-layered graphene. Nano Let 13:26–30

    Article  CAS  Google Scholar 

  • Wen ZS, Xu YL, Zou XT et al (2011) Chitosan nanoparticles act as an adjuvant to promote both Th1 and Th2 immune responses induced by ovalbumin in mice. Mar Drugs 9:1038–1055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu WP, Zhang Ch, Li JP et al (2011) Facile synthesis of silver@graphene oxide nanocomposites and their enhanced antibacterial properties. J Mater Chem 21:4593–4597

    Article  CAS  Google Scholar 

  • Yang ZR, Wang HF, Zhao J et al (2007) Recent developments in the use of adenoviruses and immunotoxins in cancer gene therapy. Cancer Gene Ther 14:599–615

    Article  CAS  PubMed  Google Scholar 

  • Yang XY, Zhang XY, Liu ZF (2008) High-efficiency loading and controlled release of doxorubicin hydrochloride on graphene oxide. J Phys Chem C 112:17554–17558

    Article  CAS  Google Scholar 

  • Yang K, Wan JM, Zhang AS et al (2011a) In vivo pharmacokinetics, long-term biodistribution, and toxicology of PEGylated graphene in mice. ACS Nano 5:516–522

    Article  CAS  PubMed  Google Scholar 

  • Yang XY, Wang YS, Huang X et al (2011b) Multi-functionalized graphene oxide based anticancer drug-carrier with dual-targeting function and pH-sensitivity. J Mater Chem 21:3448–3454

    Article  CAS  Google Scholar 

  • Yang K, Gong H, Shi X et al (2013) In vivo biodistribution and toxicology of functionalized nano-graphene oxide in mice after oral and intraperitoneal administration. Biomaterials 34:2787–2795

    Article  CAS  PubMed  Google Scholar 

  • Yue H, Wei W, Yue Z (2012) The role of the lateral dimension of graphene oxide in the regulation of cellular responses. Biomaterials 33:4013–4021

    Article  CAS  PubMed  Google Scholar 

  • Zaman M, Good MF, Toth I (2013) Nanovaccines and their mode of action. Methods 60:226–231

    Article  CAS  PubMed  Google Scholar 

  • Zapała Ł, Lasek W (2007) Natural exogenous immunostimulators. Post Biol Kom 3:581–594

    Google Scholar 

  • Zeinali M, Jammalan M, Ardestani SK et al (2009) Immunological and cytotoxicological characterization of tuberculin purified protein derivative (PPD) conjugated to single-walled carbon nanotubes. Immunol Lett 126:48–53

    Article  CAS  PubMed  Google Scholar 

  • Zhang LM, Xia JG, Zhao QH et al (2010) Functional graphene oxide as a nanocarrier for controlled loading and targeted delivery of mixed anticancer drugs. Small 6:537–544

    Article  CAS  PubMed  Google Scholar 

  • Zhang LM, Lu ZX, Zhao QH et al (2011a) Enhanced chemotherapy efficacy by sequential delivery of siRNA and anticancer drugs using PEI-grafted graphene oxide. Small 7:460–464

    Article  CAS  PubMed  Google Scholar 

  • Zhang SA, Yang K, Feng LZ et al (2011b) In vitro and in vivo behaviors of dextran functionalized graphene. Carbon 49:4040–4049

    Article  CAS  Google Scholar 

  • Zhang G, Zeng X, Ping L (2013a) Nanomaterials in cancer-therapy drug delivery system. J Biomed Nanotechnol 9:741–750

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Grüner G, Zhao Y (2013b) Recent advancements of graphene in biomedicine. J Mater Chem 1:2542–2567

    Article  CAS  Google Scholar 

  • Zhao Y, Xing G, Chai Z (2008) Nanotoxicology: are carbon nanotubes safe? Nat Nanotechnol 3:191–192

    Article  CAS  PubMed  Google Scholar 

  • Zhi X, Fang H, Bao C et al (2013) The immunotoxicity of graphene oxides and the effect of PVP-coating. Biomaterials 34:5254–5261

    Article  CAS  PubMed  Google Scholar 

  • Zhou H, Zhao K, Wei L et al (2012) The interactions between pristine graphene and macrophages and the production of cytokines/chemokines via TLR- and NF-kB-related signaling pathways. Biomaterials 33:6933–6942

    Article  CAS  PubMed  Google Scholar 

  • Zhu BY, Murali S, Cai W et al (2010) Graphene and graphene oxide: synthesis, properties, and applications. Adv Mater 22:3906–3924

    Article  CAS  PubMed  Google Scholar 

  • Zielinski A, Stefanoff P (2004) Herd immunity and effectiveness of vaccination. Przegl Epidemiol 58(Suppl 1):6–10

    Google Scholar 

  • Zwiorek K, Bourquin C, Battiany J et al (2008) Delivery by cationic gelatin nanoparticles strongly increases the immunostimulatory effects of CpG oligonucleotides. Pharm Res 25:551–562

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ilona Dudek.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dudek, I., Skoda, M., Jarosz, A. et al. The Molecular Influence of Graphene and Graphene Oxide on the Immune System Under In Vitro and In Vivo Conditions. Arch. Immunol. Ther. Exp. 64, 195–215 (2016). https://doi.org/10.1007/s00005-015-0369-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00005-015-0369-3

Keywords

Navigation