Intraindividual long term stability and response corridors of cytokines in healthy volunteers detected by a standardized whole-blood culture system for bed-side application
The variation of immune cell activities over time is an immanent property of the human immune system, as can be measured by the stimulated secretion of cytokines in cell cultures. However, inter-individual variability is considerably higher. Especially the latter is the major reason why it has not been possible to establish international standard values for cytokines as was possible for other parameters, such as leukocyte sub-population numbers. In this trial, a highly standardized whole-blood culture model (TrueCulture®), developed to characterise drug effects on cells of the human immune system in clinical trials, was used to analyse cytokine patterns in the blood samples of 12 healthy subjects over a period of one month.
After an overnight fast, 12 healthy subjects donated blood three times a week on three consecutive days over a period of 4 weeks. TruCulture® blood collection and whole-blood culture systems were used to measure whole-blood leukocyte stimulation. The levels of IL-2, IL-5, IL-13, IL-6, IL-8, IL-10, IFNγ, and MCP-1 in the culture supernatants were quantified by sandwich ELISA.
The pattern of cytokine concentrations in the supernatants of the stimulated whole-blood cultures was highly individual, but considerably stable over the whole observation period of 4 weeks.
By using TruCulture® it seems feasible to determine subject-specific cytokine reference patterns, for example under healthy conditions, or before starting an experimental treatment, e.g. during a clinical trial, against which changes in the behaviour of the immune system can be detected more accurately in future.
- Trinchieri G, Sher A: Cooperation of Toll-like receptor signals in innate immune defence. Nature Rev 2007, 7:179–190. CrossRef
- Ostrand-Rosenberg S: Immune Surveillance: a balance between pro- and anti-tumor immunity. Curr Opin Genet Dev 2008, 18:11–18. CrossRef
- Gallucci S, Matzinger P: Danger signals: SOS to the immune system. Curr Opin Immunol 2001, 13:114–119. CrossRef
- Fink SL, Cookson BT: Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eurkaryotic cells. Infect Immunity 2005, 4:1907–1916. CrossRef
- Segerstrom SC, Miller GE: Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychol Bull 2004, 130:601–630. CrossRef
- Noverr MC, Huffnagle GB: Does the microbiota regulate immune responses outside the gut? Trends Microbiol 2004, 12:562–568. CrossRef
- Khan MM: Immunopharmacology. Springer Science + Business Media, New York; 2008. CrossRef
- Li ZW, Wu Y, Sun Y, Liu LY, Tian MM, Feng GS, You WC, Li JY: Inflammatory cytokine gene polymorphisms increase the risk of atrophic gastritis and intestinal metaplasia. World J Gastroenterol 2010, 16:1788–1794. CrossRef
- Bruegger P: [Online] v02. 2002.
- Banks RE: Measurement of cytokines in clinical samples using immunoassays: problems and pitfalls. Clin Rev Clin Lab Sci 2000, 37:131–182. CrossRef
- Brooks P, Emery P, Evans JF, Fenner H, Hawkey CJ, Patrono C, Smolen J, Breedveld F, Day R, Dougados M, Ehrich EW, Gijon-Banos J, Kvien TK, van Rijswijk MH, Warner T, Zeidler H: Interpreting the clinical significance of the differential inhibition of cyclooxygenase-1 and cyclooxygenase-2. Rheumatology 1999, 38:779–788. CrossRef
- Underhill DM: Macrophage recognition of zymosan particles. J Endotox Res 2002,9(3):176–180.
- le Cabec V, Cols C, Maridonneau-Parini I: Nonopsonic phagocytosis of zymosan and Mycobacterium kansasii by CR3 (CD11b/CD18) involves distinct molecular determinants and is or is not coupled with NADPH oxidase activation. Infect Immunity 2000, 8:4736–4745. CrossRef
- Dennehy KM, Brown GD: The role of the ß-glucan receptor Dectin-1 in control of fungal infection. J Leukoc Biol 2007, 82:253–258. CrossRef
- Bondeson J, Browne KA, Brennan FM, Foxwell BMJ, Feldmann M: Selective regulation of cytokine induction by adenoviral gene transfer of IkB into human macrophages: Lipopolysaccharide-induced, but not zymosan-induced, proinflammatory cytokines are inhibited, but IL-10 is NFkB independent. J Immunol 1999, 162:2939–2945.
- Nagashima T, Aranami T, Iclozan C, Onoe : Analysis of T-cell responses to a superantigen, staphylococcal enterotoxin-B. J Clin Exp Haemopathol 2004, 44:25–32. CrossRef
- Skapenko A, Lipsky PE, Kraetsch HG, Kalden JR, Schulze-Koops H: Antigen-independent Th2 cell differentiation by stimulation of CD28: regulation via IL-4 gene expression and mitogen-activated protein kinase activation. J Immunol 2001, 166:4283–4292.
- Schroder K, Hertzog PJ, Ravasi T, Hume DA: Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Res 2004, 75:163–189. CrossRef
- O’Byrne PM: Cytokines or their antagonists for the treatment of asthma. Chest 2006, 130:244–250. CrossRef
- Santoni D, Pedicini M, Castiglione F: Implementation of a regulatory gene network to simulate the TH1/2 differentiation in an agent-based model of hypersensitivity reactions. Bioinformatics 2008, 24:1374–1380. CrossRef
- Kishimoto T: Interleukin-6: discovery of a pleiotropic cytokine. Arthr Res Ther 2006,8(S2):S2. CrossRef
- Mosser DM, Zhang X: Interleukin-10: new perspectives on an old cytokine. Immunol Rev 2008, 226:205–218. CrossRef
- Viola A, Luster AD: Chemokines and their receptors: drug targets in immunity and inflammation. Annu Rev Pharmacol Toxicol 2008, 48:171–197. CrossRef
- Yaqoob P, Newsholme EA, Calder PC: Comparison of cytokine production in cultures of whole human blood and mononuclear cells. Cytokine 1999, 11:600–6005. CrossRef
- Wurfel MM, Park WY, Radella F, Ruzinski J, Sandstrom A, Strout J, Bumgarner RE, Martin TR: Identification of high and low responders to lipopolysaccharide in normal subjects: an unbiased approach to identify modulators of innate immunity. J Immunol 2005, 175:2570–2578.
- Dickinson AM, Holler E: Polymorphisms of cytokine and innate immunity genes and GVHD. Best Pract Res Clin Haematol 2008, 21:149–164. CrossRef
- Entrez SNP Single Nucleotide Polymorphism [Online] http://www.ncbi.nlm.nih.gov/sites/entrez?db=snp&cmd=Search&dopt=DocSum&term=txid9606[Organism%3Aexp]] [Online] ]
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2288/12/112/prepub
- Intraindividual long term stability and response corridors of cytokines in healthy volunteers detected by a standardized whole-blood culture system for bed-side application
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
BMC Medical Research Methodology
- Online Date
- August 2012
- Online ISSN
- BioMed Central
- Additional Links
- Author Affiliations
- 1. Institute for Clinical Pharmacology, Medical Faculty, University of Rostock, Schillingallee 70, 18057, Rostock, Germany
- 2. Peter-Hannweg-Str. 8, 90768, Fürth, Kragujevac
- 3. EDI (Experimental & Diagnostic Immunology) GmbH, Aspenhaustr. 25, 72770, Reutlingen, Germany