Challenges for labeling and longitudinal tracking of adoptively transferred autoreactive T lymphocytes in an experimental type-1 diabetes model
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Tracking the autoreactive T-cell migration in the pancreatic region after labeling with fluorinated nanoparticles (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[3-(2-pyridyldithio)propionate]-perfluoro-15-crown-5-ether nanoparticles, PDP-PFCE NPs) in a diabetic murine model using 19F MRI.
Materials and methods
Synthesis of novel PDP-PFCE fluorine tracer was performed for in vitro labeling of T cells. Labeling conditions were optimized using different PDP-PFCE NPs concentrations. For in vivo 19F MRI, mice were longitudinally followed after adoptive transfer of activated, autoreactive, labeled T cells in NOD.SCID mice.
Established MR protocols were used for challenging T cell labeling to track inflammation in a model of diabetes after successful labeling of CD4+ and CD8+ T cells with PDP-PFCE NPs. However, T cells were difficult to be detected in vivo after their engraftment in animals.
We showed successful in vitro labeling of T cells using novel fluorinated liposomal nanoparticles. However, insufficient and slow accumulation of labeled T cells and subsequent T cell proliferation in the pancreatic region remains as limitations of in vivo cell imaging by 19F MRI.
Keywords19F MRI T cells Inflammation Nanoparticles Type 1 diabetes
The authors are grateful for financial support by the European Commission for the FP7 MC-ITN ‘BetaTrain’ (EU-FP7/207-2013/ 289932), by the European ERA-NET project ‘CryptoView’ (3rd call of the FP7 programme Infect-ERA), by the Flemish Wetenschap Onderzoek (FWO) for the projects G.0B28.14 and G.0A75.14, by the Agentschap Innoveren & Ondernemen for the IWT-SBO ‘NanoComit’ (140061).
Study conception and design: SS, HK, IL, UH. Methodology: SL, HK, RV, KR, CG. Experimentation: SS, HK, BM, RV, SL. Analysis and interpretation of data: SS, HK, BM, UH. Drafting of manuscript: SS. Critical revision: HK, CG, IL, SD, UH.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
This article does not contain any studies with human participants performed by any of the authors. Experiments involving mice were performed in accordance with regional, national and international standards on animal welfare, in particular the European Union Directive 2010/63/EU, and approved and overseen by the Animal Care and Ethical Committees of the University of Leuven.
- 1.Liang S, Louchami K, Kolster H, Jacobsen A, Zhang Y, Thimm J, Sener A, Thiem J, Malaisse W, Dresselaers T, Himmelreich U (2016) In vivo and ex vivo 19-fluorine magnetic resonance imaging and spectroscopy of beta-cells and pancreatic islets using GLUT-2 specific contrast agents. Contrast Media Mol Imaging 11:506–513. https://doi.org/10.1002/cmmi.1712 CrossRefGoogle Scholar
- 2.Kriz J, Jirak D, Berkova Z, Herynek V, Lodererova A, Girman P, Habart D, Hajek M, Saudek F (2012) Detection of pancreatic islet allograft impairment in advance of functional failure using magnetic resonance imaging. Transpl Int 25:250–260. https://doi.org/10.1111/j.1432-2277.2011.01403.x CrossRefGoogle Scholar
- 3.Malosio ML, Esposito A, Brigatti C, Palmisano A, Piemonti L, Nano R, Maffi P, De Cobelli F, Del Maschio A, Secchi A (2015) MR imaging monitoring of iron labeled pancreatic islets in a small series of patients: islets fate in successful, unsuccessful and auto-transplantation. Cell Transplant 24:2285–2296. https://doi.org/10.3727/096368914X684060 CrossRefGoogle Scholar
- 7.Alanentalo T, Lorén CE, Larefalk A, Sharpe J, Holmberg D, Ahlgren U (2008) High-resolution three-dimensional imaging of islet-infiltrate interactions based on optical projection tomography assessments of the intact adult mouse pancreas. J Biomed Opt 13:054070. https://doi.org/10.1117/1.3000430 CrossRefGoogle Scholar
- 10.Srinivas M, Boehm-Sturm P, Figdor CG, de Vries IJ, Hoehn M (2012) Labeling cells for in vivo tracking using 19F MRI. Biomaterials 33:8830–8840. https://doi.org/10.1016/j.biomaterials.2012.08.048 CrossRefGoogle Scholar
- 14.Harms C, Datwyler AL, Wiekhorst F, Trahms L, Lindquist R, Schellenberger E, Mueller S, Schütz G, Roohi F, Ide A, Füchtemeier M, Gertz K, Kronenberg G, Harms U, Endres M, Dirnagl U, Farr TD (2013) Certain types of iron oxide nanoparticles are not suited to passively target inflammatory cells that infiltrate the brain in response to stroke. J Cereb Blood Flow Metab 36(Suppl 1):139–140. https://doi.org/10.1038/jcbfm.2013.22 Google Scholar
- 21.Westermann J, Söllner S, Ehlers E-M, Nohroudi K, Blessenohl M, Kalies K (2003) Analyzing the migration of labeled T cells in vivo: an essential approach with challenging features. Lab Investig 83:459–469. https://doi.org/10.1097/01.LAB.0000062852.80567.90 CrossRefGoogle Scholar
- 22.Gonzales C, Yoshihara HAI, Dilek N, Leignadier J, Irving M, Mieville P, Helm L, Michielin O, Schwitter J (2016) In-vivo detection and tracking of T cells in various organs in a melanomatumor model by 19F-fluorine MRS/MRI. PLoS One 11:1–18. https://doi.org/10.1371/journal.pone.0164557 CrossRefGoogle Scholar
- 24.Przybylski S, Gasch M, Marschner A, Ebert M, Ewe A, Helmig G, Hilger N, Fricke S, Rudzok S, Aigner A, Burkhardt J (2017) Influence of nanoparticle-mediated transfection on proliferation of primary immune cells in vitro and in vivo. PLoS One 12:1–16. https://doi.org/10.1371/journal.pone.0176517 CrossRefGoogle Scholar
- 25.Wayteck L, Dewitte H, De Backer L, Breckpot K, Demeester J, De Smedt SC, Raemdonck K (2016) Hitchhiking nanoparticles: reversible coupling of lipid-based nanoparticles to cytotoxic T lymphocytes. Biomaterials 77:243–254. https://doi.org/10.1016/j.biomaterials.2015.11.016 CrossRefGoogle Scholar
- 27.Ferreira GB, Gysemans CA, Demengeot J, da Cunha JPMCM, Vanherwegen A-S, Overbergh L, Van Belle TL, Pauwels F, Verstuyf A, Korf H, Mathieu C (2014) 1,25-Dihydroxyvitamin D3 promotes tolerogenic dendritic cells with functional migratory properties in NOD mice. J Immunol 192:4210–4220. https://doi.org/10.4049/jimmunol.1302350 CrossRefGoogle Scholar
- 38.Waiczies S, Millward JM, Starke L, Delgado PR, Huelnhagen T, Prinz C, Marek D, Di Wecker, Wissmann R, Koch SP, Boehm-Sturm P, Waiczies H, Niendorf T, Pohlmann A (2017) Enhanced fluorine-19 MRI sensitivity using a cryogenic radiofrequency probe: technical developments and ex vivo demonstration in a mouse model of neuroinflammation. Sci Rep 7:1–10. https://doi.org/10.1038/s41598-017-09622-2 CrossRefGoogle Scholar
- 39.Liang S, Dresselaers T, Louchami K, Zhu C, Liu Y, Himmelreich U (2017) Comparison of different compressed sensing algorithms for low SNR 19F MRI applications—imaging of transplanted pancreatic islets and cells labeled with perfluorocarbons. NMR Biomed 30:e3776. https://doi.org/10.1002/nbm.3776 CrossRefGoogle Scholar