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Optical imaging of experimental arthritis using allogeneic leukocytes labeled with a near-infrared fluorescent probe

  • Gerhard H. SimonEmail author
  • Heike E. Daldrup-Link
  • Juli Kau
  • Stephan Metz
  • Juergen Schlegel
  • Guido Piontek
  • Olaf Saborowski
  • Stavros Demos
  • Justus Duyster
  • Bernd J. Pichler
Original article

Abstract

Purpose

The purpose of this study was to assess the feasibility of inflammation detection in an antigen-induced arthritis model using fluorescent leukocytes and optical imaging.

Methods

Antigen-mediated monoarthritis was induced in the right knee of 12 Sprague-Dawley rats. Six rats remained untreated and six rats were treated with cortisone. All rats received ex vivo fluorescent-labeled rat leukocytes. Optical images of both knees were acquired before and at 5 min, 1 h, 4 h, and 24 h after cell injection. Images were evaluated qualitatively and quantitatively by calculating signal intensity ratios between the right arthritic (A) and contralateral normal (N) knee. A/N ratios were tested for significant differences between baseline values and values after cell injection using a paired t test as well as between the untreated and cortisone-treated group using an unpaired t test. Synovial specimens were processed and evaluated for labeled cells with fluorescence microscopy.

Results

At 4 h and 24 h p.i., the A/N ratios of untreated arthritic knees showed a significant signal increase compared with baseline values (p<0.05) and a significant difference compared with A/N ratios of cortisone-treated animals (p<0.05). Fluorescent microscopy confirmed the presence of labeled cells in the arthritic synovium.

Conclusion

Inflammation in antigen-induced arthritis can be detected with ex vivo labeled allogenic leukocytes and optical imaging.

Keywords

Optical imaging Fluorescence Arthritis In vivo Cell tracking 

Notes

Acknowledgements

This work was supported by a Research and Education Foundation Grant from the Society of Pediatric Radiology and by a seed grant from the Department of Radiology, UCSF.

The authors would like to thank Peter Lange, MD, MRCP (UK) for his critical revision of the manuscript.

References

  1. 1.
    Winkelman J, Collica CJ, Sandler SG. The delineation of abscesses by scintiphotography using Cr51 labeled leukocytes. Am J Roentgenol Radium Ther Nucl Med 1968;103:881–885PubMedGoogle Scholar
  2. 2.
    Deysine M, Robinson RG, Wilder JR. Abscess detection by radioactive chromium labeled autologous white blood cells. Surg Gynecol Obstet 1970;131:216–220PubMedGoogle Scholar
  3. 3.
    Scott JL, Davidson JG, Marino JV, McMillan R. Leukocyte labeling with 51 chromium. 3. The kinetics of normal lymphocytes. Blood 1972;40:276–281PubMedGoogle Scholar
  4. 4.
    Uchida T, Kariyone S. Organ distribution of the 99 mTc-labeled white cells. Nippon Ketsueki Gakkai Zasshi 1973;36:78–81PubMedGoogle Scholar
  5. 5.
    Andersen BR, English D, Akalin HE, Henderson W. Inflammatory lesions localized with technetium Tc 99 m-labeled leukocytes. Arch Intern Med 1975;135:1067–1071PubMedCrossRefGoogle Scholar
  6. 6.
    Segal AW, Arnot RN, Thakur ML, Lavender JP. Indium-111-labelled leucocytes for localisation of abscesses. Lancet 1976;2:1056–1058PubMedCrossRefGoogle Scholar
  7. 7.
    Thakur ML, Coleman RE, Mayhall CG, Welch MJ Jr. Preparation and evaluation of 111In-labeled leukocytes as an abscess imaging agent in dogs. Radiology 1976;119:731PubMedGoogle Scholar
  8. 8.
    Thakur ML, Lavender JP, Arnot RN, Silvester DJ, Segal AW. Indium-111-labeled autologous leukocytes in man. J Nucl Med 1977;18:1014–1021PubMedGoogle Scholar
  9. 9.
    Thakur ML, Coleman RE, Welch MJ. Indium-111-labeled leukocytes for the localization of abscesses: preparation, analysis, tissue distribution, and comparison with gallium-67 citrate in dogs. J Lab Clin Med 1977;89:217–228PubMedGoogle Scholar
  10. 10.
    Doherty PW, Bushberg JT, Lipton MJ, Meares CF, Goodwin DA. The use of indium-111-labeled leukocytes for abscess detection. Clin Nucl Med 1978;3:108–110PubMedCrossRefGoogle Scholar
  11. 11.
    Black RE, Coleman RE, Welch DM, Maxwell JG. Abscess detection using autologous leukocytes labeled with indium-111. Curr Surg 1979;36:288–290PubMedGoogle Scholar
  12. 12.
    Martin WR, Gurevich N, Goris ML, McDougall IR. Detection of occult abscesses with 111In-labeled leukocytes. AJR Am J Roentgenol 1979;133:123–125PubMedGoogle Scholar
  13. 13.
    Alavi JB, Alavi A, Staum MM. Evaluation of infection in neutropenic patients with indium-111-labeled donor granulocytes. Clin Nucl Med 1980;5:397–400PubMedCrossRefGoogle Scholar
  14. 14.
    Ascher NL, Forstrom L, Simmons RL. Radiolabeled autologous leukocyte scanning in abscess detection. World J Surg 1980;4:395–402PubMedCrossRefGoogle Scholar
  15. 15.
    Beightol RW, Baker WJ. Labeling autologous leukocytes with indium-111 oxine. Am J Hosp Pharm 1980;37:847–850PubMedGoogle Scholar
  16. 16.
    Coleman RE, Black RE, Welch DM, Maxwell JG. Indium-111 labeled leukocytes in the evaluation of suspected abdominal abscesses. Am J Surg 1980;139:99–104PubMedCrossRefGoogle Scholar
  17. 17.
    Fawcett HD, Lantieri RL, Frankel A, McDougall IR. Differentiating hepatic abscess from tumor: combined 111In white blood cell and 99 mTc liver scans. AJR Am J Roentgenol 1980;135:53–56PubMedGoogle Scholar
  18. 18.
    Goedemans WT, Hardeman MR, Belfer AJ. Comparison of indium-111 oxinate labelled autologous granulocytes with indium-111 oxinate and indium-111 chloride as abscess scanning agents. An experimental study in an animal model. Eur J Nucl Med 1980;5:63–68PubMedCrossRefGoogle Scholar
  19. 19.
    Fawcett HD, Goodwin DA, Lantieri RL. In-111-leukocyte scanning in inflammatory renal disease. Clin Nucl Med 1981;6:237–241PubMedCrossRefGoogle Scholar
  20. 20.
    Rovekamp MH, Hardeman MR, van der Schoot JB, Belfer AJ. 111Indium-labelled leucocyte scintigraphy in the diagnosis of inflammatory disease—first results. Br J Surg 1981;68:150–153PubMedCrossRefGoogle Scholar
  21. 21.
    Segal AW, Ensell J, Munro JM, Sarner M. Indium-111 tagged leucocytes in the diagnosis of inflammatory bowel disease. Lancet 1981;2:230–232PubMedCrossRefGoogle Scholar
  22. 22.
    Kipper MS, Williams RJ. The potential role of In-111 white blood cell scans in patients with inflammatory bowel disease. Clin Nucl Med 1982;7:469–471PubMedCrossRefGoogle Scholar
  23. 23.
    Peters AM, Saverymuttu SH, Reavy HJ, Danpure HJ, Osman S, Lavender JP. Imaging of inflammation with indium-111 tropolonate labeled leukocytes. J Nucl Med 1983;24:39–44PubMedGoogle Scholar
  24. 24.
    Ahmed F, Weiland FL, Rosen PR, Borchert RD. Demonstration of occult abdominal infection with indium-111 WBC and gallium-67 scintigraphy. Clin Nucl Med 1984;9:355–356PubMedCrossRefGoogle Scholar
  25. 25.
    Bernstein RM, Mackworth-Young CG, Saverymutu SH, Gupta S, England JP, Hughes GR. Yersinia arthritis: demonstration of occult enteritis by 111indium leucocyte scanning. Ann Rheum Dis 1984;43:493–494PubMedCrossRefGoogle Scholar
  26. 26.
    Coakley AJ, Mountford PJ. 99 mTc-HMPAO for labelling leucocytes in infection. Lancet 1987;1:44PubMedCrossRefGoogle Scholar
  27. 27.
    Henneman PL, Marcus CS, Butler JA, Freedland ES, Wilson SE, Rothstein RJ. Appendicitis: evaluation by Tc-99 m leukocyte scan. Ann Emerg Med 1988;17:111–116PubMedCrossRefGoogle Scholar
  28. 28.
    Vorne M, Lantto T, Paakkinen S, Salo S, Soini I. Clinical comparison of 99Tcm-HMPAO labelled leucocytes and 99Tcm-nanocolloid in the detection of inflammation. Acta Radiol 1989;30:633–637PubMedCrossRefGoogle Scholar
  29. 29.
    Vorne M, Soini I, Lantto T, Paakkinen S. Technetium-99 m HM-PAO-labeled leukocytes in detection of inflammatory lesions: comparison with gallium-67 citrate. J Nucl Med 1989;30:1332–1336PubMedGoogle Scholar
  30. 30.
    Adonai N, Nguyen KN, Walsh J, Iyer M, Toyokuni T, Phelps ME, et al. Ex vivo cell labeling with 64Cu-pyruvaldehyde-bis(N4-methylthiosemi-arbazone) for imaging cell trafficking in mice with positron-emission tomography. Proc Natl Acad Sci U S A 2002;99:3030–3035PubMedCrossRefGoogle Scholar
  31. 31.
    Hansch A, Frey O, Hilger I, Sauner D, Haas M, Schmidt D, et al. Diagnosis of arthritis using near-infrared fluorochrome Cy5.5. Invest Radiol 2004;39:626–632.PubMedCrossRefGoogle Scholar
  32. 32.
    Hansch A, Frey O, Sauner D, Hilger I, Haas M, Malich A, et al. In vivo imaging of experimental arthritis with near-infrared fluorescence. Arthritis Rheum 2004;50:961–967PubMedCrossRefGoogle Scholar
  33. 33.
    Chen WT, Mahmood U, Weissleder R, Tung CH. Arthritis imaging using a near-infrared fluorescence folate-targeted probe. Arthritis Res Ther 2005;7:R310–R317PubMedCrossRefGoogle Scholar
  34. 34.
    Wunder A, Tung CH, Muller-Ladner U, Weissleder R, Mahmood U. In vivo imaging of protease activity in arthritis: a novel approach for monitoring treatment response. Arthritis Rheum 2004;50:2459–2465PubMedCrossRefGoogle Scholar
  35. 35.
    Haugland RP, Spence MTZ, Johnson ID. In:Handbook of fluorescent probes and research products. 9th ed.Molecular Probes, 4849 Pitchford Ave., Eugene, OR 97402, USAGoogle Scholar
  36. 36.
    Jasin HE, Cooke TD, Hurd ER, Smiley JD, Ziff M. Immunologic models used for the study of rheumatoid arthritis. Fed Proc 1973;32:147–152PubMedGoogle Scholar
  37. 37.
    Wooley PH. The usefulness and the limitations of animal models in identifying targets for therapy in arthritis. Best Pract Res Clin Rheumatol 2004;18:47–58PubMedCrossRefGoogle Scholar
  38. 38.
    Kinne RW, Brauer R, Stuhlmuller B, Palombo-Kinne E, Burmester GR. Macrophages in rheumatoid arthritis. Arthritis Res 2000;2:189–202PubMedCrossRefGoogle Scholar
  39. 39.
    Iguchi T, Kurosaka M, Ziff M. Electron microscopic study of HLA-DR and monocyte/macrophage staining cells in the rheumatoid synovial membrane. Arthritis Rheum 1986;29:600–613PubMedCrossRefGoogle Scholar
  40. 40.
    Rooney M, Whelan A, Feighery C, Bresnihan B. The immunohistologic features of synovitis, disease activity and in vitro IgM rheumatoid factor synthesis by blood mononuclear cells in rheumatoid arthritis. J Rheumatol 1989;16:459–467PubMedGoogle Scholar
  41. 41.
    Malone DG, Wilder RL, Saavedra-Delgado AM, Metcalfe DD. Mast cell numbers in rheumatoid synovial tissues. Correlations with quantitative measures of lymphocytic infiltration and modulation by antiinflammatory therapy. Arthritis Rheum 1987;30:130–137PubMedCrossRefGoogle Scholar
  42. 42.
    Ridley MG, Kingsley G, Pitzalis C, Panayi GS. Monocyte activation in rheumatoid arthritis: evidence for in situ activation and differentiation in joints. Br J Rheumatol 1990;29:84–88PubMedCrossRefGoogle Scholar
  43. 43.
    Daldrup-Link HE, Rudelius M, Metz S, Piontek G, Pichler B, Settles M et al. Cell tracking with gadophrin-2: a bifunctional contrast agent for MR imaging, optical imaging, and fluorescence microscopy. Eur J Nucl Med Mol Imaging 2004;31:1312–1321PubMedCrossRefGoogle Scholar
  44. 44.
    Shichinohe H, Kuroda S, Lee JB, Nishimura G, Yano S, Seki T, et al. In vivo tracking of bone marrow stromal cells transplanted into mice cerebral infarct by fluorescence optical imaging. Brain Res Brain Res Protoc 2004;13:166–175PubMedCrossRefGoogle Scholar
  45. 45.
    Moore A, Grimm J, Han B, Santamaria P. Tracking the recruitment of diabetogenic CD8+ T-cells to the pancreas in real time. Diabetes 2004;53:1459–1466PubMedCrossRefGoogle Scholar
  46. 46.
    Nakajima A, Seroogy CM, Sandora MR, Tarner IH, Costa GL, Taylor-Edwards C, et al. Antigen-specific T cell-mediated gene therapy in collagen-induced arthritis. J Clin Invest 2001;107:1293–1301PubMedCrossRefGoogle Scholar
  47. 47.
    Hardy J, Edinger M, Bachmann MH, Negrin RS, Fathman CG, Contag CH. Bioluminescence imaging of lymphocyte trafficking in vivo. Exp Hematol 2001;29:1353–1360PubMedCrossRefGoogle Scholar
  48. 48.
    Metz S, Bonaterra G, Rudelius M, Settles M, Rummeny EJ, Daldrup-Link HE. Capacity of human monocytes to phagocytose approved iron oxide MR contrast agents in vitro. Eur Radiol 2004;14:1851–1858PubMedCrossRefGoogle Scholar
  49. 49.
    Frank JA, Miller BR, Arbab AS, Zywicke HA, Jordan EK, Lewis BK, et al. Clinically applicable labeling of mammalian and stem cells by combining superparamagnetic iron oxides and transfection agents. Radiology 2003;228:480–487PubMedCrossRefGoogle Scholar
  50. 50.
    Daldrup-Link HE, Meier R, Rudelius M, Piontek G, Piert M, Metz S, et al. In vivo tracking of genetically engineered, anti-HER2/neu directed natural killer cells to HER2/neu positive mammary tumors with magnetic resonance imaging. Eur Radiol 2005;15:4–13PubMedCrossRefGoogle Scholar
  51. 51.
    Daldrup-Link HE, Rudelius M, Oostendorp RA, Settles M, Piontek G, Metz S, et al. Targeting of hematopoietic progenitor cells with MR contrast agents. Radiology 2003;228:760–767PubMedCrossRefGoogle Scholar
  52. 52.
    Zhang Z, Jiang Q, Jiang F, Ding G, Zhang R, Wang L, et al. In vivo magnetic resonance imaging tracks adult neural progenitor cell targeting of brain tumor. Neuroimage 2004;23:281–287PubMedCrossRefGoogle Scholar
  53. 53.
    Weissleder R, Cheng HC, Bogdanova A, Bogdanov A Jr. Magnetically labeled cells can be detected by MR imaging. J Magn Reson Imaging 1997;7:258–263PubMedCrossRefGoogle Scholar
  54. 54.
    Yeh TC, Zhang W, Ildstad ST, Ho C. In vivo dynamic MRI tracking of rat T-cells labeled with superparamagnetic iron-oxide particles. Magn Reson Med 1995;33:200–208PubMedCrossRefGoogle Scholar
  55. 55.
    Zelivyanskaya ML, Nelson JA, Poluektova L et al. Tracking superparamagnetic iron oxide labeled monocytes in brain by high-field magnetic resonance imaging. J Neurosci Res 2003;73:284–295PubMedCrossRefGoogle Scholar
  56. 56.
    Jendelova P, Herynek V, Urdzikova L, Glogarova K, Kroupova J, Andersson B, et al. Magnetic resonance tracking of transplanted bone marrow and embryonic stem cells labeled by iron oxide nanoparticles in rat brain and spinal cord. J Neurosci Res 2004;76:232–243PubMedCrossRefGoogle Scholar
  57. 57.
    Weissleder R, Ntziachristos V. Shedding light onto live molecular targets. Nat Med 2003;9:123–128PubMedCrossRefGoogle Scholar
  58. 58.
    Hansch A, Sauner D, Hilger I, Haas M, Malich A, Brauer R, et al. Noninvasive diagnosis of arthritis by autofluorescence. Invest Radiol 2003;38:578–583PubMedCrossRefGoogle Scholar
  59. 59.
    Na R, Stender IM, Ma L, Wulf HC. Autofluorescence spectrum of skin: component bands and body site variations. Skin Res Technol 2000;6:112–117PubMedCrossRefGoogle Scholar
  60. 60.
    Croce AC, Spano A, Locatelli D, Barni S, Sciola L, Bottiroli G. Dependence of fibroblast autofluorescence properties on normal and transformed conditions. Role of the metabolic activity. Photochem Photobiol 1999;69:364–374PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Gerhard H. Simon
    • 1
    • 2
    Email author
  • Heike E. Daldrup-Link
    • 1
  • Juli Kau
    • 1
  • Stephan Metz
    • 2
  • Juergen Schlegel
    • 3
  • Guido Piontek
    • 3
  • Olaf Saborowski
    • 1
  • Stavros Demos
    • 4
  • Justus Duyster
    • 5
  • Bernd J. Pichler
    • 6
  1. 1.The Department of Radiology, S-372UCSF Medical Center, University of California in San FranciscoSan FranciscoUSA
  2. 2.Department of RadiologyTechnical University of MunichMunichGermany
  3. 3.Department of PathologyTechnical University of MunichMunichGermany
  4. 4.The Lawrence Livermore National LaboratoryLivermoreUSA
  5. 5.Department of Internal Medicine, Section of Haematology/OncologyTechnical University of MunichMunichGermany
  6. 6.Department of RadiologyUniversity of TübingenTübingenGermany

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