Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

In vivo imaging using fluorescent antibodies to tumor necrosis factor predicts therapeutic response in Crohn's disease

Nature Medicine volume 20, pages 313–318 (2014)Cite this article

Subjects

Abstract

As antibodies to tumor necrosis factor (TNF) suppress immune responses in Crohn's disease by binding to membrane-bound TNF (mTNF), we created a fluorescent antibody for molecular mTNF imaging in this disease. Topical antibody administration in 25 patients with Crohn's disease led to detection of intestinal mTNF+ immune cells during confocal laser endomicroscopy. Patients with high numbers of mTNF+ cells showed significantly higher short-term response rates (92%) at week 12 upon subsequent anti-TNF therapy as compared to patients with low amounts of mTNF+ cells (15%). This clinical response in the former patients was sustained over a follow-up period of 1 year and was associated with mucosal healing observed in follow-up endoscopy. These data indicate that molecular imaging with fluorescent antibodies has the potential to predict therapeutic responses to biological treatment and can be used for personalized medicine in Crohn's disease and autoimmune or inflammatory disorders.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Ex vivo molecular imaging of mTNF in gut samples of patients with Crohn's disease using fluorescent adalimumab.
Figure 2: In vivo molecular imaging of mTNF+ mucosal immune cells in the gut of patients with Crohn's disease.
Figure 3: Clinical findings of the study.

References

  1. Strober, W., Fuss, I. & Mannon, P. The fundamental basis of inflammatory bowel disease. J. Clin. Invest. 117, 514–521 (2007).

    Article  CAS  Google Scholar 

  2. Danese, S. New therapies for inflammatory bowel disease: from the bench to the bedside. Gut 61, 918–932 (2012).

    Article  CAS  Google Scholar 

  3. Peyrin-Biroulet, L., Loftus, E.V. Jr., Colombel, J.F. & Sandborn, W.J. The natural history of adult Crohn's disease in population-based cohorts. Am. J. Gastroenterol. 105, 289–297 (2010).

    Article  Google Scholar 

  4. Atreya, R. et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in Crohn disease and experimental colitis in vivo. Nat. Med. 6, 583–588 (2000).

    Article  CAS  Google Scholar 

  5. Wajant, H., Pfizenmaier, K. & Scheurich, P. Tumor necrosis factor signaling. Cell Death Differ. 10, 45–65 (2003).

    Article  CAS  Google Scholar 

  6. Colombel, J.F. et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N. Engl. J. Med. 362, 1383–1395 (2010).

    Article  CAS  Google Scholar 

  7. Evans, A.T. & Lee, S.D. A review and expert opinion of the use of certolizumab for Crohn's disease. Expert Opin. Biol. Ther. 12, 363–370 (2012).

    Article  CAS  Google Scholar 

  8. Hanauer, S.B. et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. Gastroenterology 130, 323–333, quiz 591 (2006).

    Article  CAS  Google Scholar 

  9. Colombel, J.F. et al. Adalimumab safety in global clinical trials of patients with Crohn's disease. Inflamm. Bowel Dis. 15, 1308–1319 (2009).

    Article  Google Scholar 

  10. Vermeire, S., Van Assche, G. & Rutgeerts, P. C-reactive protein as a marker for inflammatory bowel disease. Inflamm. Bowel Dis. 10, 661–665 (2004).

    Article  Google Scholar 

  11. Hlavaty, T. et al. Predictive model for the outcome of infliximab therapy in Crohn's disease based on apoptotic pharmacogenetic index and clinical predictors. Inflamm. Bowel Dis. 13, 372–379 (2007).

    Article  Google Scholar 

  12. Kendall, C. et al. Raman spectroscopy, a potential tool for the objective identification and classification of neoplasia in Barrett's oesophagus. J. Pathol. 200, 602–609 (2003).

    Article  Google Scholar 

  13. Evans, J.A. et al. Identifying intestinal metaplasia at the squamocolumnar junction by using optical coherence tomography. Gastrointest. Endosc. 65, 50–56 (2007).

    Article  Google Scholar 

  14. Qiu, L. et al. Multispectral scanning during endoscopy guides biopsy of dysplasia in Barrett's esophagus. Nat. Med. 16, 603–606 (2010).

    Article  CAS  Google Scholar 

  15. Waldner, M.J., Wirtz, S., Neufert, C., Becker, C. & Neurath, M.F. Confocal laser endomicroscopy and narrow-band imaging-aided endoscopy for in vivo imaging of colitis and colon cancer in mice. Nat. Protoc. 6, 1471–1481 (2011).

    Article  CAS  Google Scholar 

  16. Kiesslich, R. et al. Chromoscopy-guided endomicroscopy increases the diagnostic yield of intraepithelial neoplasia in ulcerative colitis. Gastroenterology 132, 874–882 (2007).

    Article  Google Scholar 

  17. Hsiung, P.L. et al. Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy. Nat. Med. 14, 454–458 (2008).

    Article  CAS  Google Scholar 

  18. ten Hove, T., van Montfrans, C., Peppelenbosch, M.P. & van Deventer, S.J. Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn's disease. Gut 50, 206–211 (2002).

    Article  CAS  Google Scholar 

  19. Atreya, R. et al. Antibodies against tumor necrosis factor (TNF) induce T-cell apoptosis in patients with inflammatory bowel diseases via TNF receptor 2 and intestinal CD14 macrophages. Gastroenterology 141, 2026–2038 (2011).

    Article  CAS  Google Scholar 

  20. Kaymakcalan, Z. et al. Comparisons of affinities, avidities, and complement activation of adalimumab, infliximab, and etanercept in binding to soluble and membrane tumor necrosis factor. Clin. Immunol. 131, 308–316 (2009).

    Article  CAS  Google Scholar 

  21. Kiesslich, R., Goetz, M., Vieth, M., Galle, P.R. & Neurath, M.F. Technology insight: confocal laser endoscopy for in vivo diagnosis of colorectal cancer. Nat. Clin. Pract. Oncol. 4, 480–490 (2007).

    Article  Google Scholar 

  22. Neurath, M.F. & Travis, S.P. Mucosal healing in inflammatory bowel diseases: a systematic review. Gut 61, 1619–1635 (2012).

    Article  CAS  Google Scholar 

  23. Bird-Lieberman, E.L. et al. Molecular imaging using fluorescent lectins permits rapid endoscopic identification of dysplasia in Barrett's esophagus. Nat. Med. 18, 315–321 (2012).

    Article  CAS  Google Scholar 

  24. Medarova, Z., Rashkovetsky, L., Pantazopoulos, P. & Moore, A. Multiparametric monitoring of tumor response to chemotherapy by noninvasive imaging. Cancer Res. 69, 1182–1189 (2009).

    Article  CAS  Google Scholar 

  25. Monteleone, G., Pallone, F. & MacDonald, T.T. Emerging immunological targets in inflammatory bowel disease. Curr. Opin. Pharmacol. 11, 640–645 (2011).

    Article  CAS  Google Scholar 

  26. Kamada, N. et al. Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-γ axis. J. Clin. Invest. 118, 2269–2280 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Van den Brande, J.M. et al. Prediction of antitumour necrosis factor clinical efficacy by real-time visualisation of apoptosis in patients with Crohn's disease. Gut 56, 509–517 (2007).

    Article  CAS  Google Scholar 

  28. Van den Brande, J.M. et al. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's disease. Gastroenterology 124, 1774–1785 (2003).

    Article  CAS  Google Scholar 

  29. Mitoma, H. et al. Infliximab induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane TNF-α. Gastroenterology 128, 376–392 (2005).

    Article  CAS  Google Scholar 

  30. Reinisch, W. et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut 60, 780–787 (2011).

    Article  CAS  Google Scholar 

  31. Broadbridge, V.T., Karapetis, C.S. & Price, T.J. Cetuximab in metastatic colorectal cancer. Expert Rev. Anticancer Ther. 12, 555–565 (2012).

    Article  CAS  Google Scholar 

  32. Macedo, L.T., da Costa Lima, A.B. & Sasse, A.D. Addition of bevacizumab to first-line chemotherapy in advanced colorectal cancer: a systematic review and meta-analysis, with emphasis on chemotherapy subgroups. BMC Cancer 12, 89 (2012).

    Article  CAS  Google Scholar 

  33. Foersch, S. et al. Molecular imaging of VEGF in gastrointestinal cancer in vivo using confocal laser endomicroscopy. Gut 59, 1046–1055 (2010).

    Article  Google Scholar 

  34. Hueber, W. et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci. Transl. Med. 2, 52ra72 (2010).

    Article  Google Scholar 

  35. Papp, K.A. et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N. Engl. J. Med. 366, 1181–1189 (2012).

    Article  CAS  Google Scholar 

  36. Leonardi, C. et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N. Engl. J. Med. 366, 1190–1199 (2012).

    Article  CAS  Google Scholar 

  37. Tanaka, T., Narazaki, M. & Kishimoto, T. Anti-interleukin-6 receptor antibody, tocilizumab, for the treatment of autoimmune diseases. FEBS Lett. 585, 3699–3709 (2011).

    Article  CAS  Google Scholar 

  38. Rubin, D.T., Panaccione, R., Chao, J. & Robinson, A.M. A practical, evidence-based guide to the use of adalimumab in Crohn's disease. Curr. Med. Res. Opin. 27, 1803–1813 (2011).

    Article  Google Scholar 

  39. Rutgeerts, P. et al. Adalimumab induces and maintains mucosal healing in patients with crohn's disease: data from the EXTEND trial. Gastroenterology 142, 1102–1111. e1102 (2012).

    Article  CAS  Google Scholar 

  40. Riley, S.A. et al. Comparison of delayed release 5 aminosalicylic acid (mesalazine) and sulphasalazine in the treatment of mild to moderate ulcerative colitis relapse. Gut 29, 669–674 (1988).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank I. Zöller-Utz, P. Drummer and G. Göhring-Waldeck for excellent technical support, A. May for monitoring our study and S. Brand and F. Kolligs (University Hospital Munich-Grosshadern) for their contribution to the follow-up endoscopies. We thank the whole team of the Endoscopy Unit of the Medical Clinic 1 of the University Erlangen-Nuremberg, which greatly supported this work. We thank all patients who participated in this study. This research was supported by the German Research Foundation (clinical research unit KFO257) and the Emerging Fields Initiative and the Interdisciplinary Center for Clinical Research of the University Erlangen-Nuremberg, which helped to establish the infrastructure needed to conduct this study. Funds from the German Ministry for Science and Education (BMBF ZooMAP 01KI1003G) were used for intestinal sample preparation. The infrastructure of the presented project was supported by the Ludwig Demling Research Prize of the Deutsche Morbus Crohn/Colitis Ulcerosa Vereinigung (R.A.) and the United European Gastroenterology Federation Research Prize (M.F.N.).

Author information

Authors and Affiliations

  1. Medical Clinic 1, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany

    Raja Atreya, Helmut Neumann, Clemens Neufert, Maximilian J Waldner, Ulrike Billmeier, Yurdagül Zopf, Marcus Willma & Markus F Neurath

  2. Department of Biochemistry, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany

    Christine App & Ewald Hannappel

  3. Department of Anesthesiology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany

    Tino Münster

  4. Department of Surgery, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany

    Hermann Kessler

  5. Center for Clinical Studies, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany

    Stefanie Maas & Bernd Gebhardt

  6. Department of Pharmacy, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany

    Ralph Heimke-Brinck, Eva Reuter & Frank Dörje

  7. Department of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany

    Tilman T Rau

  8. Department of Medical Informatics, Biometry and Epidemiology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany

    Wolfgang Uter

  9. Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA

    Thomas D Wang

  10. Medical Clinic, St. Mary's Hospital, Frankfurt, Germany

    Ralf Kiesslich

  11. Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany

    Michael Vieth

Authors
  1. Raja Atreya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Helmut Neumann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Clemens Neufert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maximilian J Waldner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ulrike Billmeier
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yurdagül Zopf
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marcus Willma
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Christine App
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tino Münster
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hermann Kessler
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Stefanie Maas
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Bernd Gebhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ralph Heimke-Brinck
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Eva Reuter
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Frank Dörje
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Tilman T Rau
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Wolfgang Uter
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Thomas D Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Ralf Kiesslich
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Michael Vieth
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Ewald Hannappel
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Markus F Neurath
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.A. and M.F.N. designed and conducted the study, processed the data, performed the experiments, supervised the project and wrote the paper. H.N., C.N., M.J.W. and U.B. conducted the study, designed and performed the experiments and processed the data. Y.Z. and M.W. designed the study and processed the data. C.A., T.M. and H.K. performed the experiments and processed the data. S.M., B.G., T.D.W. and R.K. designed the study and processed the data. R.H.-B., E.R., F.D., T.T.R., W.U., M.V. and E.H. designed and performed the experiments and processed the data. All authors contributed to the review and editing of the manuscript.

Corresponding author

Correspondence to Markus F Neurath.

Ethics declarations

Competing interests

R. Atreya holds a professorship at the University of Erlangen-Nuremberg that is supported by a grant from Abbott. M.F.N. or R.A. have served as advisors to MSD, Pentax, Giuliani or Abbott.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 and Supplementary Table 1. (PDF 2289 kb)

Source data

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Atreya, R., Neumann, H., Neufert, C. et al. In vivo imaging using fluorescent antibodies to tumor necrosis factor predicts therapeutic response in Crohn's disease. Nat Med 20, 313–318 (2014). https://doi.org/10.1038/nm.3462

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3462

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research