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.

  • Technical Report
  • Published:

Quantitative micro positron emission tomography (PET) imaging for the in vivo determination of pancreatic islet graft survival

Nature Medicine volume 12, pages 1423–1428 (2006)Cite this article

Abstract

Islet transplantation is an attractive approach for treating type-1 diabetes, but there is a massive loss of transplanted islets. It is currently only possible to estimate islet mass indirectly, through measurement of circulating C-peptide and insulin levels. This type of estimation, however, is not sufficiently sensitive or reproducible for follow-up of individuals who have undergone islet transplantation. Here we show that islet graft survival could be assessed for 1 month in diabetic NOD mice using 9-(4-[18F]-fluoro-3-hydroxymethylbutyl)guanine ([18F]FHBG)–positron emission tomography (PET) technology, the PET signal reflecting insulin secretory capacity of transplanted islets. Expression of the gene encoding viral interleukin-10 (vIL-10), was measurable in real time with PET scanning. Additionally, we addressed the clinical potential of this approach by visualizing transplanted islets in the liver, the preferred clinical transplantation site. We conclude that quantitative in vivo PET imaging is a valid method for facilitating the development of protocols for prolonging islet survival, with the potential for tracking human transplants.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: HSV1-sr39tk expression in response to increasing doses of rAD-TK, the effect of rAD-TK on insulin secretion and cytotoxicity, and uptake of [18F]FHBG by cultured islets.
Figure 2: PET scanning of islets transplanted under the kidney capsule.
Figure 3: vIL-10 and sr39TK protein expression in response to increasing doses of rAD-vIL10-ITK and rAD-ITK.
Figure 4: Time-course monitoring of transplanted islets in diabetic NOD mice.
Figure 5: PET scanning of transplanted islets in the liver.

Similar content being viewed by others

References

  1. Shapiro, A.M. et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N. Engl. J. Med. 343, 230–238 (2000).

    Article  CAS  Google Scholar 

  2. Hathout, E., Lakey, J. & Shapiro, J. Islet transplant: an option for childhood diabetes. Arch. Dis. Child. 88, 591–594 (2003).

    Article  CAS  Google Scholar 

  3. Ryan, E.A. et al. Five-year follow-up after clinical islet transplantation. Diabetes 54, 2060–2069 (2005).

    Article  CAS  Google Scholar 

  4. Shapiro, A.M. et al. Novel approaches toward early diagnosis of islet allograft rejection. Transplantation 71, 1709–1718 (2001).

    Article  CAS  Google Scholar 

  5. Yu, Y. et al. Quantification of target gene expression by imaging reporter gene expression in living animals. Nat. Med. 6, 933–937 (2000).

    Article  CAS  Google Scholar 

  6. Gambhir, S.S. et al. A mutant herpes simplex virus type 1 thymidine kinase reporter gene shows improved sensitivity for imaging reporter gene expression with positron emission tomography. Proc. Natl. Acad. Sci. USA 97, 2785–2790 (2000).

    Article  CAS  Google Scholar 

  7. Massoud, T. & Gambhir, S.S. Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev. 17, 545–580 (2003).

    Article  CAS  Google Scholar 

  8. Herschman, H.R. Micro-PET imaging and small animal models of disease. Curr. Opin. Immunol. 15, 378–384 (2003).

    Article  CAS  Google Scholar 

  9. Chwalinski, S. & Potten, C.S. Crypt base columnar cells in ileum of BDF1 male mice—their numbers and some features of their proliferation. Am. J. Anat. 186, 397–406 (1989).

    Article  CAS  Google Scholar 

  10. Yang, Z. et al. Suppression of autoimmune diabetes by viral IL-10 gene transfer. J. Immunol. 168, 6479–6485 (2002).

    Article  CAS  Google Scholar 

  11. Carter, J.D. et al. Viral IL-10-mediated immune regulation in pancreatic islet transplantation. Mol. Ther. 12, 360–368 (2005).

    Article  CAS  Google Scholar 

  12. Stock, P.G. & Bluestone, J.A. Beta-cell replacement for type 1 diabetes. Annu. Rev. Med. 55, 133–156 (2004).

    Article  CAS  Google Scholar 

  13. Robertson, R.P. Islet transplantation as a treatment for diabetes – a work in progress. N. Engl. J. Med. 350, 694–705 (2004).

    Article  CAS  Google Scholar 

  14. Jirak, D. et al. MRI of transplanted pancreatic islets. Magn. Reson. Med. 52, 1228–1233 (2004).

    Article  Google Scholar 

  15. Evgenov, N.V., Medarova, Z., Dai, G., Bonner-Weir, S. & Moore, A. In vivo imaging of islet transplantation. Nat. Med. 12, 144–148 (2006).

    Article  CAS  Google Scholar 

  16. Oca-Cossio, J. et al. Magnetically labeled insulin-secreting cells. Biochem. Biophys. Res. Commun. 319, 569–575 (2004).

    Article  CAS  Google Scholar 

  17. Paty, B.W., Bonner-Weir, S., Laughlin, M.R., McEwan, A.J. & Shapiro, A.M.J. Toward development to imaging modalities from islets after transplantation: insights from the National Institutes of Health workshop on beta cell imaging. Transplantation 77, 1133–1137 (2004).

    Article  Google Scholar 

  18. Lu, Y. et al. Bioluminescent monitoring of islet graft survival after transplantation. Mol. Ther. 9, 428–435 (2004).

    Article  CAS  Google Scholar 

  19. Fowler, M. et al. Assessment of pancreatic islet mass after islet transplantation using in vivo bioluminescence imaging. Transplantation 79, 768–776 (2005).

    Article  Google Scholar 

  20. Salvalaggio, P.R. et al. Islet filtration: a simple and rapid new purification procedure that avoids ficoll and improves islet mass and function. Transplantation 74, 877–879 (2002).

    Article  CAS  Google Scholar 

  21. Becker, T.C. et al. Use of recombinant adenovirus for metabolic engineering of mammalian cells. Methods Cell. Biol. 43, 161–189 (1994).

    Article  CAS  Google Scholar 

  22. Ponde, D.E., Dence, C.S., Schuster, D.P. & Welch, M.J. Rapid and reproducible radiosynthesis of [18F]FHBG. Nucl. Med. Biol. 31, 133–138 (2004).

    Article  CAS  Google Scholar 

  23. Qi, J., Leahy, R.M., Hsu, C., Farquhar, T.H. & Cherry, S.R. Fully 3D Bayesian image reconstruction for the ECAT EXACT HR+. IEEE Trans. Nucl. Sci. 45, 1096–1103 (1998).

    Article  Google Scholar 

  24. Chatziioannou, A. et al. Comparison of 3-D maximum a posteriori and filtered back projection algorithms for high-resolution animal imaging with microPET. IEEE Trans. Med. Imaging 19, 507–512 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank V. Sossi for assistance with data reconstruction, M.J. Adam for advice on [18F]FHBG radiosynthesis, S. McCormick and M. Speck for technical assistance, and M.E. Black (Washington State University) for antibody to HSV1-sr39TK. These studies were supported by funding to C.H.S.M. from the Canadian Institutes of Health Research (#590007) and the Canadian Foundation for Innovation.

Author information

Authors and Affiliations

  1. Department of Cellular & Physiological Sciences and the Diabetes Research Group, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, V6T 1Z3, British Columbia, Canada

    Su-Jin Kim, Cuilan Nian & Christopher H S McIntosh

  2. Department of Medicine, Division of Neurology, 2221 Westbrook Mall, Vancouver, V6T 2B5, British Columbia, Canada

    Doris J Doudet

  3. TRI-University Meson Facility (TRIUMF), 4004 Westbrook Mall, Vancouver, V6T 2A3, British Columbia, Canada

    Andrei R Studenov & Thomas J Ruth

  4. Departments of Radiology and Bioengineering, Bio-X Program, Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, James H. Clark Center, 318 Campus Drive, Stanford, 94305, California, USA

    Sanjiv Sam Gambhir

Authors
  1. Su-Jin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Doris J Doudet
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrei R Studenov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cuilan Nian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas J Ruth
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sanjiv Sam Gambhir
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christopher H S McIntosh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christopher H S McIntosh.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Imunohistochemical staining of the left and right kidneys. (PDF 46 kb)

Supplementary Fig. 2

Imunohistochemical staining of islet transplanted kidneys. (PDF 92 kb)

Supplementary Fig. 3

The presence of DNA encoding vIL-10 in rAD-vIL10-ITK treated islet transplanted kidneys and plasma vIL-10 levels. (PDF 37 kb)

Supplementary Fig. 4

Cell viability on treatment with FHBG. Islets isolated from male C57BL/6 mice were infected with 250 m.o.i. of rAD-TK. (PDF 17 kb)

Supplementary Video 1

1 h-time course PET imaging of islets transplanted under the kidney capsule of C57 BL/6 mouse. (MOV 742 kb)

Supplementary Video 2

1 h-time course PET imaging of islet transplanted into the liver of C57 BL/6 mouse. (MOV 814 kb)

Supplementary Methods (PDF 21 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, SJ., Doudet, D., Studenov, A. et al. Quantitative micro positron emission tomography (PET) imaging for the in vivo determination of pancreatic islet graft survival. Nat Med 12, 1423–1428 (2006). https://doi.org/10.1038/nm1458

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1458

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing