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Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates

Nature Medicine volume 12, pages 301–303 (2006)Cite this article

Abstract

Cell-based diabetes therapy requires an abundant cell source. Here, we report reversal of diabetes for more than 100 d in cynomolgus macaques after intraportal transplantation of cultured islets from genetically unmodified pigs without Gal-specific antibody manipulation. Immunotherapy with CD25-specific and CD154-specific monoclonal antibodies, FTY720 (or tacrolimus), everolimus and leflunomide suppressed indirect activation of T cells, elicitation of non-Gal pig-specific IgG antibody, intragraft expression of proinflammatory cytokines and invasion of infiltrating mononuclear cells into islets.

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Figure 1: Functional and histologic islet xenograft survival.
Figure 2: Immune responses to islet xenografts.

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Acknowledgements

We thank Novartis Pharma AG (Basel, Switzerland) for providing basiliximab, ABI793, FTY720, everolimus and cyclosporine as well as drug-monitoring assays (V. Brinkmann, R. Buergi, G. Engel, F. Legay, W. Schuler); Nippon Kayaku (Tokyo, Japan) for providing 15-deoxyspergualin; E. Rieke and K. Larson for animal care; H.J. Zhang, I. Matsumoto, T. Sawada, B. Liu, L. Guenther, A. Bauer, A. Friberg, J. Kulesa and M. Abdullah for performing porcine islet processing and testing; S. Clemmings, N. Sullivan and K. Hire for assistance with immune monitoring studies; J.S. Arn for facilitating access to miniature swine donors; J. Bendrick-Peart for drug-level determinations; A.C. Gruessner and B.R. Lindgren for statistical analysis of data; M.E. Knatterud for editing the manuscript; and H. Auchincloss, Jr., D.K.C.C. Cooper, J.L. Greenstein and D.H. Sachs for scientific advice. Our study was supported by Immerge BioTherapeutics, Inc., the Eunice L. Dwan Diabetes Research Endowment, the Children with Diabetes Foundation and the Winston and Maxine Wallin Islet Xenotransplant Fund. Immerge BioTherapeutics contributed to the design and conduct of the study; collection, analysis and interpretation of the data as well as preparation of the manuscript.

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Authors and Affiliations

  1. Department of Surgery, Diabetes Institute for Immunology and Transplantation, University of Minnesota, 424 Harvard Street SE, Minneapolis, 55455, Minnesota, USA

    Bernhard J Hering, Martin Wijkstrom, Melanie L Graham, Maria Hårdstedt, Tor C Aasheim, Tun Jie, Jeffrey D Ansite, Masahiko Nakano, Charles D Mills, David E Sutherland & Pratima Bansal-Pakala

  2. Immerge BioTherapeutics, Inc., Building 75, Third Avenue, Charlestown, 02129, Massachusetts, USA

    Jane Cheng, Wei Li, Kathleen Moran & Henk-Jan Schuurman

  3. Department of Anesthesia, University of Colorado Health Sciences Center, 4200 East 9th Avenue B113, Denver, 80262, Colorado, USA

    Uwe Christians

  4. Department of Veterinary and Biomedical Sciences, University of Minnesota, 205 Veterinary Science Building, 1971 Commonwealth Avenue, St. Paul, 55108, Minnesota, USA

    Colleen Finnegan & Michael P Murtaugh

  5. Department of Veterinary Population Medicine, 225 Veterinary Medical Center, 1365 Gortner Avenue, University of Minnesota, St. Paul, 55108, Minnesota, USA

    Nicole Kirchhof

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Corresponding author

Correspondence to Bernhard J Hering.

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Competing interests

Jane Cheng, Wei Li, Kathleen Moran and Henk-Jan Schuurman were employees of Immerge Biotherapeutics, Inc. at the time of the study.

Supplementary information

Supplementary Fig. 1

Drug exposure. (PDF 140 kb)

Supplementary Fig. 2

Immunopathology of pig-to-nonhuman primate islet xenograft rejection. (PDF 168 kb)

Supplementary Fig. 3

Gal-specific IgM levels. (PDF 66 kb)

Supplementary Fig. 4

Intragraft expression of CTL effector molecule transcripts. (PDF 105 kb)

Supplementary Table 1

Immunosuppressive drugs used and their mechanism of action. (PDF 33 kb)

Supplementary Table 2

Quantitative histopathologic analysis and semiquantitative immunohistochemical characterization of cells infiltrating porcine islet xenografts in immunosuppressed cynomolgus macaques. (PDF 33 kb)

Supplementary Table 3

Adverse events. (PDF 12 kb)

Supplementary Table 4

Non-Gal pig-specific IgG antibodies as detected in a flow cytometry assay. (PDF 18 kb)

Supplementary Methods (PDF 80 kb)

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Hering, B., Wijkstrom, M., Graham, M. et al. Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nat Med 12, 301–303 (2006). https://doi.org/10.1038/nm1369

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