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

Bernhard J. Hering; Martin Wijkstrom; Melanie L. Graham; Maria Hårdstedt; Tor C. Aasheim; Tun Jie; Jeffrey D. Ansite; Masahiko Nakano; Jane Cheng; Wei Li; Kathleen Moran; Uwe Christians; Colleen Finnegan; Charles D. Mills; David E. Sutherland; Pratima Bansal-Pakala; Michael P. Murtaugh; Nicole Kirchhof; Henk Jan Schuurman

doi:10.1038/nm1369

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

Bernhard J. Hering, Martin Wijkstrom, Melanie L. Graham, Maria Hårdstedt, Tor C. Aasheim, Tun Jie, Jeffrey D. Ansite, Masahiko Nakano, Jane Cheng, Wei Li, Kathleen Moran, Uwe Christians, Colleen Finnegan, Charles D. Mills, David E. Sutherland, Pratima Bansal-Pakala, Michael P. Murtaugh, Nicole Kirchhof, Henk Jan Schuurman

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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.

Original language	English (US)
Pages (from-to)	301-303
Number of pages	3
Journal	Nature Medicine
Volume	12
Issue number	3
DOIs	https://doi.org/10.1038/nm1369
State	Published - Mar 2006

Bibliographical note

Funding Information:
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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Hering, B. J., Wijkstrom, M., Graham, M. L., Hårdstedt, M., Aasheim, T. C., Jie, T., Ansite, J. D., Nakano, M., Cheng, J., Li, W., Moran, K., Christians, U., Finnegan, C., Mills, C. D., Sutherland, D. E., Bansal-Pakala, P., Murtaugh, M. P., Kirchhof, N., & Schuurman, H. J. (2006). Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nature Medicine, 12(3), 301-303. https://doi.org/10.1038/nm1369

Hering, BJ, Wijkstrom, M, Graham, ML, Hårdstedt, M, Aasheim, TC, Jie, T, Ansite, JD, Nakano, M, Cheng, J, Li, W, Moran, K, Christians, U, Finnegan, C, Mills, CD, Sutherland, DE, Bansal-Pakala, P, Murtaugh, MP, Kirchhof, N & Schuurman, HJ 2006, 'Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates', Nature Medicine, vol. 12, no. 3, pp. 301-303. https://doi.org/10.1038/nm1369

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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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note = "Funding Information: 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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AU - Hårdstedt, Maria

AU - Aasheim, Tor C.

AU - Jie, Tun

AU - Ansite, Jeffrey D.

AU - Nakano, Masahiko

AU - Cheng, Jane

AU - Li, Wei

AU - Moran, Kathleen

AU - Christians, Uwe

AU - Finnegan, Colleen

AU - Mills, Charles D.

AU - Sutherland, David E.

AU - Bansal-Pakala, Pratima

AU - Murtaugh, Michael P.

AU - Kirchhof, Nicole

AU - Schuurman, Henk Jan

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

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