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Xenotransplantation of Genetically Modified Neonatal Pig Islets Cures Diabetes in Baboons

Xenotransplantation using porcine donors is rapidly approaching clinical applicability as an alternative therapy for treatment of many end-stage diseases including type 1 diabetes. Porcine neonatal islet cell clusters (NICC) have normalised blood sugar levels for relatively short periods in the prec...

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Autores principales: Hawthorne, Wayne J., Salvaris, Evelyn J., Chew, Yi Vee, Burns, Heather, Hawkes, Joanne, Barlow, Helen, Hu, Min, Lew, Andrew M., Nottle, Mark B., O’Connell, Philip J., Cowan, Peter J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9243461/
https://www.ncbi.nlm.nih.gov/pubmed/35784286
http://dx.doi.org/10.3389/fimmu.2022.898948
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author Hawthorne, Wayne J.
Salvaris, Evelyn J.
Chew, Yi Vee
Burns, Heather
Hawkes, Joanne
Barlow, Helen
Hu, Min
Lew, Andrew M.
Nottle, Mark B.
O’Connell, Philip J.
Cowan, Peter J.
author_facet Hawthorne, Wayne J.
Salvaris, Evelyn J.
Chew, Yi Vee
Burns, Heather
Hawkes, Joanne
Barlow, Helen
Hu, Min
Lew, Andrew M.
Nottle, Mark B.
O’Connell, Philip J.
Cowan, Peter J.
author_sort Hawthorne, Wayne J.
collection PubMed
description Xenotransplantation using porcine donors is rapidly approaching clinical applicability as an alternative therapy for treatment of many end-stage diseases including type 1 diabetes. Porcine neonatal islet cell clusters (NICC) have normalised blood sugar levels for relatively short periods in the preclinical diabetic rhesus model but have met with limited success in the stringent baboon model. Here we report that NICC from genetically modified (GM) pigs deleted for αGal and expressing the human complement regulators CD55 and CD59 can cure diabetes long-term in immunosuppressed baboons, with maximum graft survival exceeding 22 months. Five diabetic baboons were transplanted intraportally with 9,673 – 56,913 islet equivalents (IEQ) per kg recipient weight. Immunosuppression consisted of T cell depletion with an anti-CD2 mAb, tacrolimus for the first 4 months, and maintenance with belatacept and anti-CD154; no anti-inflammatory treatment or cytomegalovirus (CMV) prophylaxis/treatment was given. This protocol was well tolerated, with all recipients maintaining or gaining weight. Recipients became insulin-independent at a mean of 87 ± 43 days post-transplant and remained insulin-independent for 397 ± 174 days. Maximum graft survival was 675 days. Liver biopsies showed functional islets staining for all islet endocrine components, with no evidence of the inflammatory blood-mediated inflammatory reaction (IBMIR) and minimal leukocytic infiltration. The costimulation blockade-based immunosuppressive protocol prevented an anti-pig antibody response in all recipients. In conclusion, we demonstrate that genetic modification of the donor pig enables attenuation of early islet xenograft injury, and in conjunction with judicious immunosuppression provides excellent long-term function and graft survival in the diabetic baboon model.
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spelling pubmed-92434612022-07-01 Xenotransplantation of Genetically Modified Neonatal Pig Islets Cures Diabetes in Baboons Hawthorne, Wayne J. Salvaris, Evelyn J. Chew, Yi Vee Burns, Heather Hawkes, Joanne Barlow, Helen Hu, Min Lew, Andrew M. Nottle, Mark B. O’Connell, Philip J. Cowan, Peter J. Front Immunol Immunology Xenotransplantation using porcine donors is rapidly approaching clinical applicability as an alternative therapy for treatment of many end-stage diseases including type 1 diabetes. Porcine neonatal islet cell clusters (NICC) have normalised blood sugar levels for relatively short periods in the preclinical diabetic rhesus model but have met with limited success in the stringent baboon model. Here we report that NICC from genetically modified (GM) pigs deleted for αGal and expressing the human complement regulators CD55 and CD59 can cure diabetes long-term in immunosuppressed baboons, with maximum graft survival exceeding 22 months. Five diabetic baboons were transplanted intraportally with 9,673 – 56,913 islet equivalents (IEQ) per kg recipient weight. Immunosuppression consisted of T cell depletion with an anti-CD2 mAb, tacrolimus for the first 4 months, and maintenance with belatacept and anti-CD154; no anti-inflammatory treatment or cytomegalovirus (CMV) prophylaxis/treatment was given. This protocol was well tolerated, with all recipients maintaining or gaining weight. Recipients became insulin-independent at a mean of 87 ± 43 days post-transplant and remained insulin-independent for 397 ± 174 days. Maximum graft survival was 675 days. Liver biopsies showed functional islets staining for all islet endocrine components, with no evidence of the inflammatory blood-mediated inflammatory reaction (IBMIR) and minimal leukocytic infiltration. The costimulation blockade-based immunosuppressive protocol prevented an anti-pig antibody response in all recipients. In conclusion, we demonstrate that genetic modification of the donor pig enables attenuation of early islet xenograft injury, and in conjunction with judicious immunosuppression provides excellent long-term function and graft survival in the diabetic baboon model. Frontiers Media S.A. 2022-06-16 /pmc/articles/PMC9243461/ /pubmed/35784286 http://dx.doi.org/10.3389/fimmu.2022.898948 Text en Copyright © 2022 Hawthorne, Salvaris, Chew, Burns, Hawkes, Barlow, Hu, Lew, Nottle, O’Connell and Cowan https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Hawthorne, Wayne J.
Salvaris, Evelyn J.
Chew, Yi Vee
Burns, Heather
Hawkes, Joanne
Barlow, Helen
Hu, Min
Lew, Andrew M.
Nottle, Mark B.
O’Connell, Philip J.
Cowan, Peter J.
Xenotransplantation of Genetically Modified Neonatal Pig Islets Cures Diabetes in Baboons
title Xenotransplantation of Genetically Modified Neonatal Pig Islets Cures Diabetes in Baboons
title_full Xenotransplantation of Genetically Modified Neonatal Pig Islets Cures Diabetes in Baboons
title_fullStr Xenotransplantation of Genetically Modified Neonatal Pig Islets Cures Diabetes in Baboons
title_full_unstemmed Xenotransplantation of Genetically Modified Neonatal Pig Islets Cures Diabetes in Baboons
title_short Xenotransplantation of Genetically Modified Neonatal Pig Islets Cures Diabetes in Baboons
title_sort xenotransplantation of genetically modified neonatal pig islets cures diabetes in baboons
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9243461/
https://www.ncbi.nlm.nih.gov/pubmed/35784286
http://dx.doi.org/10.3389/fimmu.2022.898948
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