Clinically available immunosuppression averts rejection but not systemic inflammation after porcine islet xenotransplant in cynomolgus macaques

Melanie L Graham; Sabarinathan Ramachandran; Amar Singh; Meghan E.G. Moore; E. Brian Flanagan; Agnes Azimzadeh; Christopher Burlak; Kate Mueller; Kyra Martins; Takayuki Anazawa; Balamurugan N. Appakalai; Pratima Bansal-Pakala; Michael P Murtaugh; Timothy D O'Brien; Klearchos K Papas; Thomas Spizzo; Henk J. Schuurman; Wayne W. Hancock; Bernhard J. Hering

doi:10.1111/ajt.16876

Clinically available immunosuppression averts rejection but not systemic inflammation after porcine islet xenotransplant in cynomolgus macaques

Melanie L Graham, Sabarinathan Ramachandran, Amar Singh, Meghan E.G. Moore, E. Brian Flanagan, Agnes Azimzadeh, Christopher Burlak, Kate Mueller, Kyra Martins, Takayuki Anazawa, Balamurugan N. Appakalai, Pratima Bansal-Pakala, Michael P Murtaugh, Timothy D O'Brien, Klearchos K Papas, Thomas Spizzo, Henk J. Schuurman, Wayne W. Hancock, Bernhard J. Hering

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

A safe, efficacious, and clinically applicable immunosuppressive regimen is necessary for islet xenotransplantation to become a viable treatment option for diabetes. We performed intraportal transplants of wild-type adult porcine islets in 25 streptozotocin-diabetic cynomolgus monkeys. Islet engraftment was good in 21, partial in 3, and poor in 1 recipient. Median xenograft survival was 25 days with rapamycin and CTLA4Ig immunosuppression. Adding basiliximab induction and maintenance tacrolimus to the base regimen significantly extended median graft survival to 147 days (p <.0001), with three animals maintaining insulin-free xenograft survival for 265, 282, and 288 days. We demonstrate that this regimen suppresses non-Gal anti-pig antibody responses, circulating effector memory T cell expansion, effector function, and infiltration of the graft. However, a chronic systemic inflammatory state manifested in the majority of recipients with long-term graft survival indicated by increased neutrophil to lymphocyte ratio, IL-6, MCP-1, CD40, and CRP expression. This suggests that this immunosuppression regimen fails to regulate innate immunity and resulting inflammation is significantly associated with increased incidence and severity of adverse events making this regimen unacceptable for translation. Additional studies are needed to optimize a maintenance regimen for regulating the innate inflammatory response.

Original language	English (US)
Pages (from-to)	745-760
Number of pages	16
Journal	American Journal of Transplantation
Volume	22
Issue number	3
DOIs	https://doi.org/10.1111/ajt.16876
State	Published - Mar 2022

Bibliographical note

Funding Information:
We gratefully acknowledge the excellent and expert care, husbandry, and training of our animals by the team at the University of Minnesota's Preclinical Research Center, coordinated by Lucas Mutch and Jody Janecek. We thank Jean Witson, Thomas Gilmore, Jeffrey Ansite, Zachary Swanson, David Heller, Steven Kass, Emily Hennessy, Anil Pahuja, and Minna Honkanen‐Scott of the Schulze Diabetes Institute at the University of Minnesota. We thank Spring Point Project for providing donor pigs. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number 7U19AI067151 and the Juvenile Diabetes Research Foundation under Award Number 21‐2006‐881. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Juvenile Diabetes Research Foundation. This work was also supported by a generous gift from the Richard M. Schulze Family Foundation and individual philanthropy through the University of Minnesota Foundation.

Funding Information:
National Institute of Allergy and Infectious Diseases of the National Institutes of Health, Grant/Award Number: 7U19AI067151; Juvenile Diabetes Research Foundation, Grant/Award Number: 21‐2006‐881; Richard M. Schulze Family Foundation; individual philanthropy through the University of Minnesota Foundation.

Publisher Copyright:
© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons

Keywords

animal models: nonhuman primate
immune regulation
immunosuppressive regimens
islet transplantation
translational research/science
xenotransplantation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/ajt.16876

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Graham, M. L., Ramachandran, S., Singh, A., Moore, M. E. G., Flanagan, E. B., Azimzadeh, A., Burlak, C., Mueller, K., Martins, K., Anazawa, T., Appakalai, B. N., Bansal-Pakala, P., Murtaugh, M. P., O'Brien, T. D., Papas, K. K., Spizzo, T., Schuurman, H. J., Hancock, W. W., & Hering, B. J. (2022). Clinically available immunosuppression averts rejection but not systemic inflammation after porcine islet xenotransplant in cynomolgus macaques. American Journal of Transplantation, 22(3), 745-760. https://doi.org/10.1111/ajt.16876

Graham, ML , Ramachandran, S , Singh, A , Moore, MEG , Flanagan, EB, Azimzadeh, A, Burlak, C, Mueller, K, Martins, K, Anazawa, T, Appakalai, BN, Bansal-Pakala, P, Murtaugh, MP, O'Brien, TD, Papas, KK, Spizzo, T, Schuurman, HJ, Hancock, WW & Hering, BJ 2022, 'Clinically available immunosuppression averts rejection but not systemic inflammation after porcine islet xenotransplant in cynomolgus macaques', American Journal of Transplantation, vol. 22, no. 3, pp. 745-760. https://doi.org/10.1111/ajt.16876

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title = "Clinically available immunosuppression averts rejection but not systemic inflammation after porcine islet xenotransplant in cynomolgus macaques",

abstract = "A safe, efficacious, and clinically applicable immunosuppressive regimen is necessary for islet xenotransplantation to become a viable treatment option for diabetes. We performed intraportal transplants of wild-type adult porcine islets in 25 streptozotocin-diabetic cynomolgus monkeys. Islet engraftment was good in 21, partial in 3, and poor in 1 recipient. Median xenograft survival was 25 days with rapamycin and CTLA4Ig immunosuppression. Adding basiliximab induction and maintenance tacrolimus to the base regimen significantly extended median graft survival to 147 days (p <.0001), with three animals maintaining insulin-free xenograft survival for 265, 282, and 288 days. We demonstrate that this regimen suppresses non-Gal anti-pig antibody responses, circulating effector memory T cell expansion, effector function, and infiltration of the graft. However, a chronic systemic inflammatory state manifested in the majority of recipients with long-term graft survival indicated by increased neutrophil to lymphocyte ratio, IL-6, MCP-1, CD40, and CRP expression. This suggests that this immunosuppression regimen fails to regulate innate immunity and resulting inflammation is significantly associated with increased incidence and severity of adverse events making this regimen unacceptable for translation. Additional studies are needed to optimize a maintenance regimen for regulating the innate inflammatory response.",

keywords = "animal models: nonhuman primate, immune regulation, immunosuppressive regimens, islet transplantation, translational research/science, xenotransplantation",

author = "Graham, {Melanie L} and Sabarinathan Ramachandran and Amar Singh and Moore, {Meghan E.G.} and Flanagan, {E. Brian} and Agnes Azimzadeh and Christopher Burlak and Kate Mueller and Kyra Martins and Takayuki Anazawa and Appakalai, {Balamurugan N.} and Pratima Bansal-Pakala and Murtaugh, {Michael P} and O'Brien, {Timothy D} and Papas, {Klearchos K} and Thomas Spizzo and Schuurman, {Henk J.} and Hancock, {Wayne W.} and Hering, {Bernhard J.}",

note = "Funding Information: We gratefully acknowledge the excellent and expert care, husbandry, and training of our animals by the team at the University of Minnesota's Preclinical Research Center, coordinated by Lucas Mutch and Jody Janecek. We thank Jean Witson, Thomas Gilmore, Jeffrey Ansite, Zachary Swanson, David Heller, Steven Kass, Emily Hennessy, Anil Pahuja, and Minna Honkanen‐Scott of the Schulze Diabetes Institute at the University of Minnesota. We thank Spring Point Project for providing donor pigs. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number 7U19AI067151 and the Juvenile Diabetes Research Foundation under Award Number 21‐2006‐881. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Juvenile Diabetes Research Foundation. This work was also supported by a generous gift from the Richard M. Schulze Family Foundation and individual philanthropy through the University of Minnesota Foundation. Funding Information: National Institute of Allergy and Infectious Diseases of the National Institutes of Health, Grant/Award Number: 7U19AI067151; Juvenile Diabetes Research Foundation, Grant/Award Number: 21‐2006‐881; Richard M. Schulze Family Foundation; individual philanthropy through the University of Minnesota Foundation. Publisher Copyright: {\textcopyright} 2021 The American Society of Transplantation and the American Society of Transplant Surgeons",

year = "2022",

month = mar,

doi = "10.1111/ajt.16876",

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T1 - Clinically available immunosuppression averts rejection but not systemic inflammation after porcine islet xenotransplant in cynomolgus macaques

AU - Graham, Melanie L

AU - Ramachandran, Sabarinathan

AU - Singh, Amar

AU - Moore, Meghan E.G.

AU - Flanagan, E. Brian

AU - Azimzadeh, Agnes

AU - Burlak, Christopher

AU - Mueller, Kate

AU - Martins, Kyra

AU - Anazawa, Takayuki

AU - Appakalai, Balamurugan N.

AU - Bansal-Pakala, Pratima

AU - Murtaugh, Michael P

AU - O'Brien, Timothy D

AU - Papas, Klearchos K

AU - Spizzo, Thomas

AU - Schuurman, Henk J.

AU - Hancock, Wayne W.

AU - Hering, Bernhard J.

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N2 - A safe, efficacious, and clinically applicable immunosuppressive regimen is necessary for islet xenotransplantation to become a viable treatment option for diabetes. We performed intraportal transplants of wild-type adult porcine islets in 25 streptozotocin-diabetic cynomolgus monkeys. Islet engraftment was good in 21, partial in 3, and poor in 1 recipient. Median xenograft survival was 25 days with rapamycin and CTLA4Ig immunosuppression. Adding basiliximab induction and maintenance tacrolimus to the base regimen significantly extended median graft survival to 147 days (p <.0001), with three animals maintaining insulin-free xenograft survival for 265, 282, and 288 days. We demonstrate that this regimen suppresses non-Gal anti-pig antibody responses, circulating effector memory T cell expansion, effector function, and infiltration of the graft. However, a chronic systemic inflammatory state manifested in the majority of recipients with long-term graft survival indicated by increased neutrophil to lymphocyte ratio, IL-6, MCP-1, CD40, and CRP expression. This suggests that this immunosuppression regimen fails to regulate innate immunity and resulting inflammation is significantly associated with increased incidence and severity of adverse events making this regimen unacceptable for translation. Additional studies are needed to optimize a maintenance regimen for regulating the innate inflammatory response.

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KW - animal models: nonhuman primate

KW - immune regulation

KW - immunosuppressive regimens

KW - islet transplantation

KW - translational research/science

KW - xenotransplantation

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Clinically available immunosuppression averts rejection but not systemic inflammation after porcine islet xenotransplant in cynomolgus macaques

Abstract

Bibliographical note

Keywords

UN SDGs

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