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 journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)745-760
Number of pages16
JournalAmerican Journal of Transplantation
Volume22
Issue number3
DOIs
StatePublished - 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

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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