TY - JOUR
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 R.
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.
N1 - Publisher Copyright:
© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons
PY - 2022/3
Y1 - 2022/3
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.
AB - 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.
KW - animal models: nonhuman primate
KW - immune regulation
KW - immunosuppressive regimens
KW - islet transplantation
KW - translational research/science
KW - xenotransplantation
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U2 - 10.1111/ajt.16876
DO - 10.1111/ajt.16876
M3 - Article
C2 - 34704345
AN - SCOPUS:85120348851
SN - 1600-6135
VL - 22
SP - 745
EP - 760
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - 3
ER -