Abstract
Islet cell transplantation can lead to insulin independence, reduced hypoglycemia, and amelioration of diabetes complications in patients with type 1 diabetes. The systemic delivery of anti-inflammatory agents, while considered crucial to limit the early loss of islets associated with intrahepatic infusion, increases the burden of immunosuppression. In an effort to decrease the pharmaceutical load to the patient, we modified the pancreatic islet surface with long-chain poly(ethylene glycol) (PEG) to mitigate detrimental host-implant interactions. The effect of PEGylation on islet engraftment and long-term survival was examined in a robust nonhuman primate model via three paired transplants of dosages 4300, 8300, and 10 000 islet equivalents per kg body weight. A reduced immunosuppressive regimen of anti-thymocyte globulin induction plus tacrolimus in the first posttransplant month followed by maintenance with sirolimus monotherapy was employed. To limit transplant variability, two of the three pairs were closely MHC-matched recipients and received MHC-disparate PEGylated or untreated islets isolated from the same donors. Recipients of PEGylated islets exhibited significantly improved early c-peptide levels, reduced exogenous insulin requirements, and superior glycemic control, as compared to recipients of untreated islets. These results indicate that this simple islet modification procedure may improve islet engraftment and survival in the setting of reduced immunosuppression.
| Original language | English (US) |
|---|---|
| Journal | American Journal of Transplantation |
| DOIs | |
| State | Accepted/In press - Jan 1 2019 |
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Keywords
- animal models: nonhuman primate
- basic (laboratory) research/science
- immunosuppression/immune modulation
- immunosuppressive regimens
- islet transplantation
- islets of Langerhans
- translational research/science
ASJC Scopus subject areas
- Immunology and Allergy
- Transplantation
- Pharmacology (medical)
Cite this
Transplantation of PEGylated islets enhances therapeutic efficacy in a diabetic nonhuman primate model. / Stabler, Cherie L.; Giraldo, Jaime A.; Berman, Dora M.; Gattás-Asfura, Kerim M.; Willman, Melissa A.; Rabassa, Alexander; Geary, James; Diaz, Waldo; Kenyon, Norma S.; Kenyon, Norma S.
In: American Journal of Transplantation, 01.01.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Transplantation of PEGylated islets enhances therapeutic efficacy in a diabetic nonhuman primate model
AU - Stabler, Cherie L.
AU - Giraldo, Jaime A.
AU - Berman, Dora M.
AU - Gattás-Asfura, Kerim M.
AU - Willman, Melissa A.
AU - Rabassa, Alexander
AU - Geary, James
AU - Diaz, Waldo
AU - Kenyon, Norma S.
AU - Kenyon, Norma S.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Islet cell transplantation can lead to insulin independence, reduced hypoglycemia, and amelioration of diabetes complications in patients with type 1 diabetes. The systemic delivery of anti-inflammatory agents, while considered crucial to limit the early loss of islets associated with intrahepatic infusion, increases the burden of immunosuppression. In an effort to decrease the pharmaceutical load to the patient, we modified the pancreatic islet surface with long-chain poly(ethylene glycol) (PEG) to mitigate detrimental host-implant interactions. The effect of PEGylation on islet engraftment and long-term survival was examined in a robust nonhuman primate model via three paired transplants of dosages 4300, 8300, and 10 000 islet equivalents per kg body weight. A reduced immunosuppressive regimen of anti-thymocyte globulin induction plus tacrolimus in the first posttransplant month followed by maintenance with sirolimus monotherapy was employed. To limit transplant variability, two of the three pairs were closely MHC-matched recipients and received MHC-disparate PEGylated or untreated islets isolated from the same donors. Recipients of PEGylated islets exhibited significantly improved early c-peptide levels, reduced exogenous insulin requirements, and superior glycemic control, as compared to recipients of untreated islets. These results indicate that this simple islet modification procedure may improve islet engraftment and survival in the setting of reduced immunosuppression.
AB - Islet cell transplantation can lead to insulin independence, reduced hypoglycemia, and amelioration of diabetes complications in patients with type 1 diabetes. The systemic delivery of anti-inflammatory agents, while considered crucial to limit the early loss of islets associated with intrahepatic infusion, increases the burden of immunosuppression. In an effort to decrease the pharmaceutical load to the patient, we modified the pancreatic islet surface with long-chain poly(ethylene glycol) (PEG) to mitigate detrimental host-implant interactions. The effect of PEGylation on islet engraftment and long-term survival was examined in a robust nonhuman primate model via three paired transplants of dosages 4300, 8300, and 10 000 islet equivalents per kg body weight. A reduced immunosuppressive regimen of anti-thymocyte globulin induction plus tacrolimus in the first posttransplant month followed by maintenance with sirolimus monotherapy was employed. To limit transplant variability, two of the three pairs were closely MHC-matched recipients and received MHC-disparate PEGylated or untreated islets isolated from the same donors. Recipients of PEGylated islets exhibited significantly improved early c-peptide levels, reduced exogenous insulin requirements, and superior glycemic control, as compared to recipients of untreated islets. These results indicate that this simple islet modification procedure may improve islet engraftment and survival in the setting of reduced immunosuppression.
KW - animal models: nonhuman primate
KW - basic (laboratory) research/science
KW - immunosuppression/immune modulation
KW - immunosuppressive regimens
KW - islet transplantation
KW - islets of Langerhans
KW - translational research/science
UR - http://www.scopus.com/inward/record.url?scp=85075029483&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075029483&partnerID=8YFLogxK
U2 - 10.1111/ajt.15643
DO - 10.1111/ajt.15643
M3 - Article
C2 - 31597005
AN - SCOPUS:85075029483
JO - American Journal of Transplantation
JF - American Journal of Transplantation
SN - 1600-6135
ER -