TY - JOUR
T1 - Microencapsulated islet allografts in diabetic NOD mice and nonhuman primates
AU - Safley, S. A.
AU - Kenyon, N. S.
AU - Berman, D. M.
AU - Barber, G. F.
AU - Cui, H.
AU - Duncanson, S.
AU - de Toni, T.
AU - Willman, M.
AU - de Vos, P.
AU - Tomei, A. A.
AU - Sambanis, A.
AU - Kenyon, N. M.
AU - Ricordi, C.
AU - Weber, C. J.
N1 - Funding Information:
We thank Waldo Diaz and James Geary for help during surgeries and excellent NHP care; Alexander Rabassa for his assistance with islet isolations and Ena Poumian-Ruiz for her assistance with islet isolation and measurement of trough levels of anti-CD154 antibody. The anti-CD154 mAb was provided by the NIH Nonhuman Primate Reagent Resource (AI126683 and OD10976). We gratefully acknowledge Drs. Damaris Molano and Antonello Pilleggi and members of the DRI Mouse Core, as well as the laboratory of Dr. Alice Tomei, for performing the transplants in STZ-diabetic nude mice and monitoring NHP islet graft function in the immunoincompetent murine model. We acknowledge Kevin Johnson for his assistance with sample processing and Norman H. Altman, VMD, DACVP, for his expert histopathological evaluation of tissues at necropsy. We wish to thank Dr. Dongmei Han for measuring CMV levels in all transplanted animals. These studies were supported by grants from the Juvenile Diabetes Research Foundation International (17-2007-1064 and 2SRA-2017-346-Q-R 2016), the Diabetes Research Institute Foundation, and by generous gifts from Malcolm and Musette Powell, Vicki and Mark Hollingsworth, the Eckels Foundation, and the Maxine H. Clippert Foundation.
PY - 2020
Y1 - 2020
N2 - OBJECTIVE: Our goal was to assess the efficacy of encapsulated allogeneic islets transplanted in diabetic NOD mice and streptozotocin (STZ)-diabetic nonhuman primates (NHPs). MATERIALS AND METHODS: Murine or NHP islets were microencapsulated and transplanted in non-immunosuppressed mice or NHPs given clinically-acceptable immunosuppressive regimens, respectively. Two NHPs were treated with autologous mesenchymal stem cells (MSCs) and peri-transplant oxygen therapy. Different transplant sites (intraperitoneal [i.p.], omental pouch, omental surface, and bursa omentalis) were tested in separate NHPs. Graft function was monitored by exogenous insulin requirements, fasting blood glucose levels, glucose tolerance tests, percent hemoglobin A1c (% HbA1c), and C-peptide levels. In vitro assessment of grafts included histology, immunohistochemistry, and viability staining; host immune responses were characterized by flow cytometry and cytokine/chemokine multiplex ELISAS. RESULTS: Microencapsulated islet allografts functioned long-term i.p. in diabetic NOD mice without immunosuppression, but for a relatively short time in immunosuppressed NHPs. In the NHPs, encapsulated allo-islets initially reduced hyperglycemia, decreased exogenous insulin requirements, elevated C-peptide levels, and lowered % HbA1c in plasma, but graft function diminished with time, regardless of transplant site. At necropsy, microcapsules were intact and non-fibrotic, but many islets exhibited volume loss, central necrosis and endogenous markers of hypoxia. Animals receiving supplemental oxygen and autologous MSCs showed improved graft function for a longer post-transplant period. In diabetic NHPs and mice, cell-free microcapsules did not elicit a fibrotic response. CONCLUSIONS: The evidence suggested that hypoxia was a major factor for damage to encapsulated islets in vivo. To achieve long-term function, new approaches must be developed to increase the oxygen supply to microencapsulated islets and/or identify donor insulin-secreting cells which can tolerate hypoxia.
AB - OBJECTIVE: Our goal was to assess the efficacy of encapsulated allogeneic islets transplanted in diabetic NOD mice and streptozotocin (STZ)-diabetic nonhuman primates (NHPs). MATERIALS AND METHODS: Murine or NHP islets were microencapsulated and transplanted in non-immunosuppressed mice or NHPs given clinically-acceptable immunosuppressive regimens, respectively. Two NHPs were treated with autologous mesenchymal stem cells (MSCs) and peri-transplant oxygen therapy. Different transplant sites (intraperitoneal [i.p.], omental pouch, omental surface, and bursa omentalis) were tested in separate NHPs. Graft function was monitored by exogenous insulin requirements, fasting blood glucose levels, glucose tolerance tests, percent hemoglobin A1c (% HbA1c), and C-peptide levels. In vitro assessment of grafts included histology, immunohistochemistry, and viability staining; host immune responses were characterized by flow cytometry and cytokine/chemokine multiplex ELISAS. RESULTS: Microencapsulated islet allografts functioned long-term i.p. in diabetic NOD mice without immunosuppression, but for a relatively short time in immunosuppressed NHPs. In the NHPs, encapsulated allo-islets initially reduced hyperglycemia, decreased exogenous insulin requirements, elevated C-peptide levels, and lowered % HbA1c in plasma, but graft function diminished with time, regardless of transplant site. At necropsy, microcapsules were intact and non-fibrotic, but many islets exhibited volume loss, central necrosis and endogenous markers of hypoxia. Animals receiving supplemental oxygen and autologous MSCs showed improved graft function for a longer post-transplant period. In diabetic NHPs and mice, cell-free microcapsules did not elicit a fibrotic response. CONCLUSIONS: The evidence suggested that hypoxia was a major factor for damage to encapsulated islets in vivo. To achieve long-term function, new approaches must be developed to increase the oxygen supply to microencapsulated islets and/or identify donor insulin-secreting cells which can tolerate hypoxia.
KW - Diabetes
KW - Hypoxia
KW - Islet transplantation
KW - Microencapsulation
KW - Nonhuman primates
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U2 - 10.26355/eurrev_202008_22651
DO - 10.26355/eurrev_202008_22651
M3 - Article
C2 - 32894560
AN - SCOPUS:85090509138
VL - 24
SP - 8551
EP - 8565
JO - European Review for Medical and Pharmacological Sciences
JF - European Review for Medical and Pharmacological Sciences
SN - 1128-3602
IS - 16
ER -