Engraftment Site and Effectiveness of the Pan-Caspase Inhibitor F573 to Improve Engraftment in Mouse and Human Islet Transplantation in Mice.
Transplantation
; 101(10): 2321-2329, 2017 10.
Article
in En
| MEDLINE
| ID: mdl-28072753
ABSTRACT
BACKGROUND:
Islet transplantation is an effective therapy in type 1 diabetes and recalcitrant hypoglycemia. However, there is an ongoing need to circumvent islet loss posttransplant. We explore herein the potential of the pan-caspase inhibitor F573 to mitigate early apoptosis-mediated islet death within portal and extrahepatic portal sites in mice.METHODS:
Mouse or human islets were cultured in standard media ±100 µM F573 and subsequently assessed for viability and apoptosis via terminal deoxynucleotidyl transferase dUTP nick end labeling staining and caspase-3 activation. Diabetic mice were transplanted with syngeneic islets placed under the kidney capsule (KC) or into the subcutaneous deviceless (DL) site at a marginal islet dose (150 islets), or into the portal vein (PV) at a full dose (500 islets). Human islets were transplanted under the KC of diabetic immunodeficient mice at a marginal dose (500 islet equivalents). Islets were cultured in the presence of F573, and F573 was administered subcutaneously on days 0 to 5 posttransplant. Control mice were transplanted with nontreated islets and were injected with saline. Graft function was measured by nonfasting blood glucose and glucose tolerance testing.RESULTS:
F573 markedly reduced human and mouse islet apoptosis after in vitro culture (P < 0.05 and P < 0.05, respectively). Furthermore, F573 improved human islet function when transplanted under the KC (P < 0.05); whereas F573 did not enhance murine islet marginal KC transplants. Conversely, F573 significantly improved mouse islet engraftment in the PV and DL site (P < 0.05 and P < 0.05, respectively).CONCLUSIONS:
The pan-caspase inhibitor F573 markedly reduces human and mouse islet apoptosis and improves engraftment most effectively in the portal and DL subcutaneous sites.
Full text:
1
Collection:
01-internacional
Health context:
6_ODS3_enfermedades_notrasmisibles
Database:
MEDLINE
Main subject:
Islets of Langerhans Transplantation
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Islets of Langerhans
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Apoptosis
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Diabetes Mellitus, Experimental
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Diabetes Mellitus, Type 1
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Caspase 3
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Caspase Inhibitors
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Amino Acid Chloromethyl Ketones
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Graft Survival
Limits:
Animals
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Humans
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Male
Language:
En
Journal:
Transplantation
Year:
2017
Document type:
Article