Engraftment Site and Effectiveness of the Pan-Caspase Inhibitor F573 to Improve Engraftment in Mouse and Human Islet Transplantation in Mice. Issue 10 (October 2017)

• Record Type: Journal Article
• Authors: Pepper, Andrew R.; Bruni, Antonio; Pawlick, Rena; Wink, John; Rafiei, Yasmin; Gala-Lopez, Boris; Bral, Mariusz; Abualhassan, Nasser; Kin, Tatsuya; Shapiro, A.M. James
• Is Part Of: Transplantation. Volume 101:Issue 10(2017)
• Publication Date: 2017-10
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; Transplantation immunology -- Periodicals; 617.95
• DOI: 10.1097/TP.0000000000001638
• Languages: English
• ISSNs: 0041-1337

Abstract

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. Abstract : Pepper et al report that the pan-caspase inhibitor, F573, mitigates early apoptosis-mediated islet death in vitro, and within portal and extrahepatic portal sites in mouse models of syngeneic or human islet transplantation.