Session Time: 2:30pm-4:00pm
Presentation Time: 2:30pm-2:42pm
Location: Room 310
*Purpose: Vascular thrombosis activation is an important cause for early xeno-islet loss. To better understand the thrombosis process in islet xenotransplantation and the effect of CD46 in the process, we used immunohistochemistry and image analysis to observe key coagulation cascade factors in a dual transplant model with genetically modified human CD46 expressing Gal-knocked out xeno-islets (hCD46/GKO) and non-CD46 expression Gal-knocked out xeno-islets (GKO) in non-human primates.
*Methods: Neonatal hCD46/GKO and GKO piglets were obtained from Revivicor Inc. Equivalent hCD46/GKO or GKO islet mass were infused into separate hemilivers of diabetic rhesus recipients. Animals were sacrificed at 1 (n=4) or 24 hours (n=3) for detailed immunohistochemical analysis. Slides derived from predetermined anatomical locations within each hemiliver and were quantitatively analyzed with Aperio Imagescope software.
*Results: CD46 staining confirmed the separation of each type islet into their distinct hemilivers. Tissue factor stain was weaker and limited in the islets at 1 hour and increased in the islets, and significantly increased in the GKO islet areas at 24 hours (P=.026). CD31 and tissue factor dual stains demonstrated CD31 expressed in platelets on islets and endothelium with tissue factor positive cells in the islets and surrounding the venules at 24 hours. There was a large amount of platelet and factor XIIIa accumulation detected in and surrounding the islets. The platelet and factor XIIIa positivity in hCD46/GKO islets was significantly lower compared to GKO islets at 24 hours (P=.0025 and .0378, respectively).
*Conclusions: These data show that neonatal porcine xeno-islet transplantation evokes the coagulation cascade and inflammation immediately after transplantation and this is further augmented at 24 hours. Platelets and tissue factor are prominent as is the final stages of the clotting cascade-factor XIIIa accumulation on the islets and surrounding tissue. This may have a strong relationship with early islet loss. CD46 expression significantly reduces these factors. CD46 is an important co-factor controlling complement mediated injury, thus CD46 gene modified organs and early employment of anti-coagulation remedy may provide the new approaches for better transplant outcome.
To cite this abstract in AMA style:Song M, Samy K, Gao Q, Davis RP, Leopard F, Fitch Z, Bennett C, Devi GR, Collins BH, Kirk AD. CD46 Transgene Modification and Thrombosis in Neonatal Porcine Islet Xenotransplantation [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/cd46-transgene-modification-and-thrombosis-in-neonatal-porcine-islet-xenotransplantation/. Accessed February 25, 2021.
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