Session Time: 3:15pm-4:45pm
Presentation Time: 4:03pm-4:15pm
*Purpose: Vascular thrombosis is a potential cause for early intraportal xeno-islet loss. To better understand the relationship between coagulation and inflammation in early xeno-islet transplantation, we studied coagulation pathway and tissue factor expression and inflammatory infiltrates in a dual transplant model in non-human primates.
*Methods: Genetically modified human CD46 expressing Gal-knock out xeno-islets (hCD46/GKO) and non-CD46 expression Gal-knock out xeno-islets (GKO) were obtained from Revivicor Inc. In cohort 1, equivalent hCD46/GKO or GKO islet masses were infused into separate hemilivers of the same recipient; animals were sacrificed at 1 (n=3) or 24 hours (n=3). Cohort 2 used polyethylene microsphere (MS) as a control for non-islet portal thrombosis. The histology slides from each hemiliver were examined by detailed immunohistochemistry (IHC) and quantitatively analyzed with Aperio Imagescope software.
*Results: Factor XIIa and von Willebrand factor (VWF) accumulated in and surrounded transplanted islets, with no significant difference in either stain between the two islet genotypes (p>0.05). Tissue factor (TF) stained weakly at 1 hour and significantly increased in the GKO islet areas at 24 hours, especially in layers of TF+ cells around islets (p<0.05). Dual immunofluorescence staining showed some of the TF+ cells in the layers were T cells, some were macrophages, and most were vimentin+ cells. Polyethylene MS grafts evoked similar staining pattern with the notable exceptions of less TF deposition and also less platelet aggregation.
*Conclusions: Our data show that xeno-islet transplantation evokes both extrinsic and intrinsic elements of the coagulation pathway, with intrinsic factors related to generic portal thrombosis, and TF and platelet aggregation more specific to the engrafted islets. hCD46 expression significantly reduces TF and platelet deposition, but did not significantly alter intrinsic factors. Layers of TF+ T cells, TF+ macrophages, and TF+ fibroblasts (the majority of vimentin+ cells) around islets at 24 hours may have important roles in the events of thrombosis, rejection, and the outcome of transplanted grafts. These factors may represent targets for future genetic modifications and therapeutic targeting aimed at prolonging graft survival and improving outcomes.
To cite this abstract in AMA style:Song M, Fitch Z, Samy K, Gao Q, Davis RP, Leopard F, Schmitz R, Huffman N, Devi G, Collins B, Kirk AD. Coagulation and Cd46 Transgene Modification in Neonatal Porcine Islet Xenotransplantation [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/coagulation-and-cd46-transgene-modification-in-neonatal-porcine-islet-xenotransplantation/. Accessed October 26, 2020.
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