Ischemia Reperfusion Injury Induced Systemic Inflammatory Response Following Interspecies Liver Transplantation.

Abstract

<h4>Introduction</h4>Xenotransplantation has advanced through porcine genetic modifications to enhance graft survival and immunological compatibility. More recently, generating of exogenic organs from recipient-derived stem cells via blastocyst complementation has emerged as a promising strategy to achieve graft-specific tolerance and reduce dependence on long-term immunosuppression. However, ischemia-reperfusion-injury (IRI) during organ donation and transplantation activates inflammatory and innate immune pathways that compromise graft function and survival. To better understand the immunological response following interspecies transplantation, we compared xeno-adaptive and acute inflammatory responses between mouse-to-rat heterotopic liver transplants and rat allotransplants. This model will serve as baseline parameters for future studies of anti-inflammatory mechanisms to mitigate IRI, especially while testing exogenic livers.<h4>Methods</h4>Livers from retired breeder male C57BL/6 mice were heterotopically transplanted into retired breeder male Lewis rats. After 90 minutes of reperfusion, transplanted liver, recipient blood and spleen were recovered for immune and inflammatory analyses. As a control to xenografts, Sprague Dawley donor livers were transplanted into Lewis recipients to represent a clinically relevant allotransplant model. Plasma cytokine and chemokine levels were quantified, and mixed leukocyte reactions (MLR) were performed to assess CD4⁺ and CD8⁺ T cell proliferation.<h4>Results</h4>Xenografts exhibited elevated plasma levels of IL-2 (p = 0.04), IL-10 (p < 0.01), IL-13 (p = 0.01), IL-17A (p < 0.01) TNF-a (p < 0.05), and RANTES (p < 0.05) compared with naïve controls. Although xenografts demonstrated higher levels after transplant, they were not statistically distinct to allotransplant results. MLR assays revealed significantly increased CD8⁺ T cell proliferation (p = 0.01) when rat splenocytes were stimulated with mouse non-parenchymal liver cells, whereas CD4⁺ T cell proliferation was not significant in either model.<h4>Discussion</h4>Although xenograft induced heightened inflammatory and adaptive responses, these were comparable to allotransplants. For successful exogenic organ transplantation without maintenance immunosuppression, future strategies must focus on mitigating reperfusion-induced systemic inflammation to improve graft tolerance and survival.