International Journal of Molecular Zoology 2024, Vol.14, No.4, 244-254 http://animalscipublisher.com/index.php/ijmz 248 Figure 2 Inactivation of PERVs integrated in the pig genome using CRISPR/Cas and generation of piglets by somatic cell nuclear transfer (SCNT) (Adopted from Denner, 2022) 5.2 Enhancing organ compatibility through genetic modifications Genetic modifications in pigs have been pivotal in enhancing organ compatibility for xenotransplantation. By deleting pig genes responsible for the synthesis of xenoantigens and introducing human transgenes, researchers have been able to reduce immune rejection and improve physiological compatibility. For instance, the deletion of genes encoding for carbohydrate antigens such as αGal, Neu5Gc, and Sd(a) has been shown to prevent the activation of human natural antibodies and complement systems (Kemter et al., 2018). Furthermore, the expression of human complement regulatory proteins (e.g., hCD46, hCD55, hCD59) in genetically modified pigs has been effective in mitigating cellular immune responses and improving graft survival (Figure 3) (Lei et al., 2022). These genetic modifications have extended the survival of pig organs in non-human primates, paving the way for potential clinical applications (Kemter et al., 2020; Wu et al., 2023). The research of Lei et al. (2022) provides an overview of the mechanisms behind antibody-mediated xenograft rejection and the genetic modifications used to mitigate these immune responses. In hyperacute rejection (HAR), preformed antibodies bind to α-Gal antigens on pig endothelial cells (pEC), triggering the classical complement cascade that culminates in cell lysis and graft damage. To combat this, genetically modified pigs are produced with knockouts in genes such as GGTA1, CMAH, and β4GalNT2, which eliminate key xenoantigens. Additionally, transgenic pigs express human complement regulatory proteins (hCD55, hCD46, hCD59) to inactivate components of the complement cascade, thereby reducing cytolysis and thrombosis. Acute humoral xenograft rejection (AHXR) is also addressed by these genetic modifications, targeting antibodies against non-α-Gal antigens like Neu5Gc and SDa. This comprehensive approach enhances the compatibility of pig organs for transplantation into humans, improving graft survival and function.
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