International Journal of Molecular Medical Science, 2024, Vol.14, No.3, 177-192 http://medscipublisher.com/index.php/ijmms 184 Additionally, the expression of anti-inflammatory genes such as heme oxygenase-1 (HO-1) and human leukocyte antigen-G (HLA-G) in genetically modified pigs has been shown to mitigate acute cellular rejection. These genes help modulate the immune response, reduce inflammation, and promote immune tolerance (Obando et al., 2021; Ryczek et al., 2021). 6.3 Enhancing long-term graft survival through genetic stability and resistance to chronic rejection Chronic rejection develops over months to years and is driven by both immune and non-immune mechanisms, including fibrosis and vascular occlusion. Genetic modifications that enhance the graft’s intrinsic resistance to immune-mediated damage and promote tissue repair are crucial for long-term graft survival. The introduction of genes encoding for anti-apoptotic proteins, such as Bcl-2, and anti-inflammatory cytokines, such as interleukin-10 (IL-10), can help in maintaining graft function and reducing chronic inflammation (Coe et al., 2020). Furthermore, the incorporation of human CD47, which provides a "don't eat me" signal to macrophages, helps in preventing phagocytosis of the graft cells, thereby reducing chronic rejection. This modification, along with the expression of human regulatory proteins such as endothelial protein C receptor (EPCR) and tissue factor pathway inhibitor (TFPI), can significantly enhance the graft’s resistance to both immune attack and coagulation-related injuries (Burdorf et al., 2021; Lei et al., 2022). These modifications not only help in reducing hyperacute, acute, and chronic rejection but also enhance the long-term stability and functionality of the grafts, making xenotransplantation a viable solution for addressing organ shortages. 7 Ethical and Regulatory Considerations 7.1 Ethical issues related to genetic engineering in xenotransplantation Genetic engineering in xenotransplantation raises significant ethical concerns, particularly regarding the welfare and rights of the animals used as organ donors. The process of creating genetically modified pigs involves invasive procedures and often results in the animals being kept under conditions that fail to meet their biological and psychological needs. This raises questions about the ethical justification for using animals in this way, balancing the potential human benefits against the welfare of the animals (Eissa et al., 2022; Johnson, 2022). Moreover, there are broader ethical questions about the implications of genetic engineering, such as interfering with natural species boundaries and the long-term impact on both human and animal genetics (George, 2022). 7.2 Regulatory frameworks for genetic modifications in xenotransplantation The regulatory landscape for xenotransplantation is complex and varies significantly between countries. Regulatory bodies such as the United States Food and Drug Administration (FDA) and the World Health Organization (WHO) have established guidelines to ensure the safety and ethical conduct of xenotransplantation research. These frameworks require rigorous preclinical testing to demonstrate the safety and efficacy of genetically modified organs and mandate continuous monitoring to prevent zoonotic disease transmission (Goerlich et al., 2019; Arcidiacono, 2020). Additionally, some countries have specific regulations addressing the ethical issues associated with the use of animals, ensuring that animal welfare is considered in the research protocols (Hawthorne and Cowan, 2020). 7.3 Public perception and acceptance of genetically modified xenografts Public perception and acceptance of xenotransplantation are critical for its successful implementation. There are significant concerns about the safety of xenotransplantation, particularly the risk of cross-species disease transmission. Ethical concerns about animal welfare and the naturalness of using genetically modified animals also influence public opinion. To address these issues, it is essential to engage with the public through transparent communication about the risks and benefits of xenotransplantation and the measures taken to mitigate these risks (Entwistle et al., 2022; Gusmano, 2022). Educational initiatives and public consultations can help build trust and acceptance, ensuring that the ethical and societal implications are thoroughly considered and addressed.
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