International Journal of Molecular Medical Science, 2024, Vol.14, No.3, 177-192 http://medscipublisher.com/index.php/ijmms 181 the graft and contribute to the inflammatory milieu. The presence of these immune cells and the associated inflammatory response lead to swelling, hemorrhage, and compromised function of the xenograft (Coe et al., 2020; Reichart et al., 2020). 3) Chronic rejection: Chronic rejection is a long-term process that develops over months to years post-transplantation. Unlike hyperacute and acute vascular rejection, chronic rejection involves both immune and non-immune mechanisms. It is characterized by progressive fibrosis, vascular occlusion, and a gradual decline in graft function. Chronic rejection is driven by a persistent, low-grade immune response, involving both cellular and humoral components. T cells and antibodies continuously attack the graft, leading to sustained inflammation and tissue remodeling. Additionally, non-immune factors such as ischemia, reperfusion injury, and drug toxicity contribute to the pathogenesis of chronic rejection. The slow and insidious nature of chronic rejection makes it difficult to diagnose and treat, often resulting in eventual graft failure (Burdorf et al., 2018; Firl and Markmann, 2022). 3.3 Role of genetic modifications in overcoming immunological barriers Genetic modifications in donor pigs have been instrumental in mitigating the immunological barriers to xenotransplantation. Key strategies include: Knockout of Xenoantigens: The deletion of genes encoding major xenoantigens, such as alpha-Gal, has been crucial in reducing hyperacute rejection. Pigs genetically modified to lack the alpha-Gal antigen have shown significantly improved graft survival (Reichart et al., 2020). Expression of Human Complement Regulatory Proteins: Transgenic expression of human proteins such as CD46, CD55, and thrombomodulin in pigs helps protect the graft from complement-mediated damage. These proteins regulate the complement cascade and prevent excessive immune activation (Singh et al., 2018). Coagulation and Inflammation Control: Genetic modifications to include human thromboregulatory proteins and anti-inflammatory genes have also been shown to reduce the incidence of acute vascular rejection and improve overall graft survival. These modifications help in maintaining the normal physiological function of the graft and reducing inflammatory responses (Burdorf et al., 2018). Immune Modulation through Costimulation Blockade: Genetically modified pigs can be used in conjunction with advanced immunosuppressive therapies, such as costimulation blockade. This involves using antibodies that block critical pathways in T-cell activation, such as the CD40-CD154 interaction. Studies have shown that the combination of genetically modified pigs and costimulation blockade can significantly prolong graft survival and reduce the risk of acute rejection (Firl and Markmann, 2022). Development of Multi-Transgenic Pigs: The use of multi-transgenic pigs, which incorporate multiple genetic modifications to address various aspects of the immune response, has shown promising results. These pigs may express combinations of human regulatory proteins, lack multiple xenoantigens, and include additional modifications to enhance graft survival. Such comprehensive genetic engineering efforts are essential for overcoming the complex immunological barriers in xenotransplantation (Tatapudi and Griesemer, 2022). In summary, overcoming the immunological barriers to xenotransplantation requires a multifaceted approach, incorporating advanced genetic modifications and tailored immunosuppressive therapies. These strategies hold the promise of significantly enhancing the success rates of pig-to-human xenotransplantations. 4 Key Genetic Determinants for Graft Survival 4.1 Genes involved in immune evasion and tolerance The success of xenotransplantation largely hinges on the ability to evade the host's immune system and promote tolerance. Several genes have been identified that play critical roles in immune evasion and tolerance, including those that modulate the expression of surface antigens and immune regulatory proteins. For instance, the expression of human leukocyte antigen-G (HLA-G) and HLA-E in genetically modified pigs has been shown to
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