Journal of Vaccine Research 2024, Vol.14, No.3, 120-134 http://medscipublisher.com/index.php/jvr 125 One key element of innate immunity is the complement system, which can trigger hyperacute rejection responses. To mitigate such responses, genetically engineered pigs typically lack specific carbohydrate xenoantigens (such as GGTA1, CMAH, and β4GalNT2) known to elicit strong human immune reactions. Additionally, transgenic pig organs express human complement regulatory proteins (such as CD46 and CD55) to help control complement activity. Inhibitors of the C3 complement component, like Cp40, are used to reduce tissue damage caused by the activation of neutrophils. Natural Killer (NK) cells and macrophages also participate in immune responses by recognizing and attacking xenogeneic cells, and transgenic pigs expressing human immune modulatory proteins (such as HLA-E, HLA-G, β2-microglobulin, and CD47) effectively reduce these cells' attacks (Rosales and Colvin, 2019). In adaptive immunity, T cells and B cells are critical for graft rejection. Co-stimulatory blockade therapies, such as the CD40-CD40L pathway blockade, inhibit the activation and proliferation of T cells, thereby extending graft survival. Genetically modified pigs reduce the immunogenicity of cells, lowering the antibody response from B cells. Furthermore, the use of soluble polymers like Gas914 and specific immunosuppressants (such as anti-CD19, anti-CD20, bortezomib), as well as modulators of B cell activating factors (such as BAFF/APRIL inhibitors), are effective strategies for controlling B cell activity (Singh et al., 2018). The combined application of these strategies, including genetic modification and immunosuppressive treatment, is key to improving graft outcomes and extending their lifespan. Through these methods, it is possible to significantly reduce the rejection responses in xenotransplantation, enhancing its success rate. 5.2 Inflammatory pathways and their modulation Inflammation is a significant factor in graft rejection and failure. The modulation of inflammatory pathways is essential for prolonging graft survival. Genetically modified pigs often express anti-inflammatory genes such as human heme oxygenase-1 (HO-1) and A20, which help mitigate the inflammatory responses induced by the graft. HO-1 has been shown to have protective effects against oxidative stress and inflammation, thereby enhancing graft survival (Fischer et al., 2016). In addition, regulatory macrophages (Mregs) play a critical role in controlling inflammation. Mregs secrete anti-inflammatory cytokines like interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), which help suppress immune responses and promote the development of regulatory T cells. This approach has been shown to reduce the required dosages and durations of immunosuppressive medications, potentially improving graft outcomes (Hoang and Kim, 2023). Further advancements in the modulation of inflammatory pathways involve the use of gene editing technologies to remove or add specific inflammatory mediators. For instance, modifying pigs to express human anti-inflammatory proteins such as thrombomodulin can help control thrombotic and inflammatory reactions, which are common in xenotransplantation. These modifications have been shown to improve graft function and survival in non-human primate models (Singh et al., 2018). 5.3 Cellular stress response and protection mechanisms Cellular stress responses play a pivotal role in graft survival, particularly in response to ischemia-reperfusion injury, which occurs during the transplantation process. Genetic modifications that enhance cellular protection mechanisms can significantly improve graft outcomes. For example, the expression of heat shock proteins (HSPs) such as HSP70 helps stabilize cellular proteins and prevent apoptosis under stress conditions, thus enhancing graft viability (Coe et al., 2020). Additionally, anti-apoptotic genes like Bcl-2 and A20 have been introduced into pig organs to prevent programmed cell death triggered by transplantation-related stress. These genes help maintain cellular integrity and function, thereby extending graft survival. Studies have shown that organs from pigs expressing these genes exhibit lower levels of apoptosis and improved overall function in transplanted models (Hryhorowicz et al., 2017).
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