International Journal of Molecular Medical Science, 2024, Vol.14, No.3, 177-192 http://medscipublisher.com/index.php/ijmms 179 2.2 Current advancements and breakthroughs in xenotransplantation Recent years have witnessed significant advancements in xenotransplantation, primarily driven by breakthroughs in genetic engineering and immunosuppression techniques. One of the most pivotal developments has been the creation of genetically modified pigs that are specifically engineered to be more compatible with the human immune system. These pigs have undergone modifications to eliminate or alter the expression of certain pig antigens that are typically recognized and attacked by the human immune system. Notably, the knockout of the alpha-1,3-galactosyltransferase (Gal) gene in pigs has been a major milestone, as this gene is responsible for producing a sugar molecule that is a primary target for human antibodies. Additionally, the expression of human complement regulatory proteins such as CD46, CD55, and thrombomodulin in these pigs helps to further protect the transplanted organs from immune attack by inhibiting the complement cascade, a part of the immune system involved in inflammation and cell lysis (Singh et al., 2018; Coe et al., 2020). In addition to genetic modifications, advancements in immunosuppressive therapies have played a crucial role in the success of xenotransplantation. Traditional immunosuppressive drugs used in allotransplantation have been supplemented with novel regimens designed specifically to address the unique challenges of xenotransplantation. Co-stimulation blockade therapies, which inhibit the interaction between co-stimulatory molecules on immune cells, have shown great promise in reducing immune responses against xenografts. For instance, antibodies targeting the CD40-CD154 pathway have been effective in prolonging graft survival by preventing the activation of T cells, which are essential for initiating immune responses. These advancements have led to significant improvements in the survival rates of xenotransplanted organs in preclinical studies. For example, genetically modified pig kidneys transplanted into non-human primates have shown survival times extending into months, marking a substantial improvement over earlier attempts (Reichart et al., 2020; Hawthorne et al., 2022). These breakthroughs highlight the potential of xenotransplantation to become a viable clinical option, pending further research and refinement of these techniques. 2.3 Comparison of xenotransplantation with allotransplantation Xenotransplantation offers several potential advantages over traditional allotransplantation, which involves the transfer of organs or tissues between individuals of the same species. The most significant advantage is the potential to alleviate the severe shortage of human donor organs. Genetically modified pigs can be bred in large numbers, providing a consistent and readily available source of organs. This capability could dramatically reduce waiting times for patients in need of transplants and decrease mortality rates associated with long waiting periods. Additionally, the controlled breeding of pigs allows for specific genetic modifications to enhance compatibility and reduce rejection rates, which is not possible with human donors (Cooper et al., 2020; Reichart et al., 2020). However, xenotransplantation faces unique challenges that are less prevalent or absent in allotransplantation. One of the primary challenges is the risk of zoonotic infections, where diseases could potentially be transmitted from pigs to humans. While significant progress has been made in producing pathogen-free pigs, this remains a critical concern. Furthermore, the human immune system often mounts a stronger rejection response against pig tissues compared to human tissues, necessitating more complex and robust immunosuppressive therapies. Despite the success of these therapies in preclinical trials, their long-term efficacy and safety in humans remain uncertain. In contrast, allotransplantation has a well-established history with protocols that have been refined over decades to manage immune rejection and ensure long-term graft survival. Thus, while xenotransplantation holds immense promise for addressing organ shortages, it must overcome substantial scientific and medical hurdles to match the reliability and success of allotransplantation (Burdorf et al., 2018; Firl and Markmann, 2022). 3 Immunological Barriers in Xenotransplantation 3.1 Host immune response to xenografts The host immune response to xenografts is a significant barrier in xenotransplantation. The immune system recognizes the xenograft as foreign, leading to a robust immune response aimed at rejecting the transplanted organ. This response involves both humoral and cellular components of the immune system. Humoral responses are primarily mediated by antibodies that target specific antigens on the xenograft, while cellular responses involve T
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