International Journal of Molecular Zoology 2024, Vol.14, No.2, 72-83 http://animalscipublisher.com/index.php/ijmz 73 This study aims to discuss the development of improved xenograft models by leveraging advanced gene editing technology to enhance the immune compatibility of transgenic pigs. The objectives include refining gene editing strategies to improve the adaptability and longevity of pig organs in humans, optimizing immunosuppressive protocols to reduce postoperative risks, and extending the lifespan of transplanted organs. Additionally, the study will address economic and ethical considerations to ensure the responsible development of xenograft technology. The ultimate goal is to establish a robust foundation for translating xenotransplantation from laboratory research to global clinical application, thereby potentially improving the quality of life for transplant patients worldwide. 1 Background on Xenotransplantation 1.1 Definition and history of xenotransplantation Xenotransplantation refers to the transplantation of living cells, tissues, or organs from one species to another. Historically, the concept of xenotransplantation dates back to the early 20th century, with initial attempts involving the transplantation of animal organs into humans. However, these early efforts were largely unsuccessful due to severe immunological rejection and other complications. The advent of modern genetic engineering techniques has reignited interest in xenotransplantation, particularly using pigs as donor animals due to their anatomical and physiological similarities to humans (Hryhorowicz et al., 2017; Lei et al., 2022). 1.2 Current challenges in xenotransplantation Despite significant advancements, xenotransplantation faces several critical challenges. The primary obstacle is immunological rejection, which includes hyperacute rejection (HAR), acute humoral xenograft rejection (AHXR), and chronic rejection. These immune responses are triggered by the recognition of pig-specific antigens by the human immune system (Klymiuk et al., 2010; Carvalho-Oliveira et al., 2021). Additionally, there is a risk of zoonotic infections, particularly from porcine endogenous retroviruses (PERVs), which can potentially be transmitted to human recipients (Klymiuk et al., 2010; Lei et al., 2022). Addressing these challenges is crucial for the successful clinical application of xenotransplantation. 1.3 Advances in genetic modification techniques for xenotransplantation Recent advances in genetic engineering have significantly improved the prospects of xenotransplantation. Techniques such as CRISPR/Cas9 have enabled precise modifications of the pig genome to reduce immunogenicity and enhance compatibility with the human immune system. For instance, the deletion of alpha-1,3-galactosyltransferase (GGTA1) gene, which is responsible for the synthesis of alpha-Gal epitopes, has been shown to mitigate hyperacute rejection (Klymiuk et al., 2010). Additionally, the insertion of human complement and coagulation regulatory genes, such as CD46 and thrombomodulin, has further reduced the risk of immune-mediated rejection and coagulation dysfunctions (Klymiuk et al., 2010; Hryhorowicz et al., 2017; Lei et al., 2022). Moreover, strategies to knock down PERVs have been developed to minimize the risk of zoonotic infections (Klymiuk et al., 2010; Lei et al., 2022). These genetic modifications collectively enhance the immunotolerance of pig organs, making them more viable for xenotransplantation into humans. While xenotransplantation holds great promise for addressing the shortage of human organs, overcoming immunological and infectious challenges remains critical. Advances in genetic modification techniques are paving the way for safer and more effective xenotransplantation practices, bringing us closer to clinical applications (Klymiuk et al., 2010; Hryhorowicz et al., 2017; Carvalho-Oliveira et al., 2021; Lei et al., 2022). 2 Immunotolerance: Concepts and Importance 2.1 Definition and mechanisms of immunotolerance Immunotolerance refers to the immune system's ability to recognize and accept foreign tissues or organs without mounting an aggressive immune response. This is crucial in the context of xenotransplantation, where organs from genetically modified pigs are transplanted into human recipients. The mechanisms of immunotolerance involve both central and peripheral tolerance. Central tolerance occurs in the thymus, where T cells that react strongly to self-antigens are eliminated. Peripheral tolerance involves regulatory T cells (Tregs) and other mechanisms that suppress immune responses to non-self antigens (Shimizu et al., 2012; Carvalho-Oliveira et al., 2021; Lei et al., 2022).
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