International Journal of Molecular Zoology 2024, Vol.14, No.2, 72-83 http://animalscipublisher.com/index.php/ijmz 72 Research Report Open Access Enhancing Immunotolerance in Genetically Modified Pigs for Xenotransplantation: Mechanisms and Outcomes TaoZhang Hangzhou Mono Biotechnology Co., Ltd, Hangzhou, 310000, Zhejiang, China Corresponding email: dibada88_2m6@outlook.com International Journal of Molecular Zoology, 2024, Vol.14, No.2 doi: 10.5376/ijmz.2024.14.0009 Received: 16 Jan., 2024 Accepted: 25 Feb., 2024 Published: 10 Mar., 2024 Copyright © 2024 Zhang, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Zhang T., 2024, Enhancing immunotolerance in genetically modified pigs for xenotransplantation: mechanisms and outcomes, International Journal of Molecular Zoology, 14(2): 72-83 (doi: 10.5376/ijmz.2024.14.0009) Abstract The shortage of human organs for transplantation has driven significant interest in xenotransplantation, particularly using genetically modified pigs. This study explores the mechanisms and outcomes of enhancing immunotolerance in genetically modified pigs for xenotransplantation. Recent advancements in genetic engineering, such as the deletion of xenoantigens and the expression of human complement and coagulation regulatory proteins, have shown promise in reducing immune rejection and prolonging graft survival. Studies have demonstrated that genetically engineered pig hearts and kidneys can survive for extended periods in non-human primates, with some grafts functioning beyond one year. These findings suggest that targeted genetic modifications, combined with specific immunosuppressive regimens, can significantly improve the viability of pig organs for clinical xenotransplantation. However, challenges remain, including the need for further optimization of genetic modifications and immunosuppressive protocols to prevent chronic rejection and ensure long-term graft function. Keywords Genetically modified pigs; Xenotransplantation; Immunotolerance; Organ transplantation; Genetic engineering Xenotransplantation, the transplantation of organs, tissues, or cells from one species to another, has emerged as a promising solution to the critical shortage of human organs available for transplantation. This shortage has led to thousands of patients dying each year while waiting for a suitable donor organ (Sykes and Sachs, 2019). The domestic pig (Sus scrofa domesticus) has been identified as an optimal donor species due to its anatomical and physiological similarities to humans (Klymiuk et al., 2010; Hryhorowicz et al., 2017). However, xenotransplantation faces significant challenges, primarily due to the high immune incompatibility between species, which leads to complex rejection processes (Klymiuk et al., 2010; Hryhorowicz et al., 2017). Recent advancements in genetic engineering, particularly the development of CRISPR-Cas9-based gene editing methodologies, have enabled the creation of genetically modified pigs that are less prone to immune rejection (Sykes and Sachs, 2019). These modifications include the deletion of major xenoantigens, such as alpha-1,3-galactosidase, and the expression of human complement regulatory proteins, coagulation-regulatory proteins, and anti-inflammatory molecules (Klymiuk et al., 2010; Cooper et al., 2019). Such genetic modifications have significantly prolonged the survival of xenografts in preclinical studies, with some genetically engineered pig hearts surviving over a year in non-human primates (Mohiuddin et al., 2014; Yamamoto et al., 2019). These advancements provide hope for the clinical application of xenotransplantation as a viable solution to the organ shortage crisis (Mohiuddin et al., 2014; Sykes and Sachs, 2019). The primary objective of enhancing immunotolerance in genetically modified pigs is to further reduce the immune response and rejection of xenografts, thereby increasing the survival and functionality of transplanted organs. This involves not only the genetic modification of donor pigs but also the development of targeted immunosuppressive therapies to manage the recipient's immune response (Mohiuddin et al., 2014; Yamamoto et al., 2019). By achieving long-term graft survival and function, xenotransplantation could become a routine clinical practice, significantly alleviating the organ shortage and saving countless lives (Mohiuddin et al., 2014; Cooper et al., 2019; Sykes and Sachs, 2019).
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