International Journal of Molecular Medical Science, 2024, Vol.14, No.3, 177-192 http://medscipublisher.com/index.php/ijmms 178 Additionally, it can reduce the economic costs associated with prolonged hospital stays and repeated medical interventions for patients awaiting transplants. Despite its potential, pig-to-human xenotransplantation faces numerous challenges that must be addressed to achieve successful and long-term graft survival. These challenges include hyperacute rejection, where the human immune system rapidly attacks the transplanted pig organ, as well as chronic rejection, which can occur over a longer period. Additionally, there is a risk of zoonotic infections, where diseases can be transmitted from pigs to humans. The primary goal of pig-to-human organ transplants is to overcome these immunological barriers and ensure that the transplanted organs can function effectively and safely in the human body over the long term (Burdorf et al., 2018; Reichart et al., 2020). The primary objective of this study is to elucidate the genetic determinants that contribute to the long-term survival of xenografts from pigs to humans. Understanding these genetic factors is crucial for optimizing the genetic modification of donor pigs to enhance graft survival and function. By thoroughly reviewing the current literature on the genetic engineering of pigs for xenotransplantation, the most effective genetic modifications and their impacts on overcoming immune rejection and physiological incompatibilities are identified. This study will provide a foundation for future research and clinical trials, ultimately advancing the field of xenotransplantation and offering new hope to patients in need of life-saving organ transplants. 2 Background on Xenotransplantation 2.1 Definition and historical context Xenotransplantation, defined as the transplantation of living cells, tissues, or organs from one species to another, has a long and complex history. The term "xeno" is derived from the Greek word for "foreign," highlighting the fundamental challenge of overcoming species-specific biological differences. The earliest recorded attempts at xenotransplantation date back to the early 20th century when researchers explored the potential of using animal organs to address the shortage of human donors. One of the first significant attempts was by French surgeon Alexis Carrel, who, in the 1900s, experimented with transplanting animal organs into humans. However, these early experiments faced numerous obstacles, primarily due to the body's immune response, which led to immediate and catastrophic rejection of the transplanted organs. The lack of understanding of immunology and the absence of effective immunosuppressive therapies at the time resulted in these early attempts being largely unsuccessful (Gulyaev et al., 2019). The mid-20th century saw renewed interest in xenotransplantation with advancements in surgical techniques and a better understanding of transplantation immunology. Notably, in the 1960s, Dr. Keith Reemtsma at Tulane University transplanted chimpanzee kidneys into human patients. Although one patient survived for nine months, the overall outcomes were poor due to immune rejection and infections. These experiments underscored the need for more sophisticated immunosuppressive strategies and a better understanding of cross-species immunological barriers (Hess and Kaczorowski, 2023). The 1980s brought further attention to xenotransplantation with the case of Baby Fae, an infant born with a fatal heart defect who received a baboon heart transplant. Despite initial success, the infant's body rejected the heart after 21 days, leading to her death. This case highlighted both the potential and the significant challenges of xenotransplantation, particularly the need for better immunosuppressive treatments and the ethical considerations involved in such procedures (Loike and Kadish, 2018). In recent decades, the focus has shifted towards the use of pigs as the preferred source of xenotransplant organs due to their anatomical and physiological similarities to humans. Advances in genetic engineering have enabled the development of transgenic pigs that express human proteins to mitigate immune rejection. For instance, the knockout of the alpha-1,3-galactosyltransferase (Gal) gene in pigs, which eliminates a major xenoantigen responsible for hyperacute rejection, has been a pivotal breakthrough (Cyprian, 2020).
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