International Journal of Molecular Medical Science, 2024, Vol.14, No.3, 177-192 http://medscipublisher.com/index.php/ijmms 186 The histological sections in Figure 2 illustrate the adaptation process of pig kidneys in the human body and the changes in immune response following xenotransplantation. The initial stages (Figures 2A and 2B) display mild to moderate acute tubular damage in the kidneys, primarily due to cold ischemia. The glomeruli and capillary structures remain normal, indicating that the initial transplantation did not immediately trigger significant vascular or tissue damage. On the first day post-transplant (Figures 2C and 2D), significant congestion and thrombosis in the glomerular capillaries are evident, indicating the presence of thrombotic microangiopathy (TMA). The emergence of TMA may be related to the immune system's response to unique antigens in the pig kidney, although no deposition of antibodies or complement components was detected in this experiment. This reaction suggests that, despite genetic editing reducing antigenicity, the human immune system may still recognize and react to pig kidney cells. By the third day post-transplant (Figures 2E and Figures 2F), although there is some improvement in glomerular lesions, the tubular damage has worsened to acute necrosis, likely related to hypoxia and ongoing immune attacks. The kidney's response may be influenced by various factors, including post-transplant management, the effectiveness of immunosuppressive treatments, and other unknown biological interactions. These pathological changes display the kidney's adaptation process when faced with challenges from the human immune system and also reveal the importance of optimizing immunosuppressive strategies in future clinical applications of xenotransplantation to minimize organ damage and improve graft survival. Another study involving the transplantation of genetically engineered pig kidneys into a brain-dead human recipient showed no signs of hyperacute rejection. The kidneys produced urine and remained viable for 54 hours, highlighting the potential for these genetically modified organs to function in a human environment (Montgomery et al., 2022). Montgomery et al. (2022) explored the potential of using genetically modified pigs as donors to address the human organ transplant demand. Due to acute rejection reactions caused by human antibodies to specific glycosylation changes, the pigs in the study were genetically edited to remove the alpha-1,3-galactosyltransferase gene to reduce immune rejection. The study involved transplanting pig kidneys into two brain-dead human recipients and observing them for 54 hours with ventilator support. Post-transplant, recipients immediately produced urine, and kidney function indicators, such as the glomerular filtration rate, improved. Biopsy examinations found no acute or antibody-mediated rejection responses. Additionally, the experiment included monitoring and prevention of potential porcine-derived diseases. This study demonstrated the short-term compatibility and functionality of genetically modified pig kidneys in human recipients, providing important data for future clinical applications. Figure 3 displays the condition of pig kidneys transplanted into human recipients. Part A shows the immediate observation of the pig kidney post-transplant, where the kidney appears pink and healthy, with no obvious signs of ischemia or infarction. Part B presents the pig kidney 54 hours after transplantation, maintaining a pink color and healthy appearance. Parts C and D show the kidney conditions of the second recipient immediately after transplantation and 54 hours later, respectively, demonstrating a similarly good appearance. Part E depicts the setup connecting the ureter to the drainage system, specifically designed to collect urine produced by the pig kidney to assess its functionality. These images indicate that the pig kidneys were able to maintain good blood supply and functional status post-transplantation. 8.2 Ongoing and future clinical trials focusing on genetic determinants Ongoing and future clinical trials are focusing on optimizing genetic modifications to improve graft survival and reduce rejection. Several trials are investigating the efficacy of triple-knockout (TKO) pigs, which lack the three major carbohydrate xenoantigens, combined with the expression of human complement regulatory proteins. These genetic modifications are crucial for reducing the antigenicity of pig organs and improving compatibility with human recipients (Cooper et al., 2019). Upcoming trials aim to test the long-term functionality and safety of these genetically engineered organs in human recipients, paving the way for broader clinical applications (Xu et al., 2022).
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