Journal of Vaccine Research 2024, Vol.14, No.3, 120-134 http://medscipublisher.com/index.php/jvr 127 Image caption: Samples with hematoxylin and eosin staining (Panels A and B) revealed normal-appearing glomeruli with capillary loops, which showed no evidence of microvascular inflammation (arrowheads), and tubulointerstitium with no demonstrable lymphocytic infiltration (arrows). Immunofluorescence microscopy of a sample from Recipient 1 re- vealed no C4d staining in the peritubular capillaries (Panel C). Immunofluorescence microscopy of a sample from Recipient 2 revealed focal C4d staining in the peritubular capillaries (Panel D, arrowhead). Ultrastructural imaging at the same time points (Panels E and F) showed glomerular capillary loops with a normal-appearing glomerular basement membrane (arrows) and intact podocyte foot processes (arrowheads). (Adapted from Montgomery et al., 2022) These case studies highlight the potential of genetically modified pig organs in human recipients, emphasizing the effectiveness of specific genetic modifications like the GGTA1 knockout in reducing rejection risks. The generally positive short-term results, along with occasional immune challenges such as focal C4d staining, underline the need for continued refinement of immunosuppressive strategies. These findings lay a foundation for future research aimed at enhancing graft longevity and functionality in xenotransplantation through combined genetic and immunosuppressive interventions(Singh et al., 2018). 6.2 Experimental results on graft survival and function Genetic modification of pigs can significantly enhance the survival and function of transplants. For example, human complement regulatory proteins (such as CD46 and CD55) and coagulation regulatory proteins (such as thrombomodulin) expressed in genetically modified pigs are crucial in preventing acute rejection and coagulation disorders. These modifications enable pig kidneys to function for a long time in non-human primates, with some grafts surviving for over a year (Cooper et al., 2019). Further research by Coe et al. (2020) involved ex vivo perfusion of genetically modified pig livers with human blood. The livers demonstrated prolonged function and improved biochemical parameters compared to non-modified pig livers. The genetically modified livers showed reduced antibody and complement deposition, highlighting the effectiveness of specific genetic modifications in improving graft compatibility and function (Coe et al., 2020). A study on pig-to-human liver xenotransplantation using genetically modified pigs with multiple gene knockouts (GGTA1, CMAH, and β4GalNT2) showed improved survival and function of the grafts. The modifications helped mitigate hyperacute rejection and inflammation, with the grafts exhibiting near-normal liver function during the perfusion period. 6.3 Comparative analysis of different genetic modifications and their outcomes Comparative analyses of different genetic modifications have provided valuable insights into the most effective strategies for enhancing graft survival and function. For instance, pigs with triple knockouts of GGTA1, CMAH, and β4GalNT2 combined with the expression of human complement regulatory proteins (CD46, CD55) and coagulation regulatory proteins (thrombomodulin) have shown superior outcomes in terms of graft survival and function compared to pigs with fewer modifications. These multiple modifications address various immune and coagulation challenges simultaneously, leading to more stable and functional grafts (Kemter et al., 2020). Another comparative study highlighted the importance of anti-inflammatory and anti-apoptotic genes in improving graft outcomes. Pigs expressing human heme oxygenase-1 (HO-1) and A20 genes exhibited reduced inflammatory responses and lower levels of apoptosis in transplanted organs, resulting in better graft survival and function compared to those without these modifications (Fischer et al., 2016). The role of macrophage inhibitory proteins, such as human CD47, has also been emphasized in comparative studies. Pigs expressing human CD47 showed reduced phagocytosis by recipient macrophages, leading to enhanced graft tolerance and prolonged survival in non-human primate models. These findings suggest that combining multiple genetic modifications targeting different pathways can synergistically improve the outcomes of xenotransplantation.
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