International Journal of Molecular Medical Science, 2024, Vol.14, No.3, 177-192 http://medscipublisher.com/index.php/ijmms 180 cells that attack the graft tissue. Studies have shown that genetically modified pigs, which lack certain antigens or express human regulatory proteins, can mitigate these immune responses to some extent (Firl and Markmann, 2022; Lei et al., 2022; Wu et al., 2023). This response involves both the innate and adaptive immune systems, leading to various types of graft rejections. Key components of this immune response include natural antibodies, particularly those targeting the alpha-Gal antigen, and complement activation, which contribute to the rapid rejection of the xenograft (Singh et al., 2018). 3.2 Hyperacute rejection, acute vascular rejection, and chronic rejection Xenotransplantation faces several types of graft rejection, each posing significant challenges to the long-term success of pig-to-human transplants (Fiugre 1). Understanding the mechanisms and manifestations of these rejections is crucial for developing effective strategies to prevent and manage them. Figure 1 Antibody-mediated xenograft rejection (Adopted from Liu et al., 2020) Image caption: (A) Hyperacute rejection. Hyperacute rejection of vascularized porcine xenografts in untreated primates is triggered by the binding of preformed antibodies to the xenoantigenic epitopes (predominantly α1,3Gal) on the surface of donor endothelial cells. The binding antibody deposition induces the activation of complement proteins and formation of the membrane attack complex, leading to lysis of endothelial cells destruction of the graft vasculature and subsequent graft failure. Loss of endothelial barrier function contributes to bleeding, leading to tissue ischemia and necrosis. (B) Acute humoral xenograft rejection. Acute humoral xenograft rejection can be induced by low levels of natural and elicited xenoreactive antibodies. The binding of xenoreactive antibodies to endothelial cells results in complement activation, vascular endothelial activation, and injury caused by antibody-dependent cell-mediated cytotoxicity. Innate immune cells are recruited by activated endothelia and proinflammatory signals. Simultaneously, human antipig antibodies are triggered by natural killer cells and macrophages. MAC, membrane attack complex; C, Complement; NK, natural killers (Adopted from Liu et al., 2020) 1) Hyperacute rejection: Hyperacute rejection (HAR) is the most immediate and severe form of xenograft rejection, occurring within minutes to hours after transplantation. It is primarily mediated by pre-existing natural antibodies in the recipient's blood, which recognize specific antigens on the surface of the xenograft, such as the alpha-Gal epitope. These antibodies activate the complement system, leading to a cascade of events that result in rapid and extensive damage to the graft’s endothelial cells. This causes the blood vessels within the graft to become occluded by clots, resulting in ischemia and necrosis of the transplanted tissue. The rapid onset and severity of HAR make it a major obstacle in xenotransplantation (Singh et al., 2018; Tatapudi and Griesemer, 2022). 2) Acute vascular rejection: Acute vascular rejection (AVR), also known as delayed xenograft rejection, typically occurs days to weeks after transplantation. AVR is characterized by an immune response that targets the blood vessels of the xenograft, leading to endothelial cell activation and inflammation. This results in vascular injury, thrombosis, and eventual graft failure. Key players in AVR include activated macrophages, natural killer cells, and T cells, which infiltrate
RkJQdWJsaXNoZXIy MjQ4ODYzNQ==