Animal Molecular Breeding 2024, Vol.14, No.1, 106-118 http://animalscipublisher.com/index.php/amb 107 1 The Need for Immune-Compatible Organs 1.1 Challenges of organ rejection in transplantation Organ transplantation has been a critical medical advancement for treating end-stage organ failure. However, one of the most significant challenges in transplantation is the risk of organ rejection, which can be acute, chronic, or hyperacute. Rejection occurs when the recipient's immune system recognizes the transplanted organ as foreign and mounts an immune response against it. This immune response can be mediated by T-cells, antibodies, or innate immune cells such as macrophages and natural killer (NK) cells (Yılmaz et al., 2020; Nguyen et al., 2021; Lu et al., 2022). The use of immune checkpoint inhibitors (ICI) has shown clinical benefits in cancer patients but has also been associated with increased risks of transplant rejection, particularly in kidney and liver transplant recipients (Nguyen et al., 2021). 1.2 Importance of immune compatibility in xenotransplantation Xenotransplantation, the transplantation of organs from one species to another, has emerged as a promising solution to the shortage of human organs available for transplantation. Pigs are considered ideal donors due to their physiological similarities to humans and the feasibility of genetic modifications. However, the genetic and molecular incompatibilities between pigs and humans pose significant barriers, leading to xenogeneic rejection (Sykes and Sachs, 2019; Yılmaz et al., 2020; Lu et al., 2022). Innate immune responses, including those mediated by macrophages, NK cells, and neutrophils, play a crucial role in xenogeneic rejection (Maeda et al., 2020; Lu et al., 2022). Addressing these immune compatibility issues is essential for the success of xenotransplantation. 1.3 Current strategies to address organ rejection Several strategies have been developed to mitigate the risk of organ rejection in both allotransplantation and xenotransplantation. These include the use of immunosuppressive therapies, genetic modifications, and pretransplant desensitization techniques. Advances in gene-editing technologies, such as CRISPR-Cas9, have enabled the creation of genetically modified pigs with reduced expression of antigens that trigger immune responses, such as galactose-α1,3-galactose and N-glycolylneuraminic acid (Sykes and Sachs, 2019; Yılmaz et al., 2020). Additionally, overexpression of inhibitory ligands on porcine cells has been shown to suppress macrophage-mediated rejection (Maeda et al., 2020). Understanding the mechanisms of innate immune responses and developing targeted therapies to modulate these responses are critical for improving the outcomes of xenotransplantation. In conclusion, while significant progress has been made in addressing the challenges of organ rejection, ongoing research and development of innovative strategies are essential to achieve immune-compatible organs for transplantation. The integration of genetic modifications and advanced immunosuppressive therapies holds promise for the future of xenotransplantation and the potential to save countless lives. 2 Genetic Basis of Immune Rejection 2.1 Overview of the human immune response to foreign organs The human immune system is highly adept at recognizing and responding to foreign tissues, a process that is critical in the context of organ transplantation. The primary immune response to transplanted organs involves both the innate and adaptive immune systems. The innate immune response is the first line of defense and includes mechanisms such as inflammation and the activation of macrophages and natural killer (NK) cells (Figure 1) (Ravichandran et al., 2022; Zhang et al., 2022). The adaptive immune response, which is more specific and involves memory, is mediated by T and B lymphocytes. T cells recognize foreign antigens presented by major histocompatibility complex (MHC) molecules on the surface of donor cells, leading to T-cell activation and proliferation (Ronca et al., 2020; Morazán-Fernández et al., 2022). B cells produce antibodies against donor antigens, contributing to antibody-mediated rejection (ABMR) (Yazdani et al., 2019; Morazán-Fernández et al., 2022).
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