International Journal of Molecular Zoology 2024, Vol.14, No.4, 244-254 http://animalscipublisher.com/index.php/ijmz 249 Figure 3 Mechanisms of antibody-mediated xenograft rejection and related genetic targets (Adopted from Lei et al., 2022) Image caption: (A) Hyperacute rejection (HAR). In the classical complement activation cascade, the Fc regions of antibodies contact C1q, causing C1r and then C1s to autoactivate. Afterward, C4 and C2 are cleaved by activated C1s, resulting in the production of C4b2a (also known as C3 convertase). C3 convertase then cleaves C3 into C3a and C3b, with C3b binding to C4b2a to generate C4b2a3b (also known as C5 convertase). C5 convertase cleaves C5 into C5a and C5b, and then C5b is attached to C6, C7, C8, and multiple molecules of C9 to create the membrane attack complex (MAC), which ultimately causes cytolysis. (B) Acute humoral xenograft rejection (AHXR). AHXR can be induced by low levels of natural and elicited xenoreactive antibodies directed at non-α-Gal antigens (predominantly anti-Neu5Gc and -SDa), which also lead to complement activation via the classical pathway. The histopathology of AHXR is characterized by progressive destruction of the microvasculature (glomeruli and peritubular capillaries) and formation of fibrin-platelet thrombi. (C) Gene modifications. To prevent HAR, CD59, CD55, hCD46and GGTA1were modified. To shun AHXR, CMAH-/- and β4GalNT2-/- knockout pigs were produced. Notably, these target genes were not edited individually, but in combination to obtained better tolerized pig xenograft (Adopted from Lei et al., 2022) 5.3 Case studies of successful pathogen-free pig organ transplants Several preclinical studies have demonstrated the success of pathogen-free pig organ transplants. For example, genetically engineered pigs with multiple modifications, including PERV inactivation and the expression of human transgenes, have shown normal physiology and fertility, with their organs exhibiting resistance to human
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