Journal of Vaccine Research 2024, Vol.14, No.3, 120-134 http://medscipublisher.com/index.php/jvr 122 3 Mechanisms of Graft Longevity 3.1 Definition and importance of graft longevity Graft longevity refers to the duration a transplanted organ remains functional and free from significant rejection or failure in the recipient's body. It is a critical measure of the success of organ transplantation, directly correlating with improved patient outcomes and quality of life. Achieving long-term graft survival reduces the need for re-transplantations, which in turn lowers healthcare costs and alleviates the strain on the limited supply of donor organs (Sykes and Sachs, 2019). The importance of graft longevity is underscored by the challenges of chronic rejection and graft loss, which remain significant despite advancements in immunosuppressive therapies. Chronic rejection involves a complex interplay of immunological and non-immunological factors, leading to gradual deterioration and eventual failure of the graft. Enhancing graft longevity is therefore a primary goal in transplantation research, aiming to improve long-term patient survival and overall health outcomes (Rosales and Colvin, 2019). Furthermore, graft longevity impacts not only the individual patient but also the broader healthcare system. Long-term graft survival reduces the frequency of hospital visits and the need for continuous medical interventions, thus contributing to better resource allocation and patient care management (Pan et al., 2019). 3.2 Biological and immunological factors influencing graft longevity Several biological and immunological factors are crucial in determining the longevity of a graft. Key biological factors include the health and viability of the donor organ, ischemia-reperfusion injury, and the presence of pre-existing conditions in the recipient. Ischemia-reperfusion injury occurs when the blood supply returns to the tissue after a period of ischemia, causing oxidative stress and inflammation that can damage the graft. Strategies to mitigate this injury are critical for enhancing graft survival (Cooper et al., 2019). Immunological factors are paramount in graft longevity, with the recipient's immune system playing a central role in graft rejection. The three primary immune responses include hyperacute rejection, acute cellular rejection, and chronic rejection. Hyperacute rejection occurs within minutes to hours post-transplantation, mediated by pre-existing antibodies against the donor antigens. Acute cellular rejection involves T-cell mediated immune responses leading to graft inflammation and damage, typically within the first few months after transplantation. Chronic rejection is a slow, progressive process involving both cellular and humoral immune responses, ultimately leading to long-term graft failure (Lei et al., 2022). Additionally, the role of inflammation and immune regulation is significant in graft survival. Persistent inflammation can lead to tissue damage and fibrosis, reducing graft functionality over time. Effective management of immune responses and inflammation is therefore essential for prolonging graft longevity (Ekser et al., 2015). 3.3 Role of genetic modifications in enhancing graft survival Genetic modifications in donor pigs have shown substantial promise in enhancing graft survival and longevity. These modifications aim to address immunological barriers and improve the compatibility of pig organs with the human immune system. One of the most impactful genetic modifications is the knockout of the GGTA1 gene, which eliminates the expression of the α-Gal antigen, a major target of pre-existing human antibodies. This modification significantly reduces the risk of hyperacute rejection, thereby enhancing graft survival (Petersen et al., 2016). In addition to eliminating problematic antigens, the introduction of human complement regulatory proteins such as CD46, CD55, and CD59 into the pig genome has been successful in mitigating complement-mediated damage to the graft. These proteins help regulate the complement system, an integral part of the immune response, thus preventing excessive immune attacks on the transplanted organ (Fischer et al., 2016). Further advancements include the insertion of genes that enhance the anti-inflammatory and anti-apoptotic properties of the graft. For example, the expression of human heme oxygenase-1 (HO-1) in genetically modified pigs provides cytoprotective effects, reducing ischemia-reperfusion injury and improving the overall resilience of
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