Current Advances in Xenotransplantation and Strategies for Preventing Xenograft Rejection

Makin Pascal^*
*Correspondence: Makin Pascal, Department of Xenotransplantation, Yunnan Agricultural University, Kunming 650201, China, Email:

Introduction

Xenotransplantation, the process of transplanting organs or tissues from one species to another, has long been considered a potential solution to the shortage of human donor organs. The idea of using animal organs, particularly from pigs, to replace human organs in patients facing life-threatening organ failure has generated significant interest in the medical and scientific communities. However, the key challenge to the success of xenotransplantation remains xenograft rejection — the body’s immune response against foreign tissue. Overcoming this challenge has been a major focus of research, and recent advances in xenotransplantation have brought us closer to making animal-to-human transplants a viable clinical option. Xenotransplantation involves transplanting cells, tissues, or organs from one species to another. While human-to-human organ transplants are common today, they are limited by the number of available donor organs. Xenotransplantation offers a potential solution to this shortage, as animals like pigs have similar organ size and function to humans. Pigs, in particular, are considered ideal candidates due to their size, biological compatibility, and the potential to breed animals with specific genetic modifications [1]. Xenotransplantation could alleviate the severe shortage of human organs available for transplantation. For example, in the United States alone, more than 100,000 people are on the waiting list for organ transplants, with many waiting for years. Xenotransplantation could provide more immediate and widespread access to life-saving organ transplants, especially for patients who face long waiting times or have rare blood types or specific organ needs. With the possibility of genetic modification, xenotransplantation could help reduce the likelihood of organ rejection and improve long-term survival for transplant recipients. The primary obstacle to successful xenotransplantation is the immune system’s response to foreign tissue. When animal organs are transplanted into humans, the human immune system recognizes them as "foreign" and mounts a rejection response. This can lead to the rapid destruction of the transplanted organ, sometimes within hours or days. his is the most immediate type of rejection and occurs within minutes to hours after transplantation. It is triggered by pre-existing antibodies in the human immune system that recognize the animal tissue as foreign [2].

Description

This occurs within a few days to weeks and is driven by the activation of T-cells, which attack the foreign tissue. This is a slower process that can occur over months or years. It results in the gradual damage to the transplanted organ, and it is difficult to reverse. In recent years, significant progress has been made in understanding and overcoming the biological barriers to xenotransplantation. Much of the research has focused on using genetic modification to make animal organs more compatible with the human immune system. One major approach is the modification of pig organs to make them more similar to human organs, particularly by adding human genes that can prevent immune rejection. For example, researchers have inserted human genes for proteins that help evade immune attacks, such as CD47. Scientists also use gene editing to remove or "knock out" specific pig genes that make their organs more likely to be recognized as foreign. For instance, the gene responsible for producing the carbohydrate α-gal (alpha-galactose) on the surface of pig cells has been deleted. Humans have antibodies against this carbohydrate, and its presence triggers hyperacute rejection. By removing this gene, the likelihood of hyperacute rejection is reduced [3].

Researchers are exploring drugs and antibodies that target specific components of the immune system, such as T-cells, which play a key role in rejecting transplanted organs. Some strategies focus on suppressing the T-cell response specifically to the transplanted xenograft without compromising the body’s overall immune defense. This involves blocking the secondary signals needed to activate the immune system’s T-cells. By inhibiting co-stimulatory molecules, scientists can reduce the immune response and make the xenograft more likely to survive. Some researchers are investigating ways to induce immune tolerance to xenografts. This involves manipulating the immune system so that it recognizes the xenograft as "self," thereby preventing an immune attack. One of the most promising recent developments in xenotransplantation research was the successful pig kidney transplant into a brain-dead human. In October 2021, researchers at the NYU Langone Health in New York performed the first-ever transplant of a genetically modified pig kidney into a human. While the patient was brain-dead, the kidney functioned normally for over 50 hours, which is a major breakthrough. This experiment demonstrated that genetically modified pig organs could survive in a human body, at least temporarily, and provided valuable data on the barriers to xenotransplantation. Additionally, several companies and research institutions are moving toward clinical trials involving genetically modified pig hearts, kidneys, and other organs. These clinical trials are being carefully monitored, and researchers are working on strategies to improve organ function and longevity. Hyperacute Rejection (HAR) is typically defined as a rapid graft destruction occurring within 24 hours after transplantation, often lasting from minutes to hours [4].

It results from the binding of pre-existing antibodies, either human or non-human primate (NHP), to antigens present on the graft. These antibodies, most commonly IgM and IgG, recognize the galactose-α 1,3-galactose (α-Gal) epitopes found on glycoproteins and glycolipids. These epitopes are added by the α1,3 galactosyltransferase (α1,3GT) enzyme, which is present in the genomes of non-primates and New World monkeys (such as howlers, spider monkeys, and woolly monkeys). Humans, Old World monkeys (such as baboons and mandrills), and apes lack α-Gal epitopes due to a mutation in the α1, 3GT gene, rendering it nonfunctional. As a result, approximately 70-90% of the antibodies produced in these species target α-Gal epitopes specifically. When a pig organ is transplanted into a human or NHP, the pre-existing anti-Gal antibodies recognize and bind to the α-Gal epitopes on the graft's endothelial cells. This binding activates the complement system, leading to the production of complement component 3b (C3b), which triggers the formation of a Membrane Attack Complex (MAC). These immune reactions result in endothelial cell lysis, disruption of the vascular endothelium, and ultimately, rejection of the graft [5].

The loss of endothelial integrity causes interstitial hemorrhage, tissue ischemia, and necrosis. Additionally, capillary thrombotic occlusion, fibrinoid necrosis of arterial walls, and the accumulation of neutrophils exacerbate graft failure . Nitric Oxide Species (NOS), Reactive Oxygen Species (ROS), and other free radicals play significant roles in the rejection process. Histologically, HAR is characterized by disrupted vascular integrity, edema, fibrin-platelet-rich thrombi, interstitial hemorrhage, and widespread deposition of immunoglobulins and terminal complement products on the vessel walls.

Conclusion

Xenotransplantation may face public resistance, especially concerning the use of animals for organ donation. Public acceptance and understanding of xenotransplantation will play a crucial role in determining whether this technology can be widely adopted. Xenotransplantation holds tremendous potential as a solution to the global organ shortage, but several technical, biological, and ethical challenges remain. The advances in gene editing and immunosuppressive strategies are promising, and clinical trials are providing valuable insights into the feasibility of transplanting genetically modified animal organs into humans. However, much work remains to be done to ensure the safety, efficacy, and public acceptance of xenotransplantation. If ongoing research continues to address the hurdles of immune rejection, disease transmission, and animal welfare, xenotransplantation could one day become a viable clinical option for treating organ failure, offering hope to millions of patients worldwide.

Acknowledgement

None.

Conflict of Interest

None.

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