ABSTRACT
Human life expectancy is increasing, resulting in an increase in the number of individuals with chronic diseases and end-stage organ failure. Xenotransplantation promises an endless supply of organs and cells for clinical transplantation, alleviating the acute lack of human tissues preventing the majority of patients on the transplant waiting list from obtaining treatment. The concept of xenotransplantation isn't new, and there have been countless clinical experiments over the previous 300 years or so.
Clinical xenotransplantation has become more realistic due to the breakthroughs in gene editing technologies and immunosuppressive medication, as well as longer xenograft survival time in pig-to-non-human primate models. David Bennett Sr. is the first person to have a genetically-modified pig heart xenotransplanted into him on January 7, 2022, at the age of 57. This is a new and significant ray of hope for the medical community. But there are still many immunological barriers that need to be overcome, i.e. three types of rejections can occur: hyperacute xenograft rejection, acute humoral xenograft rejection, and acute cellular rejection. To date, three pig antigens have been identified and genetically modified, which are present on the surfaces of pig cells and serves as a foreign tissue marker. Even while progress is being made in the field, there are still numerous immunological obstacles to overcome.
KEYWORDS
Cardiac xenografts, renal xenografts, pancreatic xenografts, lung xenografts, NHP(non- human primate), GTKO pigs, galactose-a1,3-galactose (Gal),N-glycolylneuraminic acid (NeuGc), Sd(a) antigen, transgenic pigs
INTRODUCTION
In the present scenario, in many fatal situations, terminal organ failure can only be treated via surgical transplantation. Due to a severe lack of human organ donors, many patients in need do not receive this treatment. Furthermore, many people are waiting for a life-saving organ, and over 6,500 people have died while waiting in the last five years.[1] The scarcity of donated human organs and cells for clinical transplantation continues to be a major issue around the world. The kidney is the most often transplanted organ, accounting for 68% of all organ transplants. In several nations, deceased donors account for 60–65 % of all transplanted kidneys. The death of eligible donor organs could be solved through xenotransplantation, or cross-species transplantation utilising pig organs. Moreover, as more patients and new diseases are considered eligible for transplantation, the demand for organ donors will continue to grow.[5]Xenografts can help to close the gap as the benefits of successfully transplanting pig organs or cells into human patients would be immense.[1]
1. HISTORY
A study of Greek mythology and religious texts, particularly from the Hindu religion, reveals that people have been fascinated by the idea of combining physical attributes from different animal species for hundreds of years. The effort by Daedalus and his son, Icarus, to fly across the sea from Crete to mainland Greece with the use of bird wings connected to their arms is one of the oldest examples of xenotransplantation.[4]The notion of xenotransplantation is not
new, and numerous clinical trials have taken place over the last 300 years or more. Jean Baptiste Denis attempted clinical blood xenotransfusion in the 17th century, corneal xenotransplantation from pig to human in the early 19th century, and nonhuman primate (NHP) kidney xenotransplantation in the 1960s by Reemtsma and others have been reported.[3] Blood was transfused from many animal species into humans with an array of medical diseases during the 17th and 20th centuries. In the nineteenth century, skin transplants were performed using grafts from several species, with frogs being the most common. Reemtsma transplanted chimpanzee kidneys into 13 patients in 1963–4 when human organs were unavailable and dialysis was not yet in use.[4] Pig heart valves have been used for many years without causing any problems, but that's because they're essentially inert tissue that rarely causes rejection.[5]
2. CURRENT STATUS
Clinical xenotransplantation has become more feasible thanks to breakthroughs in gene editing technologies and immunosuppressive medication, as well as longer xenograft survival time in pig-to-non-human primate models.[6]The breeding of pigs with the key antigen galactose-a1,3-galactose removed via gene-knockout (GTKO pigs) in 2003 sparked xenotransplantation research. Identification of other xenoantigens has become increasingly significant in recent years.[3] A 57-year-old terminally ill patient, David Bennett underwent a successful heart transplant from a genetically engineered pig, according to the University of Maryland School of Medicine (UMSOM). He had been ruled ineligible for a human transplant, a choice that doctors frequently make when a patient is in critical condition.The human body has a predisposition to turn against foreign tissue when it detects it. To date, 3 pig antigens have been identified, the most important of which is galactose-a1,3-galactose (Gal), the others being N-glycolylneuraminic acid (NeuGc) and the Sd(a) antigen, which is found on the surfaces of pigs' cells, are the most essential biomarker of oddness. Antibodies to suppress this molecule exist in humans, even though the molecule itself does not exist in humans. As a result, no alpha-Gal transplant from a pig would last more than a few minutes in a human body. Hence, pigs were produced with a genome modified to suppress the enzyme responsible for making alpha-Gal. The genes responsible for the quick rejection of foreign organs by the human body are knocked out in the donor pig via ten genetic modifications. Six human genes are inserted to replace four pig genes. According to the AFP news agency, the pig used in the transplant had been genetically modified to knock off multiple genes that would have caused the organ to be rejected by Mr.Bennett's body.[8]
2.1 CARDIAC XENOGRAFTS
Cardiac transplantation is the recommended remedy for end-stage heart failure; yet, due to a significant global donor heart scarcity, cardiac allotransplantation is limited.[7]Biological valves, also known as bioprosthetic valves, are often derived from cows or pigs. Human donor valves are only used on rare occasions by doctors. Biological valves typically span 10 to 15 years, so you may need another replacement procedure in the future. Because they don't increase the danger of blood clots, you won't need to take a blood thinner.[8] Furthermore, the use of cyclosporine as the major immunosuppressive medication for heart transplant recipients has resulted in high survival rates (85% 1-year survival at most centres) and a reduction in infection and rejection-related morbidity.[9,10]
2.2 RENAL XENOGRAFTS
The transplantation of kidneys from genetically altered pigs, known as xenotransplantation, holds the potential of addressing the ongoing lack of deceased and living human donors. These genetic manipulations can include:
1) The genes responsible for the production of antigens against which the primate (human or nonhuman primate) has "preformed" antibodies that bind and trigger complement-mediated destruction are knocked out.
2) inserting human transgenes that protect human complement, coagulation, or inflammatory responses.
Kidney xenotransplantation has a lengthy history, dating back over 100 years, mostly involving the clinical transplantation of nonhuman primates' kidneys (NHPs). Significant success in the experimental laboratory with the transplanting of pig kidneys has just lately been made. Because of the activity of primate natural antibodies and the innate immune response, primate rejection of a pig organ is significantly more vigorous than that of an allograft.
Even though pig kidneys are extremely comparable to human kidneys in shape and relative size, there may be physiological incompatibilities between pigs and primates that could be troublesome. Hemodialysis can help patients with end-stage kidney illness, but also raises ethical concerns regarding the earliest clinical trials of xenotransplantation, which must be addressed.
However, when compared to staying on dialysis, allotransplantation improves patient lifespan and quality of life, and pig kidney transplantation could likely offer a comparable benefit in patients who are candidates for an allograft but can't get one for medical reasons.[10]
2.3 LUNG XENOGRAFTS
Compared to other organs, the lung's unique anatomic structure, which includes a large surface area of vascular endothelium intimately associated with alveolar epithelium as well as robust immune surveillance and rapid response system, is primed to trigger inflammation and is susceptible to infection. According to a recent review by the same group, genetic modification of pigs combined with drugs targeting complement activation, coagulation, and inflammation significantly increased the duration of pig lung function in ex-vivo human blood perfusion models, as well as life-sustaining lung xenograft survival in vivo. As a result, only 30–40% of human lungs are functional and are retrieved and transplanted from willing organ donors at a far lower rate than liver transplants. Currently, recipient-directed treatment approaches are required to control the particularly high inflammatory response seen in lung xenografts, which persists despite significant genetic changes tested to date. Thromboxane synthase inhibitors and histamine receptor blockers have been demonstrated to reduce the inflammatory response and improve graft survival and function. Based on genetic engineering of the donor pig and targeted recipient and donor therapy, lung xenograft survival has grown from hours to days in the last year. [11]
2.4 PANCREAS XENOGRAFTS
Roughly 1000 pancreatic and islet transplants are performed each year, with a diabetic population of more than 20 million people. Type 2 diabetes, which is about 20 times more frequent than type 1 diabetes, is rarely treated with transplantation. Whole pancreas or islet transplantation necessitates the administration of powerful immunosuppressive medicines, which can have serious side effects. In patients with type 1 diabetes, a clinical trial using encapsulated neonatal wild-type pig islets was published. Their research found that islet xenotransplantation improved HbA1c levels in patients, especially when a larger number of islets were transplanted.[11]
Although the immune-suppressing regimens employed were not clinically practical, studies have shown positive results after xenotransplantation of wild-type adult or neonatal pig islets in non-human primates, although the immunosuppressive regimens utilised were not clinically applicable. The use of transgenic pigs that express hCD46 (a human complement regulating protein), and modest immunosuppression maintained normoglycaemia in a diabetic patient for more than a year.
3. POTENTIAL RISKS
1. Those who want to reduce the genetic gap between donors and recipients have supported nonhuman primate organ donors. Chimpanzees, despite meeting the majority of traditional selection criteria (e.g., size and blood type compatibility), are not an appropriate source of therapeutic xenotransplantation. Another option is the baboon, which is not endangered, has a human-like structure and physiology, and can reach a weight of about 70 pounds. The therapeutic applicability of xenotransplantation with baboon organs would be limited to young patients and tiny adults due to the baboon's size. The baboon's small body size, the rarity of blood group O (universal donor) animals, and the small number of colony-bred animals all work against it as a donor. [11]
2. Hyperacute rejection: The immune response enables the graft's endothelial cells to switch from an anticoagulant to a procoagulant phenotype i.e. the depletion of antipig antibodies or complement from the human serum. Hyperacute rejection is the outcome of activating the complement and coagulation mechanisms. [11]
3. Cellular xenograft rejection: Both whole organ and cellular grafts are affected by cellular xenograft rejection. It causes rejection, which can happen days or weeks after transplantation (37). Innate and adaptive immune responses can cause cellular rejection of a xenograft. NK cells, macrophages, neutrophils, dendritic cells, T cells, and B cells are among them.[11] 4. The spread of swine infections to human recipients is a major concern in the field of xenotransplantation. Selection of negative donor animals, breeding in sterile and isolated settings, early weaning, and embryo transfer can all help to remove most porcine viruses, bacteria, and fungus (181, 182). However, because pig endogenous retroviruses (PERVs) are integrated into the swine genome with numerous copies, such tactics are impractical. [11]
CONCLUSION
Thanks to recent achievements and the accumulation of expertise with xenotransplantation in preclinical research, a first-inhuman clinical trial could be possible in the near future. The use of pigs modified with various genes as xenotransplantation donor animals is unavoidable. New gene-editing techniques allow for the faster and more efficient production of large numbers of genetically engineered pigs. Various types of gene-modified pigs are now available, with the majority conducting preclinical pig-to-NHP xenotransplantation research. New xenoreactive antigens are discovered on a regular basis, allowing new knockout and transgenic pigs to be developed.
REFERENCES:
[1] Yang, YG; Sykes.M; Xenotransplantation: current status and a perspective on the future; 2007
[2] Ekser, Burcin; Cooper, David K.C.; Tector, A. Joseph (2015). The need for xenotransplantation as a source of organs and cells for clinical transplantation. International Journal of Surgery
[3] Ekser, Burcin; Li, Ping; Cooper, David K.C. (2017). Xenotransplantation. Current Opinion in Organ Transplantation
[4] A BRIEF HISTORY OF CLINICAL XENOTRANSPLANTATION David K. C. Cooper,(1) Burcin Ekser,(2) and A. Joseph Tector(2)
[5] Weiss, R. A (1998). Science, medicine, and the future: Xenotransplantation. BMJ, 317
[6]Lu, Tianyu; Yang, Bochao; Wang, Ruolin; Qin, Chuan (2020). Xenotransplantation: Current Status in Preclinical Research. Frontiers in Immunology
[7]Shu, Songren; Ren, Jie; Song, Jiangping (2020). Cardiac xenotransplantation: a promising way to treat advanced heart failure.
[8] https://www.bbc.com/news/world-us-canada-59944889
[9]https://www.economist.com/science-and-technology/2022/01/15/the-science-behindthe-first-s uccessful-pig-to-human-heart-transplant
[10] Wijkstrom, Martin; Iwase, Hayato; Paris, Wayne; Hara, Hidetaka; Ezzelarab, Mohamed; Cooper, David K.C. (2017). Renal xenotransplantation: experimental progress and clinical prospects. Kidney International
[11] Harris DG, Quinn KJ, Dahi S, Burdorf L, Azimzadeh AM, Pierson RN 3rd. Lung xenotransplantation: recent progress and current status. Xenotransplantation. 2014 Nov-Dec;
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