The first pig kidney transplant to a human being is a big step forward in xenotransplantation

Recently, a major breakthrough has been made in xenotransplantation technology. Researchers at New York University Langone Medical Center transplanted a pig kidney into a brain-dead patient with symptoms of renal failure. During the subsequent 50-hour observation period, the transplanted kidney worked well, no immune rejection occurred, and all indicators in the patient's body returned to normal.

The success of this experiment once again ignited the public's attention to xenotransplantation.

Xenotransplantation

Xenotransplantation refers to the transplantation of tissues and organs from one species into another species.

In the early civilizations of mankind, there was already the idea of ​​"transplanting" animal organs to humans, such as the Sphinx (a lion with a human body) in ancient Egyptian mythology and Nuwa (a snake god with a human face) in Chinese mythology. In ancient Indian mythology, Lord Shiva accidentally cut off the head of his son Ganesha. In order to revive his son, he cut off the head of an elephant and "transplanted" it to his son's body, successfully resurrecting his son. This is the Ganesha in Indian mythology.

(The elephant-headed god in Indian mythology. Legend has it that in order to make up for the fact that Lord Shiva accidentally chopped off his head, he required all the gods to unconditionally meet all of the elephant-headed god's requests. Therefore, the elephant-headed god is very effective and has a large number of believers among the Indian people)

Since the 17th century, medical scientists have attempted to treat patients' diseases through xenotransplantation.

Initially, European physicians transfused animal blood into patients to treat their mental illnesses, but the patients usually died within a day due to severe immune rejection reactions.

In 1893, British doctor Watson Williams transplanted a fragment of a sheep's pancreas into a critically ill patient with diabetes. Although the insulin secreted by the sheep's pancreas relieved the patient's symptoms, the patient died of an immune rejection reaction three days later.

In the 1920s, Russian physician Fronov sewed monkey testicles into human scrotums in order to restore youth. Although the patients were lucky and did not die, the implanted monkey testicles became ineffective due to fibrosis after 1-2 years.

From 1963 to 1964, American transplant surgeon Dr. Thomas Starzer transplanted baboon hearts into several patients. The patients survived for 19 to 98 days before dying of immune rejection.

For xenotransplantation, transplant rejection has always been an insurmountable obstacle.

Immune rejection

The human immune system is a barrier that protects us from harmful substances from the outside world. When foreign substances invade the human body, the immune system will identify these foreign harmful substances and eliminate them through various means. Organs transplanted into the human body are also foreign harmful substances in the eyes of the immune system, so the immune system will try every means to get rid of them.

Organ transplant rejection can be divided into two types: host versus graft reaction and graft versus host reaction. Usually, what we call immune rejection refers to host versus graft reaction, which is also the most common problem in clinical transplantation.

When the transplanted organ enters the human body, the antigens on the surface of the transplanted organ cells will be recognized by the human immune system. Antigens are a special type of glycoprotein on the cell surface, which is the "identity certificate" of the cell. The antigens on the cell surface are different between different people and different species. The greater the species difference, the more obvious the difference between the antigens, and the stronger the immune rejection reaction caused.

Host versus graft reactions are usually divided into three categories, depending on when rejection occurs:

1. Hyperacute rejection. Hyperacute rejection usually occurs 24 hours after transplantation. The immune system will react quickly, and the antibodies in the body will attack the transplanted organ, eventually leading to severe ischemia and necrosis of the transplanted organ. Once hyperacute rejection occurs, there is no effective treatment method, which will eventually lead to transplant failure.

(II) Acute rejection. Acute rejection is the most common type of rejection reaction, which usually occurs within a few days to a few months after transplantation and progresses rapidly. Cellular immune response is the main cause of acute transplant rejection, and CD4+T cells and CD8+TC cells are the main effector cells. Most acute rejections can be alleviated by increasing the dosage of immunosuppressants.

(III) Chronic rejection. Chronic rejection usually occurs several months to years after organ transplantation. Its main feature is the proliferation of endothelial cells in the capillary bed of the transplanted organ, which narrows the vascular lumen and gradually causes fibrosis. Chronic immune inflammation is the main cause of the above-mentioned tissue pathological changes. Currently, there is no ideal treatment for chronic rejection.

Due to the huge differences between xenogeneics, xenotransplantation often fails in the first two stages.

Experimental significance

Domestic pigs are ideal donors for human organs due to their high litter size, fast growth rate, and organ size similar to that of human organs. They can provide humans with an "inexhaustible" supply of transplanted organs, thus alleviating the increasing shortage of allogeneic donor organs. However, how to overcome the strong immune rejection during xenotransplantation is a difficult problem that scientists must solve.

(Organs that pigs can provide to humans)

There are a lot of α-galactosidase (α-gal) antigens in the kidneys of pigs. α-gal antigen is a natural xenoantigen that is widely present in non-primate mammals (also in lemurs and New Century monkeys), but not in apes and humans. Previous studies have shown that α-gal antigen is an important cause of hyperacute rejection of xenotransplantation, and antibodies naturally present in human plasma can recognize α-gal. α-gal is synthesized by α-1,3-galactosyltransferase (GGTA1). In 2002, scientist Professor Dai Yifan developed a heterozygous pig with GGTA1 knocked out. Subsequently, scientists used heterozygous pigs to develop homozygous piglets with GGTA1 knocked out, thus avoiding hyperacute reactions during xenotransplantation.

In addition to rejection, pigs also have an endogenous retrovirus in their bodies, which is lethal to humans. In 2017, scientists such as George Church and Yang Luhan used genetic technology to knock out the endogenous retrovirus (PERV) sequence in the pig genome and cloned several PERV-inactivated piglets, thus solving this problem.

In order to better prevent immune rejection, scientists also knocked human genes such as CD46 into pigs.

In 2018, scientists from the University of Munich in Germany transplanted a genetically modified pig heart into a baboon. The pig heart transplanted into the baboon successfully maintained full functionality and beat for 195 days.

After years of laboratory research, scientists and medical professionals decided to move into (sub)clinical medicine.

In this experiment, medical scientists used pigs that had been genetically modified to have α-gal knocked out as donors, avoiding hyperacute rejection by the host's immune system. The pig kidneys successfully worked in the host for more than 50 hours. This experiment successfully proved that removing α-gal can avoid hyperacute rejection by the human immune system.

Of course, the success of this experiment does not mean that we have realized the dream of xenotransplantation. α-gal is only the cause of hyperacute rejection, but not the cause of acute rejection and chronic rejection. Scientists took the initiative to end the experiment 54 hours after the successful transplantation, and failed to observe long-term effects (I believe that the experimenters also know that if the observation is not terminated in time, the transplanted kidney will most likely become necrotic over time). Therefore, on the road to xenotransplantation, we have only taken a small step towards success, and there is still a long way to go.

Author: Zhang Yuanchao, attending physician

This article was published by Tencent's "Everyone Loves Science" team

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