LivingOrgan transplants when immunity is the problem

Organ transplants when immunity is the problem

Naiara, a baby just two months old, made history by becoming the recipient of the world’s first transplant of a stopped infant heart, even with blood incompatibility with the donor. To recover the deceased’s organ before its removal, a procedure called extracorporeal circulation was used, which allows the heart to be oxygenated through a machine. As explained by the team that intervened with little Naiara, at the Gregorio Marañón hospital in Madrid, this type of transplant, until recently unviable, significantly increases the life expectancy of pediatric patients, for whom there are very few donations.

Not a week goes by without us knowing of a new advance in the field of transplants. A child with a serious intestinal malformation leaves the operating table at the Hospital Universitario La Paz in Madrid with a new stomach, liver, duodenum, small intestine, colon segment and pancreas. Also in the capital, but at the Puerta de Hierro hospital, the medical team faces a simultaneous transplant of two hearts for the first time. And at the Hospital Clínic de Barcelona, a patient receives a uterus transplant from a living donor, which has opened up the possibility of becoming pregnant.

Donation and transplantation activity in 2020 was marked by the COVID-19 crisis, but, despite multiple difficulties, 4,427 organ transplants were performed in Spain, which corresponds to a rate of 93.3 per million patients. population (pmp). The figure is much higher than the rest of the countries in the pre-pandemic period, hence our country is an international benchmark. Even so, at the end of the year, 4,794 patients were on the waiting list, 92 of them children. “There is a huge disproportion between supply and demand or an inability to meet the needs of organs for transplantation of the population, which also ages and develops pathologies,” says Beatriz Domínguez-Gil, general director of the National Transplant Organization (ONT ).

A transplant consists of replacing a diseased organ or tissue with another that is working properly. It can be a solid organ (kidney, heart, liver), tissues (bone, tendon, corneas, skin) or hematopoietic progenitors (those that generate blood, that is, bone marrow). In any case, it is the best solution – and sometimes the only one – to prevent death or improve the lives of people who suffer irreversible damage to any of their organs. In Spain, this procedure is regulated by a law that ensures altruism in donation and equity in access to transplantation.

The implantation of a foreign body in the body represents a major medical and pharmacological battle. Unlike what happens with a blood transfusion, transplanted organs, although there is a high compatibility, are usually rejected, either immediately or in the long term. For example, the expiration date of a kidney is ten years; that of a lung, five; that of a heart, thirteen; and that of a liver, seventeen. In pediatric patients, this means that they may need replacement several times throughout their lives, when the availability of children’s organs is also very scarce.


Pharmacological immunosuppression

Rejection occurs because the immune system is designed to seek out and destroy cells that it recognizes as foreign. To avoid this, the body’s defenses are reduced to a minimum through immunosuppressive drugs. “Most patients need this therapy for life,” explains the director of the ONT. The problem is that “immunosuppression generates pathology, and, on the other hand, the transplanted patient already has, in a large percentage, a lot of associated comorbidity”. This is what justifies that you are more likely to develop serious diseases, from kidney problems to infections, osteoporosis and even cancer. In children, in addition, growth and cognitive problems may occur, among others.

Hence, scientists from all over the world are working on developing strategies to minimize dependence on pharmacological immunosuppression to prevent rejection of solid organs and to ensure “a single organ transplanted for life”, in the words of Antonio Pérez, Head of the Pediatric Hemato-Oncology and Hematopoietic Transplantation Service in La Paz.

This Madrid hospital is a pioneer in the induction of immunological tolerance, a strategy that proposes transferring, together with the organ, hematopoietic progenitors of the same donor. “This approach is based on the observation that, in bone marrow transplantation, almost 90% of patients eliminate immunosuppressive medication after one or two years,” explains Dr. Pérez. Translated to solid organ transplants, it involves tricking the patient’s immune system into not rejecting the graft, because it is also accompanied by its own immune system. “The immune cells of the donor and the recipient coexist in parallel as in marrow transplants.”

Thus, in 2020, the world’s first simultaneous visceral and hematopoietic stem cell transplantation was performed at the Hospital Universitario La Paz. The patient, a fifteen-year-old boy, suffered from intestinal epithelial dysplasia, a congenital and inherited disease in which the intestine does not absorb nutrients due to a mucosal problem and requires intravenous feeding from birth. Previously, he had received two transplants, one intestinal and the other multivisceral, with rejection of the organs in both cases. In this third intervention, the specialists transplanted a stomach, small and large intestine, pancreas and liver, as well as bone marrow from the donor (previously manipulated to recover stem cells). In this way the risk of the ghost of rejection was reduced.

Although today it still sounds like science fiction, the truth is that regenerative medicine promises, in the not too distant future, to end the problem of organ shortages and the need for immunosuppressive medication. Cells can be genetically engineered to reintroduce them into the body. And tissues, such as a piece of skin or heart, can be grown in the laboratory to repair those that are affected. In fact, it has already been achieved. There are very promising alternatives to traditional transplantation, such as xenotransplantation, that is, humanized organs from animals, such as pigs; the development of synthetic organs; and the three-dimensional printing of viscera from scratch, using cells instead of ink.

In 2019, for example, a group of scientists from Tel Aviv University, in Israel, presented the first prototype of a human heart printed in 3D from human tissue and with blood vessels, including capillaries. “We take a small biopsy of the patient’s fatty tissue, we remove all the cells and separate them from collagen and other biomaterials, we reprogram them to be stem cells and then we differentiate them to be heart cells and blood vessel cells,” explained then one of the study authors, Professor Tal Dvir. The biomaterials were processed into biotin, which allowed the cells to be printed. Her heart, the size of a cherry, throbbed with life.

Xenotransplantation, that is, transplants in which the donor and the recipient are of different species, have been practiced for decades and have helped, for example, to replace the aortic valve in humans thanks to porcine or bovine tissue. The next step, however, is the creation of human organs within the animal, something that the Spanish Juan Carlos Izpisúa, a researcher at the Salk Institute of Biological Sciences, in California, tried without success with pigs in 2017. This year, without However, he announced that he had first developed a monkey embryo with human cells in collaboration with a group of Chinese scientists. Specifically, they have been able to reprogram cells with a chemical cocktail to become any tissue (skin, muscle, liver, heart), they have injected them into a Macacus fascicularis embryo and allowed the resulting embryo to grow for twenty days. The objective of these experiments with chimeric embryos (with genetic content from two different species) is the possibility of performing organ transplants between species or the regeneration of human tissues with material from other animals. But it certainly raises great ethical dilemmas that the scientific community has already been in charge of putting on the table, such as the possibility of creating an intermediate species or the production of unwanted organs.

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