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A new study by Weizmann Institute scientists may allow the use of stem cell transplantation to treat various blood diseases, and in the future perhaps also to facilitate the reception of transplanted organs

Prof. Yair Reisner. The cells cast a veto
Prof. Yair Reisner. The cells cast a veto

Transplantation of the blood stem cells, which are usually found in the bone marrow, is a complex medical process that doctors undertake only when there are no other good treatment options. These are usually cases of acute leukemia. But new research by scientists at the Weizmann Institute of Science, led by Prof. Reisner from the department of immunology at the institute, may allow the use of stem cell transplantation to treat also those suffering from various blood diseases, such as thalassemia and sickle cell anemia, and in the future perhaps also to facilitate the absorption of various transplanted organs in the body ( such as heart, liver, kidneys, etc.).

Prof. Reisner's new research is a continuation of a series of studies that began more than a decade ago, in which, together with his research partner, Prof. Massimo Martelli from the University of Perugia in Italy, he developed a method that allows leukemia patients to be transplanted into bone marrow from a donor that does not exactly match the genetic immune characteristics of the transplant recipient.

Leukemia patients, who need a stem cell transplant (contained in the bone marrow), in many cases have to wait a long time until they find, if at all, a bone marrow donor whose immune and genetic characteristics will be the same as their own. The medical concept that prevailed until about a decade ago determined - based on many attempts - that a bone marrow transplant from an incompatible donor endangers the recipient of the transplant, and its chances of success are small.

At this point, more or less, Reisner and Martelli entered the picture. They began transplanting extremely large doses of bone marrow from the donor into the treated patients. These large quantities overcome - by the force of the quantity - the rejection mechanisms of the recipient's immune system. But here a new difficulty arose: it turns out that it is not so easy to collect such large doses of stem cells from the donor. To overcome this difficulty, Reisner and Martelli used a new method, based on the use of a chemical messenger of the immune system (cytokine), which causes the secretion of many stem cells from the bone marrow into the peripheral blood - where it is easier, simpler and much safer to collect them.

A long series of experiments, first in animals and then in humans, brought the scientists to the ability to determine the exact processes and quantities necessary for the success of transplants using this method. Indeed, this method is currently implemented in several hospitals in Israel and abroad, after it was successfully tested in clinical trials (in the first and second stages). These days, it will begin to be tested in large-scale clinical trials (phase three), which will take place in 35 medical centers in Europe.

Prof. Reisner: "The new method we developed - a transplant from a donor with only a partial match - may be just as effective as a transplant from a donor registered in the database of the health system (about six to seven million potential donors are registered in a global database established for this purpose). A partial match, such as that required to apply our method, always exists between parents and children, and there is a 75 percent probability of finding it between brothers and sisters. Even in an extended family there is a good chance of finding a donor who is partially suitable. According to these criteria, donors can be found for more than 95 percent of the leukemia patients who need a transplant."

In fact, the transplantation of stem cells may help the absorption of transplanted organs in the body of those who need it, as well as in reducing the unwanted activity of the immune system in the body of those who suffer from various blood diseases. But here comes up again, in all its acuteness, the question of the survivability of stem cells transplanted into the body. It is possible to increase the survival chances of these cells by increasing the intensity of the radiation applied to the patient before the transplant. The radiation damages the immune system, thereby weakening its attacks on the transplanted cells, but at the same time it damages healthy and vital cells, causing unwanted side effects. Because of this, doctors today refrain from applying this method of treatment to patients whose life expectancy is long (relative to the life expectancy of leukemia patients), such as patients with thalassemia, sickle cell anemia, and patients whose bodies have been transplanted organs such as heart, liver, kidney, etc.

But Prof. Reisner's latest research may greatly improve the survivability of transplanted stem cells, which will make it possible to significantly reduce the intensity of radiation required before transplantation. This reduction may make the stem cell transplant process safe and "worth it" also for patients with several types of blood diseases, and organ transplant recipients.

To increase the survivability of the transplanted stem cells, Prof. Reisner suggests transplanting them accompanied by "bodyguards": cells with a "veto" feature, which inhibit the activity of the immune system in the transplant recipient's body. He suggests getting these cells from two separate sources. The first source is cultures of stem cells grown in the laboratory. These cells go through a process of differentiation in the framework of which some of them acquire the "veto" feature. The second source is the "killer" T cells of the immune system. These cells may, naturally, cause "graft-versus-host disease", but in the process of their reproduction, subgroups are also created that lack this undesirable feature. Prof. Reisner suggests using these two types of cells as "bodyguards" to accompany the transplanted stem cells. The "veto" cells disrupt the operation of the immune system in the body of the transplant recipient, thereby increasing the survivability of the stem cells.

The use of "selected" T cells (which are not potentially harmful) has been successfully tried in mice. Some of the findings from this study were published in the scientific journal Immunity. The use of human cells grown in laboratory stem cell cultures has been successfully tested in laboratory human cell cultures. These findings were recently published in the scientific journal Blood. Along with Prof. Reisner, Dr. Esther Becher Lustig, Rita Krautgemmer, Judith Gan, and doctoral students Hilit Gor and Shlomit Reich-Zeliger also participated in these studies. The scientists hope that in the near future it will be possible to test the method in clinical trials.

A Veto cell attaches to a target cell, causing its death through apoptosis

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