Organ transplantation: immunotherapy instead of immunosuppression
Their own!Copper news based on the materials of New Scientist:
Kidney recipients freed from lifelong drugs
American scientists have developed a technique to prevent rejection of a transplanted kidney. In the experiment, she helped eight recipients to do without the constant use of immunosuppressive drugs.
Rejection of transplanted organs and tissues is one of the main problems of transplantology. It occurs because the human immune system perceives the graft, which has an antigenic structure different from the rest of the body, as a foreign agent and attacks it. Such an attack of immunity causes inflammation and destruction of the transplanted organ.
Currently, prevention of graft rejection is carried out in two ways.
First of all, a donor with the same type of human leukocyte antigens (HLA) is selected for each person awaiting transplantation. These antigens "inform" the immune system that this tissue is "its own" and is not subject to attack. The mismatch of HLA causes an immune response of exceptional strength. However, leukocyte antigens are not the only ones (though the main ones) that give out a "stranger", so the selection of a donor for them does not exclude a transplant rejection reaction.
Therefore, after organ transplantation, the recipient is prescribed immunosuppressive drugs that suppress the part of immunity that is responsible for attacking the tissues of other people. At the same time, these drugs cannot act absolutely selectively, so their intake suppresses other parts of the immune system that are necessary for a person. This can cause serious side effects such as the development of severe infections, cancer, diabetes and heart disease.
This state of affairs has long been forcing researchers to look for fundamentally new, preferably universal methods of preventing transplant rejection.
For example, in 2008, the team of David Sachs from Massachusetts General Hospital in Boston reported that an experimental bone marrow transplant of a donor helped four out of five patients to do without immunosuppressants after kidney transplantation – leukocytes from the transplanted bone marrow "taught" their immunity to consider the organ "their own". Moreover, the recipients did not coincide with the donors on the main complex of tissue compatibility.
To date, these four people have been living without taking drugs for eight years. However, such a technique is extremely inconvenient for mass use due to technical complexity, high cost and the risk of complications.
Researchers from Stanford University in California, led by Samuel Strober, also decided to use the donor's immune system to "train" the patient's immunity, but went the other way.
At first, everything was done as usual: donors were selected, transplantation was performed and two traditional cyclosporine-type immunosuppressants were prescribed. But the treatment was not limited to this.
Shortly after the operation, researchers began treating patients' lymph nodes, spleen and thymus gland with moderate-intensity radioactive radiation in order to temporarily weaken (but not completely suppress) their immune system. In addition, the volunteers were injected with antigens against the main population of immune cells that ensure rejection of the graft – undifferentiated helper T-lymphocytes (Th0 cells).
Approximately 10 days after the transplant, scientists injected patients with donor leukocytes, including CD34+ hematopoietic cells, capable of multiplying and becoming part of the recipient's immune system.
After that, the donor cells prevent immune attacks on the transplanted organ, thanks to the process of negative selection – the destruction of cytotoxic lymphocytes reacting to the body's own antigens.
During this process, the thymus gland "demonstrates" to mature T-lymphocytes the antigens of "its" tissue, and the tissue is considered "its own" if a sufficient number of immune cells considers it such. Lymphocytes, ready to attack their own body, are thus discarded.
Since the donor cells that have become part of the immune system and their offspring consider the transplanted kidney "their own", the patient's thymus gland begins to do the same and destroy T-lymphocytes ready to attack the organ.
The researchers monitored this process by blood tests, monitoring the correct fusion of the immune systems of the donor and recipient, as well as the absence of signs of kidney rejection.
A month after the introduction of donor cells, one of the immunosuppressive drugs was canceled for patients. The reception of the second was allowed to stop after six months.
As a result of experimental treatment, the need for taking immunosuppressants disappeared in eight out of 12 volunteers – they have been without drugs for three years (one patient died in the third year after surgery from a myocardial infarction unrelated to transplantation and subsequent treatment).
The remaining four participants of the experiment continue to receive immunosuppressive therapy. "So far, they don't meet all of our strict criteria for drug withdrawal," Strober explained. Nevertheless, the observation of these volunteers continues – the researchers do not lose hope to remove them from the drugs.
The technique developed by Strober is significantly less traumatic and associated with less risk than bone marrow transplantation proposed by Sachs. Moreover, the effectiveness of these methods in the experiment, as the Boston researcher admitted, is almost the same.
What is inferior to Strober's technique so far is that experimental treatment was carried out with the selection of donors by HLA. Its effectiveness in the case of non-conformity of tissue compatibility systems has yet to be proved. So far, such "training" of the recipient's immune system in the future solves only the question of the need for risky and expensive immunosuppressive therapy, which in itself is already a lot. With the success of larger-scale clinical trials, it has a good chance of becoming a new standard of treatment for patients who have undergone kidney transplantation (and possibly other organs in the future).
So a lot of work has been done for a reason – it took Strober 30 years to develop a new technique.
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07.10.2011