The dangerous complication of bone marrow transplantation was suppressed
Approximately 50% of patients who have undergone bone marrow transplantation for the treatment of leukemia (a malignant disease of the hematopoietic system, which is not very correctly called blood cancer) develop a "graft versus host" reaction – a condition in which donor immune cells attack the recipient's body. In this case, as a rule, organs such as the skin, liver and intestines suffer.
Researchers at the University of Washington, working under the leadership of Professor John F. DiPersio, have proposed a method of "distracting" immune cells from vital organs. This not only protects healthy tissues from damage, but also directs more lymphocytes to fight their true enemies – tumor cells, enhancing the so-called "transplant against leukemia" effect.
In experiments on mice, the authors demonstrated that the removal or blocking of the membrane protein – receptor for interferon-gamma – on donor T-lymphocytes deprives them of the ability to migrate to important organs, especially to the gastrointestinal tract, completely preserving their cytotoxic activity against malignant cells.
According to the researchers, the intestinal form of the "graft versus host" reaction is the main cause of death of patients who underwent bone marrow transplantation. A person can survive the cutaneous form of this reaction, whereas the intestinal form is manifested by persistent diarrhea and is accompanied by severe infectious complications caused by intestinal bacteria penetrating into the blood.
The role of interferon-gamma, its receptor and the components of the signaling mechanism triggered by them in inflammation has been known for a long time, but their involvement in the graft-versus-host reaction has only recently been discussed. This cascade begins with the fact that the gamma interferon activates the corresponding receptor, which, in turn, activates molecules known as JAK kinases. After that, STAT and CXCR3 proteins are activated. The latter mediates the movement of donor T-lymphocytes into the digestive tract and other target organs.
Since the elimination of the interferon-gamma receptor distracted donor T cells from vital organs, the researchers decided to test whether the same effect could be achieved by inhibiting signaling molecules located at the lower levels of the signaling cascade. Further experiments showed that the neutralization of CXCR3 also suppresses the graft-versus-host reaction, but not completely.
Currently, the authors are searching for molecular targets other than the known components of the interferon-gamma receptor-mediated signaling mechanism (JAK kinases, STAT and CXCR3), the impact on which would block the movement of T-lymphocytes to vital organs.
In order to bring their discovery closer to clinical practice, the authors also demonstrated that well-known drugs that suppress the activity of JAK kinases have the desired effect. They tested two such drugs, one of which is approved by the U.S. Food and Drug Administration as a treatment for myelofibrosis, a pre–leukemic condition in which the bone marrow is replaced by connective tissue. Both drugs effectively prevented the migration of donor T-lifocytes to target organs, reducing the severity of the graft-versus-host reaction in recipient mice, but researchers have not yet analyzed their ability to preserve and enhance the positive effect of graft-versus-leukemia.
Article by Choi J et al. INF gamma receiver signaling mediates alloreactive T cell trafficking and GvHD is published in the journal Blood.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Washington University:
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