Stem cell transplants can save lives, for example in sufferers with leukemia. However , these treatments are not free of dangers. One complication that may occur is graft-versus-host disease (GVHD), basically donor-derived immune cells attacking the recipient’s entire body. A team at the Technical University of Munich (TUM) has identified molecular mechanisms that may protect patients from this dangerous response in the future. The key to preventing GVHD is within the gut.
In order to allow foreign stem cells to multiply in the body and create healthy blood cells, doctors first need to make space for them. This is achieved by destroying existing cells in the bone tissue marrow using drugs or radiation.
Among the risks resulting from this pre-treatment is GVHD, which happens in about half of all treatments. In simple terms, during GVHD the particular transplanted stem cells become T lymphocytes. These defense cells, which are supposed to fight intruders such as bacteria, have a wrong turn and start attacking the recipient’s already destabilized body.
In a paper published in the log Science Translational Medicine , an international group headed by TUM adjunct teaching professor Dr . Hendrik Poeck and Dr . Tobias Haas, heads of an analysis group at the third medical clinic of TUM’s Klinikum rechts der Isar, and Professor Marcel van living room Brink at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York City, describes how this process could be prevented.
Triggered in the gut
The attacks by the T cells primarily affect the pores and skin, liver and in particular the gastrointestinal tract. The intestine is certainly believed to be the key organ where GVHD starts. The medications and radiation cause damage to the epithelial cells, which type part of the intestinal mucosal layer. Stress signals emitted with the dying epithelial cells and the arrival of intestinal germs in the previously germ-free areas of the gut due to the lack of the epithelium trigger a sort of red alert that triggers aggressive donor T cells. “If the epithelium might be protected or quickly restored, the risk of an immune reaction would be much lower, ” says Hendrik Poeck. “Up in order to now, however , there have been very few treatment strategies that look for to regenerate the epithelium. ”
The particular scientists working with Dr . Poeck studied two proteins created naturally in the body and known for their role in battling bacteria and viruses: RIG-I and STING. “We could demonstrate for the first time that both of them can also be used to bring in regards to a regenerative effect, ” says Julius Fischer, first writer of the study. Both proteins are part of signal stores that cause type I interferon (IFN-I) to be created. IFN-I triggers many different immune responses, but can also accelerate the replacement of epithelial cells.
Time is key
It is well established that the RIG-I signal pathway can be deliberately stimulated using triphosphate-RNA (3pRNA). Poeck and his team were able to demonstrate in mice that will 3pRNA can indeed protect the epithelial cells. The time is decisive: Measurable protection was only seen once the 3pRNA was administered exactly one day before the start associated with radiation and drug treatment. “We assume that after just one day time of treatment, there would no longer be enough intact epithelial cells in the gut for the RIG-I/IFN signal path to functionality, ” explains Tobias Haas. Although fewer activated To cells were generated after a treatment with 3pRNA, good effect of the leukemia therapy was not reduced to a considerable degree.
“Both RIG-I agonists, such as 3pRNA, and STING agonists are currently in clinical development, inch says Hendrik Poeck. The research points to a wide range of possible applications, especially in the treatment of tumors. “Our study shows that regenerative processes can also be triggered through selective activation of these transmission paths, ” adds Poeck, explaining his team’s outcomes. “It thus appears quite possible that these selective agonists will be administered in the future to patients who are candidates regarding allogeneic stem cell transplants. However , further studies is going to be needed to learn how they actually work before applications within human medicine are possible. ”
Materials provided by Technical University associated with Munich (TUM) . Note: Content might be edited for style and length.