An international group of scientists led by investigators at the Specialized University of Munich (TUM) says it has discovered molecular mechanisms that might prevent the development of graft-versus-host disease (GVHD) in individuals receiving stem cell transplants.
During GVHD transplanted stem cells become To lymphocytes, which are supposed to fight intruders such as bacteria. Rather, they start attacking the recipients already weakened entire body.
Researchers from TUM and the Funeral Sloan Kettering Cancer Center published a study (“RIG-I/MAVS plus STING signaling promote gut integrity during irradiation- plus immune-mediated tissue injury”) in Science Translational Medicine that provides details on how to prevent the development of GVHD.
The attacks by the T cells mainly affect the skin, liver and in particular the gastrointestinal tract. The particular intestine is believed to be the key organ where GVHD begins. The drug treatment and radiation involved in stem cell transplants damage epithelial cells, which form part of the intestinal mucosal layer. Stress signals emitted by the dying epithelial tissues and the arrival of intestinal bacteria in the previously germ-free areas of the gut due to the loss of the epithelium cause the activation of aggressive donor T cells.
“If the epithelium could be protected or even quickly restored, the risk of an immune response would be reduced, ” says Hendrik Poeck, who, along with Tobias Haas, heads a research group at the third medical center of TUM’s Klinikum rechts der Isar. “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, ” notes Julius Fischer, first writer of the study.
Both proteins are usually part of signal chains that cause type I interferon (IFN-I) to be produced. IFN-I triggers many different immune reactions, but can also speed up the replacement of epithelial cells.
The RIG-I signal pathway can be deliberately activated using triphosphate-RNA (3pRNA). Poeck and his team were able to show in mice that 3pRNA can indeed protect the epithelial cells. Timing is critical. Measurable protection was only noticed when the 3pRNA was administered exactly one day before the begin of radiation and drug treatment.
“We assume that after just one day of treatment, there might no longer be enough intact epithelial cells in the gut for that RIG-I/IFN signal path to function, ” explains Haas. Even though fewer activated T cells were generated after a therapy with 3pRNA, the positive effect of the leukemia therapy had not been reduced to a measurable degree.
Both RIG-I agonists, such as 3pRNA, and STING agonists are currently within clinical development. The research points to a wide range of potential programs, especially in the treatment of tumors.
“Our research shows that regenerative processes can also be triggered through selective service of these signal paths, ” adds Poeck. “It hence appears quite possible that these selective agonists will be given in the future to patients who are candidates for allogeneic originate cell transplants. However , further studies will be needed to understand how they actually work before applications in human medication are possible. ”