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April 21, 2017

Preventing Graft-Versus-Host Disease in Stem Cell Transplant Recipients

  • An international group of scientists led by investigators at the Technical 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 T lymphocytes, which are supposed to fight intruders such as bacteria. Instead, they start attacking the recipients already weakened body.

    Researchers from TUM and the Memorial Sloan Kettering Cancer Center published a study ("RIG-I/MAVS and STING Signaling Promote Gut Integrity during Irradiation- and 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 primarily affect the skin, liver, and, in particular, the gastrointestinal tract. The intestine is believed to be the key organ where GVHD starts. 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 cells and the arrival of intestinal bacteria in the previously germ-free areas of the gut due to the loss of the epithelium trigger the activation of aggressive donor T cells. 

    "If the epithelium could be protected or quickly restored, the risk of an immune response would be much lower," says Hendrik Poeck, M.D., Ph.D., who, along with Tobias Haas, M.D., heads a research group at the third medical clinic of TUM's Klinikum rechts der Isar. "Up to now, however, there have been very few treatment strategies that seek to regenerate the epithelium."

    The scientists working with Dr. Poeck studied two proteins produced naturally in the body and known for their role in fighting bacteria and viruses: RIG-I (retinoic acid-inducible gene I) and STING (stimulator of interferon genes). "We were able to demonstrate for the first time that both of them can also be used to bring about a regenerative effect," notes Julius Fischer, first author of the study.

    Both proteins are part of signal chains that cause type I interferon (IFN-I) to be produced. IFN-I triggers many different immune responses, but can also speed up the replacement of epithelial cells.

    The RIG-I signal pathway can be deliberately stimulated using triphosphate-RNA (3pRNA). Poeck and his team were able to demonstrate in mice that 3pRNA can indeed protect the epithelial cells. Timing is critical. Measurable protection was only seen when the 3pRNA was administered exactly 1 day before the start of radiation and drug treatment. 

    "We assume that after just 1 day of treatment, there would no longer be enough intact epithelial cells in the gut for the RIG-I/IFN signal path to function," explains Haas. Although fewer activated T cells were generated after a treatment with 3pRNA, the positive effect of the leukemia therapy was not reduced to a measurable degree.

    Both RIG-I agonists, such as 3pRNA, and STING agonists are currently in clinical development. The research points to a wide range of potential applications, especially in the treatment of tumors. 

    "Our study shows that regenerative processes can also be triggered through selective activation of these signal paths," adds Poeck. "It thus appears quite possible that these selective agonists will be administered in the future to patients who are candidates for allogeneic stem cell transplants. However, further studies will be needed to learn how they actually work before applications in human medicine are possible."

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