Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Stem cell transplants: activating signal paths may protect from graft-versus-host disease

20.04.2017

Stem cell transplants can save lives, for example in patients with leukemia. However, these treatments are not free of risks. One complication that may occur is graft-versus-host disease (GVHD), basically donor-derived immune cells attacking the recipient’s body. A team at the Technical University of Munich (TUM) has identified molecular mechanisms that may protect patients against this dangerous response in the future. The key to preventing GVHD is in the gut.

In order to enable foreign stem cells to multiply in the body and produce healthy blood cells, doctors first need to make room for them. This is achieved by destroying existing cells in the bone marrow using drugs or radiation.


A team led by PD Dr. Hendrik Poeck (center) and Dr. Tobias Haas has developed a new approach to protect patients from graft-versus-host disease. First author Julius Fischer is seen in the back.

Benz /TUM Verwendung frei für Berichterstattung über die TU München unter Nennung des Copyrights / Free for use in reporting on TU München with the copyright noted.


Cross-section of mouse intestines: OLFM4-stem cells (red) are crucial for epithel regeneration. During treatment leading up to allo-hematopoietic stem cell transplantation, they are often destroyed.

Poeck / TUM Verwendung frei für Berichterstattung über die TU München unter Nennung des Copyrights / Free for use in reporting on TU München with the copyright noted.

One of the risks resulting from this pre-treatment is GVHD, which occurs in about half of all treatments. In simple terms, during GVHD the transplanted stem cells become T lymphocytes. These immune cells, which are supposed to fight intruders such as bacteria, take a wrong turn and start attacking the recipient’s already weakened body.

In a paper published in the journal Science Translational Medicine, an international team headed by TUM adjunct teaching professor Dr. Hendrik Poeck and Dr. Tobias Haas, heads of a research group at the third medical clinic of TUM's Klinikum rechts der Isar, and Professor Marcel van den 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 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 cause damage to the 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 a sort of red alert that activates 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. "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 and STING. "We were able to demonstrate for the first time that both of them can also be used to bring about a regenerative effect," says 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.

Timing 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 3pRNA can indeed protect the epithelial cells. The timing is decisive: Measurable protection was only seen when the 3pRNA was administered exactly one day before the start of radiation and drug treatment. "We assume that after just one 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 Tobias 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," says Hendrik Poeck. 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, explaining his team's results. "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."

Publication:

J. C. Fischer, M. Bscheider, G. Eisenkolb, C.-C. Lin, A. Wintges, V. Otten, C. A. Lindemans, S. Heidegger, M. Rudelius, S. Monette, K. A. Porosnicu Rodriguez, M. Calafiore, S. Liebermann, C. Liu, S. Lienenklaus, S. Weiss, U. Kalinke, J. Ruland, C. Peschel, Y. Shono, M. Docampo, E. Velardi, R. Jenq, A. M. Hanash, J. A. Dudakov, T. Haas, M. R.M. van den Brink and H. Poeck. "RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury". Science Translational Medicine (2017). 9:386. DOI: 10.1126/scitranslmed.aag2513

Further Information:

The research group's website:
http://www.med3.med.tum.de/forschung/Grundlagenforschung/Tumorimmunologie/haaspo...

Contact:

PD Dr. med. Hendrik Poeck
Klinik und Poliklinik für Innere Medizin III, Hämatologie und Onkologie
Klinikum Rechts der Isar
Technische Universität München
Tel: +49 (0) 89 4140 8065
Email: hendrik.poeck@tum.de

High-resolution images:

https://mediatum.ub.tum.de/1356990

Dr. Ulrich Marsch | Technische Universität München

More articles from Health and Medicine:

nachricht UC San Diego researchers develop sensors to detect and measure cancer's ability to spread
06.12.2018 | University of California - San Diego

nachricht New cancer immunotherapy approach turns immune cells into tiny anti-tumor drug factories
05.12.2018 | University of California - San Diego

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Researchers develop method to transfer entire 2D circuits to any smooth surface

What if a sensor sensing a thing could be part of the thing itself? Rice University engineers believe they have a two-dimensional solution to do just that.

Rice engineers led by materials scientists Pulickel Ajayan and Jun Lou have developed a method to make atom-flat sensors that seamlessly integrate with devices...

Im Focus: Three components on one chip

Scientists at the University of Stuttgart and the Karlsruhe Institute of Technology (KIT) succeed in important further development on the way to quantum Computers.

Quantum computers one day should be able to solve certain computing problems much faster than a classical computer. One of the most promising approaches is...

Im Focus: Substitute for rare earth metal oxides

New Project SNAPSTER: Novel luminescent materials by encapsulating phosphorescent metal clusters with organic liquid crystals

Nowadays energy conversion in lighting and optoelectronic devices requires the use of rare earth oxides.

Im Focus: A bit of a stretch... material that thickens as it's pulled

Scientists have discovered the first synthetic material that becomes thicker - at the molecular level - as it is stretched.

Researchers led by Dr Devesh Mistry from the University of Leeds discovered a new non-porous material that has unique and inherent "auxetic" stretching...

Im Focus: The force of the vacuum

Scientists from the Theory Department of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science (CFEL) in Hamburg have shown through theoretical calculations and computer simulations that the force between electrons and lattice distortions in an atomically thin two-dimensional superconductor can be controlled with virtual photons. This could aid the development of new superconductors for energy-saving devices and many other technical applications.

The vacuum is not empty. It may sound like magic to laypeople but it has occupied physicists since the birth of quantum mechanics.

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

EGU 2019 meeting: Media registration now open

06.12.2018 | Event News

Expert Panel on the Future of HPC in Engineering

03.12.2018 | Event News

Inaugural "Virtual World Tour" scheduled for december

28.11.2018 | Event News

 
Latest News

A new molecular player involved in T cell activation

07.12.2018 | Life Sciences

High-temperature electronics? That's hot

07.12.2018 | Materials Sciences

Supercomputers without waste heat

07.12.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>