A new University of Michigan study in mice suggests that a drug recently approved to fight cancer tumors is also able to reduce the effects of graft-versus-host disease, a common and sometimes fatal complication for people who have had bone marrow transplants.
Plans are under way at U-M for an initial trial of the drug in people as a new way to prevent graft-versus-host disease. Researchers expect to begin a trial within a year.
The U-M scientists tested the effects of the drug SAHA, as well as another member of a group of drugs known as HDAC inhibitors, on key immune system cells called dendritic cells. In mice, both drugs were able to significantly diminish the destructive inflammatory effects that these cells cause in graft-versus-host disease.
Graft-versus-host disease occurs when immune cells in the transplanted bone marrow mount a misguided attack on body tissues. If HDAC inhibitors turn out to be safe and effective in people, they might offer a treatment option preferable to the immunosuppressant drugs used now to treat the disease. These leave people vulnerable to infection and have other significant side effects.
"To make bone marrow transplants more effective, we need better control of the very powerful reactions between the immune systems of the donor and recipient. This study shows how drugs like SAHA regulate those reactions, and takes us a major step closer to bringing this new approach to patients who need transplants," says James L.M. Ferrara, M.D., director of the U-M Combined Bone Marrow Transplant Program and a senior author on the study. Ferrara is also professor of internal medicine and pediatric and communicable diseases at U-M.
"These HDAC inhibitors were thought to just kill cancer cells, but at lower doses, it's possible they can modulate a number of immune diseases," says Pavan Reddy, M.D., the study's lead and corresponding author, and an assistant professor of internal medicine at the U-M Medical School. "The mechanism we have identified in graft-versus-host disease may be involved in autoimmune diseases as well."
The study appears in the July issue of the Journal of Clinical Investigation.Context:
But as many as half of bone marrow transplant recipients develop acute or chronic symptoms of graft-versus-host disease, which can affect the skin, liver and gastrointestinal tract. Reddy calls the disease "the single biggest barrier to bone marrow transplant."
The study suggests a novel way to treat graft-versus-host disease with an already available drug that is stirring considerable interest as an anti-cancer agent. The FDA approved SAHA, marketed under the name Vorinostat, as a treatment for one kind of lymphoma in 2006 and for leukemia in 2007. SAHA is being used off label for other cancers, including lung, brain and colon cancer.
The U-M study adds to a growing body of research suggesting HDAC inhibitors also may be useful tools to reign in misguided immune responses. Researchers elsewhere have recently shown that HDAC inhibitors have been beneficial in animal studies of lupus and inflammatory bowel disease. Other studies suggest the drugs could be useful in regulating the immune response in heart and islet cell transplants.Research details:
The scientists looked at the two HDAC inhibitors' effects on mouse and human dendritic cells in culture. They found that as they suspected, the drugs acted to diminish the dendritic cells' key role in promoting pro-inflammatory proteins called cytokines. Specifically, the researchers found that the HDAC inhibitors increase the expression of IDO, an enzyme which represses dendritic cell activity.
They tested the HDAC inhibitors in mice bred to display the effects of graft -versus-host disease. When they injected the mice with dendritic cells treated with the drugs, they found the drugs were able to reduce the disease's effects.
The clinical trial: The trial is not yet recruiting patients. For questions and information on the U-M bone marrow transplant program, contact the U-M Cancer AnswerLine, 800-865-1125, email@example.com
Journal citation: Journal of Clinical Investigation, Vol. 118, no. 7, July 2008, www.jci.org
Funding: National Institutes of Health, Doris Duke Clinical Scientist Development Award, Amy Strelzer Manasevit-National Marrow Donor Program
Additional authors: Yaping Sun, M.D., Ph.D., Elizabeth Weisiger, B.S., Yoshinobu Maeda, M.D., Ph.D., Oleg Krijanovski, M.D., Ph.D., Chelsea Malter, B.S. and Tomorni Toubai, M.D., Ph.D., U-M Department of Internal Medicine; Raimon Duran Struuck, D.V.M., Shawn G. Clouthier, M.S., Isao Tawara, M.D., Ph.D. and Erin Gatza, Ph.D., Department of Pediatrics, U-M Comprehensive Cancer Center; Cen Liu, M.D., Ph.D., University of Florida; Paolo Mascagni, Ph.D., ItalFarmaco S.p.A., Milan, Italy; and Charles A. Dinarello, M.D., University of Colorado Health Sciences Center.
Anne Rueter | University of Michigan
Millions through license revenues
27.04.2017 | Rheinische Friedrich-Wilhelms-Universität Bonn
New High-Performance Center Translational Medical Engineering
26.04.2017 | Fraunhofer ITEM
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
20.04.2017 | Event News
18.04.2017 | Event News
03.04.2017 | Event News
27.04.2017 | Health and Medicine
27.04.2017 | Information Technology
26.04.2017 | Materials Sciences