Home  |  Top News  |  Most Popular  |  Video  |  Multimedia  |  News Feeds  |  Feedback
  Medicine  |  Nature & Earth  |  Biology  |  Technology & Engineering  |  Space & Planetary  |  Psychology  |  Physics & Chemistry  |  Economics  |  Archaeology
Top > Medicine, Health Care > Deadly Complication of Stem Cell… >
Deadly Complication of Stem Cell Transplants Reduced in Mice

Published: September 27, 2012.
By Washington University School of Medicine
http://www.medicine.wustl.edu

Studying leukemia in mice, researchers at Washington University School of Medicine in St. Louis have reduced a life-threatening complication of stem cell transplants, the only curative treatment when leukemia returns.

About 50 percent of leukemia patients who receive stem cells from another person develop graft-versus-host disease, a condition where donor immune cells attack the patient's own body. The main organs affected are the skin, liver and gut. Now, the scientists have shown they can redirect donor immune cells away from these vital organs. Steering immune cells away from healthy tissue also leaves more of them available for their intended purpose – killing cancer cells.

"This is the first example of reducing graft-versus-host disease not by killing the T- cells, but simply by altering how they circulate and traffic," says John F. DiPersio, MD, PhD, the Virginia E. and Sam J. Golman Professor of Medicine. "Donor T-cells do good things in terms of eliminating the recipient's leukemia, but they can also attack normal tissues leading to death in a number of patients. The goal is to minimize graft-versus-host disease, while maintaining the therapeutic graft-versus-leukemia effect."

The study is now available online in Blood.

Working with mice, Jaebok Choi, PhD, research assistant professor of medicine, showed that eliminating or blocking a particular protein – the interferon gamma receptor – on donor T-cells makes them unable to migrate to critical organs such as the intestines but still leaves them completely capable of killing leukemia cells.

"The fact that blocking the interferon gamma receptor can redirect donor T-cells away from the gastrointestinal tract, at least in mice, is very exciting because graft-versus-host disease in the gut results in most of the deaths after stem cell transplant," DiPersio says. "People can tolerate graft-versus-host disease of the skin. But in the GI tract, it causes relentless diarrhea and severe infections due to gut bacteria leaking into the blood, which can result in severe toxicity, reduction in the quality of life or even death in some patients."

Long known to be involved in inflammation, the roles of interferon gamma, its receptor and their downstream signaling molecules are just beginning to be described in the context of graft-versus-host disease, says DiPersio, who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

The cascade begins when interferon gamma activates its receptor. The interferon gamma receptor then activates molecules known as JAK kinases, followed by STAT, and finally CXCR3. CXCR3 mediates the trafficking of donor T-cells to the GI tract and other target organs.

Since deleting the interferon gamma receptor from donor T-cells directs them away from target organs, the researchers asked whether they could produce the same beneficial effects by inhibiting some of the receptor's downstream signaling molecules. Indeed, Choi also found that knocking out CXCR3 reduces graft-versus- host disease, but not completely.

"There are probably additional downstream targets of interferon gamma receptor signaling other than JAKs, STATs and CXCR3 that are responsible for T-cell trafficking to the GI tract and other target organs," DiPersio says. "We're trying to figure out what those are."

To move their findings closer to possible use in humans, Choi and DiPersio also showed that they could mimic the protective effect of deleting the interferon gamma receptor with existing drugs that block JAK kinases. In this case, they tested two JAK inhibitors, one of which is currently approved by the U.S. Food and Drug Administration to treat myelofibrosis, a pre-leukemic condition in which the bone marrow is replaced with fibrous tissue.

While they showed that JAK inhibitors are effective in redirecting donor T-cells away from target organs and reducing graft-versus-host disease in mice with leukemia, they have not yet tested whether these drugs also preserve the desired anti-leukemia effect.

"The proof-of-principle behind these experiments is the exciting part," DiPersio says. "If you can change where the T-cells go as opposed to killing them, you prevent the life-threatening complications and maintain the clinical benefit of the transplant."


Show Reference »


Translate this page: Chinese French German Italian Japanese Korean Portuguese Russian Spanish


Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the ScienceNewsline.

Most Popular - Medicine »
MARIJUANA »
Casual Marijuana Use Linked to Brain Abnormalities in Students
CHICAGO --- Young adults who used marijuana only recreationally showed significant abnormalities in two key brain regions that are important in emotion and motivation, scientists report. The study was …
IMMUNE »
The Immune System's Redesigned Role in Fighting Cancerous Tumors
LOS ANGELES (March 11, 2014) – Researchers in the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute eradicated solid tumors in laboratory mice using a novel combination of two targeted agents. …
SURVIVORS »
New Research Shows People Are Thinking About Their Health Early in the Week
San Diego, Calif. (April 18, 2014) ― A new study in the American Journal of Preventive Medicine analyzing weekly patterns in health-related Google searches reveals a recurring pattern that …
DEPRESSION »
Treating Depression in PD Patients: New Research
LEXINGTON, Ky. (April 21, 2014) -- A group of scientists from the University of Kentucky College of Medicine and the Sanders-Brown Center on Aging has found interesting new information …
PILL »
Counterfeit Contraceptives Found in South America
ScienceNewsline  |  About  |  Privacy Policy  |  Feedback  |  Mobile  |  Japanese
The selection and placement of stories are determined automatically by a computer program. All contents are copyright of their owners except U.S. Government works. U.S. Government works are assumed to be in the public domain unless otherwise noted. Everything else copyright ScienceNewsline.