Immune System Modulation Can Halt Liver Failure In Animals
Massachusetts General Hospital researchers have a developed a totally
new approach to treating liver failure - manipulating the immune
response. If the results of the animal study can be applied in human
patients, the approach may be able to keep patients alive until donor
organs become available or to support liver function until the organ
can regenerate itself, eliminating the need for a transplant. The
findings are being reported in the journal PLOS One.
"We have identified a non-hepatic source of cells that can easily be
expanded to the scale required for clinical application,
Yarmush, MD, PhD, director of the Center for Engineering in Medicine
at MGH, the paper's senior author. He also is the Helen Andrus
Benedict Professor of Surgery and Bioengineering in the Harvard-MIT
Division of Health Science and Technology (HST) and a senior
scientific staff member at the Boston Shriners Burns Hospital.
The liver is one of the few major organs that is able to regenerate
itself. But when the organ is damaged by diseases like chronic
hepatitis, long-term alcohol consumption, or other causes, ongoing
inflammation can increase cell death and suppress the natural
regenerative process. The only current treatment for end-stage liver
failure is transplantation, which is limited by the organ supply and
requires long-term immunosuppressive treatment. While external liver
assist devices have successfully supported some patients, such
machines require a supply of preferably human liver cells, which have
been difficult to acquire and expand.
For their investigation, the MGH research team used mesenchymal stem
cells (MSCs) - cells from the bone marrow that develop into tissues
supporting blood cell development in the marrow cavity. Previous
research has shown that MSCs are able to inhibit several immune
system activities. A supply of MSCs can be extracted from a patient's
own marrow and expanded to levels that could be therapeutically
useful. To evaluate the ability of human MSCs to treat organ failure
involving inflammatory activity, the investigators tested several
ways of using the cells to treat rats in which liver failure had been
induced.
Several approaches to administering MSCs reduced the biological signs
of liver failure and improved the animals' survival. Although simply
transplanting MSCs was not effective, two methods of delivering
molecules secreted by the cells lessened inflammation within the
liver and halted cell death. Cycling the blood of rats with liver
failure through an external bioreactor containing MSCs also greatly
reduced the metabolic signs of liver failure in the animals. Even
more significantly, 71 percent of the rats treated with the MSC-
seeded bioreactor survived, while only 14 percent of those in a
control group were alive one week later.
"One essential function of MSCs in the bone marrow is to secrete
molecules that promote the growth and maturation of blood cells," say
co-lead author Biju Parekkadan, an HST graduate student working in
Yarmush's lab. "We are now finding that these same molecules can be
used as potent immunotherapeutics and envision a multi-tiered
treatment of liver failure based on this work. A patient presenting
with liver failure could first be treated with an intravenous
injection of an 'off-the-shelf' drug containing MSC-produced factors
in an effort to halt cell damage and allow the organ to regenerate.
If that is not effective, an MSC-based support device could be used
as a bridge to transplantation or even as a long-term treatment."
The researchers note that exactly how MSC-produced molecules inhibit
the movement of immune cells into a damaged organ is not yet known
and is currently under investigation. They also hope to examine the
possibility of combining both MSCs and liver cells in a potential
support device and to test the potential of MSCs to treat other
immunological diseases.
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