When Transplant Rejects Host
Cytokines key to common bone marrow complication
U-M scientists have discovered how graft-versus-host disease,
a common and deadly complication of bone marrow transplants,
attacks and often kills its victims. The discovery could help
prevent the deaths of at least 500 Americans each year, and
reduce the risk of hospitalization and debilitating side-effects
for more than 5,000 others who receive donor bone marrow transplants
annually, primarily to treat leukemia and other cancers.
Results from the study, published in the June 2002 issue of
Nature Medicine, show how skin, liver and gastrointestinal cells
in mice with the disease are destroyed from a distance by a
firestorm of immune system proteins called inflammatory cytokines.
"Cytokines turn healthy immune cells in donated bone
marrow — something given to cure patients — into lethal weapons
capable of killing them," says James L.M. Ferrara, M.D.,
director of the U-M Blood and Marrow Transplantation Program
and a professor of internal medicine and pediatrics in the
U-M Medical School.
Ferrara says the study calls into question a widely accepted
assumption that T cells -immune cells which attach to and
kill just one target cell at a time — are the major cell-killing
agents of graft-versus-host disease. "It's the difference
between a direct attack by ground troops and a general air
strike,"
Ferrara explains.
The study's findings will help scientists focus graft-versus-host
disease prevention strategies on its primary killing agents.
"Now that we know cytokines are the major cause of graft-versus-host
disease-induced cell damage, we can look for ways to neutralize
them or block their production," Ferrara says.
Instead of the patient's body rejecting a donated organ, as
occurs in an organ transplant, the donated bone marrow, called
the graft, rejects cells in the host or patient. Damaged by
heavy doses of radiation and chemotherapy used to destroy the
patient's cancerous bone marrow before the transplant, these
cells secrete substances that activate antigen-presenting cells
in the patient's immune system.
Previously, researchers assumed that pre-transplant radiation
killed all the host's antigen-presenting cells, so scientists
discounted the importance of these cells in graft-versus-host
disease But the U-M study found that a few antigen-presenting
cells remain deep inside tissue. If even one percent survives,
it is enough to trigger the graft-versus-host reaction.
When immune cells from the donor's bone marrow meet antigen-presenting
cells carrying substances from host cells, some of the donor
cells are sensitized to see the patient's cells as the "enemy."
These cells respond by firing salvos of inflammatory cytokines.
The cytokine barrage transforms "good" immune cells
in the patient's new bone marrow into an army of destructive
effector cells all primed to attack and kill the host.
In clinical trials under way at the U-M Cancer Center, Ferrara
and colleagues are investigating new drugs to determine if they
can prevent cell damage in patients with graft-versus-host disease
and lung disease after a bone marrow transplant. In a future
study, Ferrara hopes to determine whether other drugs can block
the original interaction between host antigen-presenting cells
and donor immune cells, preventing the initial activation phase
of acute graft-versus-host disease.
The study was supported by the National Institutes of Health.
Additional U-M collaborators were Takanori Teshima, M.D., Ph.D.,
now at Japan's Okayama University; Kenneth R. Cooke, M.D., assistant
professor of pediatrics and communicable diseases; Rainer Ordemann,
M.D., research fellow; Pavan Reddy, M.D., lecturer in internal
medicine; and Svetlana Gagin, M.D., research assistant.
-SFP
Read the complete story at:
www.med.umich.edu/opm/newspage/2002/gvhd.htm
To learn more about the U-M Blood and Marrow Transplantation
Program, go to:
www.cancer.med.umich.edu/clinic/bmtclinic.htm
For information on clinical trials, call U-M's Cancer Answer
Line at 1-800-865-1125.
 
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