At least 500 Americans die from GVHD every year. The U-M discovery could help prevent these deaths, and reduce the risk of hospitalization and debilitating side-effects for more than 5,000 Americans who receive donor bone marrow transplants annually, primarily to treat leukemia and other cancers.
Results from the U-M study, to be published in the June 2002 issue of Nature Medicine, show how skin, liver and gastrointestinal cells in mice with GVHD are destroyed from a distance by a firestorm of immune system proteins called inflammatory cytokines. Human clinical trials, based on findings from the Nature Medicine study, are now under way at the U-M’s Comprehensive Cancer Center.
“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 Bone 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 GVHD prevention strategies on its primary killing agents – especially two powerful cytokines called tumor necrosis factor-alpha and interleukin-1. “Now that we know cytokines are the major cause of GVHD-induced cell damage, we can look for ways to neutralize them or block their production,” Ferrara says.
The risk of graft-versus-host disease is highest following a bone marrow transplant from an allogeneic donor – someone other than the patient or the patient’s identical twin. Symptoms of acute GVHD usually begin three to six weeks after the transplant, often after the patient has been discharged and appears to be recovering well.
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. GVHD’s primary targets are skin, liver and epithelial cells lining the stomach and intestines of the host. 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.
“Until now, researchers assumed that pre-transplant radiation killed all the host’s antigen-presenting cells, so scientists discounted the importance of these cells in GVHD,” says Takanori Teshima, M.D., Ph.D., a former U-M research scientist now at Japan’s Okayama University. “But we found that a few APCs remain deep inside tissue. If even one percent survive, it is enough to trigger the graft-versus-host reaction.”
When immune cells from the donor’s bone marrow meet APCs 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, especially tumor necrosis factor-alpha and interleukin-1. The cytokine barrage transform “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.
“Cytokines can travel through the bloodstream and, therefore, inflict their damage from a distance,” Ferrara adds. “So there’s no need for direct contact between donor effector cells and host target cells, and antigen expression on the host’s epithelial cells is not required for development of graft-versus-host disease. ”
In his study, Teshima used strains of genetically altered laboratory mice, which expressed specific classes of antigens on APCs derived from donor bone marrow, but not on host target cells. “The availability of chimeric mice allowed us to test most donor-recipient combinations involving major antigens called MHC molecules,” he says. “Neutralizing TNF-alpha and interleukin-1 suppressed dramatically the mortality and morbidity of GVHD in mice.”
Teshima and Ferrara believe blocking cytokines could preserve the ability of donor T cells to bind to and kill the patient’s leukemia cells without risking the toxic effects of graft-versus-host disease. “Since 90 percent of bone marrow transplants are given to patients with leukemia, it is important not to interfere with the direct-contact killing mechanism,” Ferrara says.
In clinical trials under way at the U-M Cancer Center, Ferrara and colleagues are investigating new drugs that bind to and neutralize tumor necrosis factor. U-M physicians are testing these drugs to determine if they can prevent cell damage in patients with GVHD 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 APCs and donor immune cells, preventing the initial activation phase of acute GVHD.
The study was supported by the National Institutes of Health. Additional U-M collaborators were 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. Chen Liu, from the University of Florida College of Medicine, also collaborated in the study.
For information on bone marrow transplant clinical trials, call U-M’s Cancer Answer Line at 1-800-865-1125.
Contact: Sally Pobojewski,
pobo@umich.edu or 734-615-6912
or Kara Gavin, 734-764-2220
NOTE: Images available on request
Journal
Nature Medicine