Scientists Discover Cause of GVHD

A study has shown how skin, liver, and gastrointestinal cells in mice with graft-versus-host disease (GVHD) are destroyed from a distance by a violent outburst of immune system proteins called inflammatory cytokines. The results were reported in the June 2002 issue of Nature Medicine.

The risk of GVHD is highest after a bone marrow transplant from an allogeneic donor. Symptoms of acute GVHD often begin three to six weeks after the transplant. 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 (APCs) in the patient's immune system.

Researchers at the University of Michigan (Ann Arbor, USA) found that 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 (TNF)-alpha and interleukin-1. The cytokine barrage transforms good immune cells in the patient's bone marrow into an army of destructive effector cells primed to attack and kill the host.

"Cytokines can travel through the bloodstream and, therefore, inflect their damage from a distance,” said James L.M. Ferrara, M.D., director of the U-M Bone Marrow Transplantation Program at the U-M Medical School. "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 GVHD.”

The researchers believe that 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 GVHD. In a test of donor-recipient combinations involving major antigens, they found that neutralizing TNF-alpha and interleukin-1 dramatically suppressed the mortality and morbidity of GVHD.

"Cytokines turn healthy immune cells in donated bone marrow--something given to cure patients--into lethal weapons capable of killing them,” added Dr. Ferrara.



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