"An allogeneic bone marrow transplant is a double-edged sword," says Pavan Reddy, M.D., an assistant professor of internal medicine in the U-M Medical School and corresponding author of the PNAS paper. "The good side is the graft-versus-leukemia (GVL) effect, which means that T cells from donated bone marrow, called the graft, will attack and kill any cancer cells remaining in the patient. GVL represents the most potent known form of immune therapy against malignant diseases. Without GVL, the cancer will most likely return.
"The bad side is graft-versus-host disease. In GVHD, T cells from donated bone marrow, in concert with inflammatory cytokines, attack the patient's skin, liver and gastrointestinal tract," Reddy explains. "The key is to block the inflammatory cytokines, which exacerbate GVHD, but leave the cancer-killing donor T cells untouched, since they are vital for an effective GVL response."
In previous research published in the June 2002 issue of Nature Medicine, Ferrara and Reddy, with colleagues from the U-M Cancer Center, discovered that inflammatory cytokines are the major cause of GVHD-induced cell damage. Since then, they have been searching for ways to neutralize cytokines or block their production. Their current work with HDAC inhibitors is an extension of this earlier research.
"No one has looked at this class of drugs in a post-bone-marrow-transplant setting before, but two other groups have found similar anti-inflammatory effects in mouse models used for research on lupus and sepsis," says Reddy. "So now there are several studies showing that HDAC inhibitors are more than just anti-tumor agents."
Reddy and his U-M research colleagues conducted two sets of experiments with strains of laboratory mice commonly used in research related to bone marrow transplants. In the first experiment, three groups of mice were given standard bone marrow transplants. Mice received bone marr
Contact: Sally Pobojewski
University of Michigan Health System