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Preventing graft-versus-host disease disease after bone marrow transplant -- without toxicity

organ failure and death. It strikes some 30-60 percent of transplant patients, depending on how closely matched the donor is, and is kept in check only by eliminating otherwise useful donor immune cells or by using powerful immune-suppressing drugs.

Studies in mice had shown that the chemotherapy regimens used in HSCT not only wipe out white blood cells (with the intended effect of suppressing the immune system), but also damage the intestinal lining. This breach of the lining allows endotoxin, which is produced by bacteria living in the intestines, to enter the bloodstream. The endotoxin, in turn, provokes an inflammatory response that mobilizes donor immune cells, helping to trigger GVHD.

Levy, in Childrens Division of Infectious Diseases, had long been studying BPI, which naturally blocks and neutralizes endotoxin.(1) BPI is found in neutrophils, the very white blood cells that are virtually wiped out by pre-transplant chemotherapy. Studies in mice had shown that blocking endotoxin reduces the incidence of GVHD after chemotherapy and HSCT.(2)

Intrigued by these findings, Levy and Guinan began to study endotoxin and BPI in human patients undergoing HSCT with pre-transplant chemotherapy. In 2003 they showed, in a study of 57 children, that patients blood endotoxin levels rise markedly within a week of the transplant.(3) And now, in a study of 30 patient:donor pairs to be presented at the ASH meeting, they show that patients undergoing HSCT also have a sharp drop in BPI levels just as their endotoxin levels are rising and that BPI deficiency is associated with a greater likelihood of GVHD.

"BPI is markedly deficient 100 to 1000-fold lower in our transplant patients," says Guinan, associate director of the Center for Clinical and Translational Research at Dana-Farber. "If we can replenish this host defense factor, we might be able to moderate the damaging effects of GVHD."

The multicenter clinical trial, expec
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Contact: Anna Gonski
anna.gonski@childrens.harvard.edu
617-355-6420
Children's Hospital Boston
11-Dec-2006


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