Patients receiving a bone-marrow transplant must first receive chemotherapy (and sometimes radiation) to wipe out their immune systems to prevent them from rejecting the transplant. Unfortunately, research has found that chemotherapy increases the risk of a serious transplant complication: graft-versus-host disease (GVHD), in which the donor's immune cells attack the patient. But new research from Children's Hospital Boston suggests a way to avoid GVHD—by simply replacing a natural antibiotic that's depleted when patients' white blood cells are destroyed by the chemotherapy.
A multicenter clinical trial led by Children's and the Dana-Farber Cancer Institute is about to test this idea, using a manufactured form of the antibiotic, called bactericidal/permeability-increasing protein, or BPI. "Many basic and translational studies, including our own, have provided a strong rationale for trying BPI," says Ofer Levy, MD, PhD, in Children's Division of Infectious Diseases. "We hope to reduce the complications patients suffer after transplants."
Studies in mice have shown that pre-transplant chemotherapy damages the intestinal lining, allowing endotoxin, made by intestinal bacteria, to enter the bloodstream. The endotoxin then provokes an inflammatory response that helps trigger GVHD. When endotoxin was blocked, GVHD was prevented.
Levy was intrigued, since BPI, which he'd studied for years, is a natural endotoxin blocker. So he and long-time collaborator Eva Guinan, MD, in the Division of Hematology/Oncology, studied the blood of patients undergoing chemotherapy and bone marrow transplant. Not only did the patients have a marked post-transplant rise in endotoxin, they also had a sharp drop in BPI—just when they needed it most. Reporting at the American Society of Hematology annual meeting in December, Levy and Guinan also showed that BPI-deficient patients were more likely to develop GVHD.
"By replenishing BPI, we might be able to make bone marrow transplant significantly less toxic," says Guinan, associate director of the Center for Clinical and Translational Research at Dana-Farber.
Unlike other treatments to prevent GVHD, BPI doesn't suppress the immune system and has shown virtually no toxicity when used in other settings. If all goes well in initial safety tests, Levy and Guinan will lead a national trial of BPI in 30 to 40 patients undergoing bone marrow transplant for cancer or blood diseases.
Research from Children's Hospital Boston and the Massachusetts Eye and Ear Infirmary (MEEI) may help explain how glaucoma causes blindness, revealing the chain of events that damages the optic nerve and prevents visual information from getting to the brain.
Glaucoma affects at least three million Americans, striking elderly people and African-Americans the most. Its primary risk factor is increased pressure in the eye. If caught early, lowering the pressure can often halt vision loss, but exactly how the high pressure damages the optic nerve has been a mystery.
Researchers led by Toru Nakazawa, MD, PhD, of Children's and MEEI, Larry Benowitz, PhD, of Children's Neurobiology Program and Department of Neurosurgery, and Joan Miller, MD, chief of Ophthalmology at MEEI, showed in mice that increased pressure in the eye raises levels of an inflammatory molecule called TNF-alpha. This over-activates immune cells in the eye, which then kill off many of the optic nerve's supporting cells. The result is a loss of retinal ganglion cells, which talk to the brain via the optic nerve. When TNF-alpha's action was blocked with an antibody, the retinal ganglion cells remained healthy even when pressures in the eye were raised.
"We now have good evidence that TNF-alpha plays an essential role in glaucoma," says Benowitz, senior author of the study, which was published online December 6 in the Journal of Neuroscience.
The results are exciting because TNF-alpha inhibitors already exist and have been used to treat other inflammatory diseases like rheumatoid arthritis. Miller speculates that slow-release versions of these drugs could be placed just outside the eye. "These findings give a whole new approach to thinking about glaucoma therapy," she says.